Friday, May 5, 2017

Table of Contents

• NIAAA BUDGET
• COLLABORATIVE RESEARCH ON ADDICTION AT NIH CRAN UPDATE
• DIRECTOR'S ACTIVITIES
• NIAAA WELCOMES NEW COUNCIL MEMBERS
• STAFF TRANSITIONS
• HONORS & AWARDS
• NEW REQUESTS FOR APPLICATIONS AND PROGRAM ANNOUNCEMENTS
• NOTABLE NIAAA STAFF ACTIVITIES
• WHAT'S AHEAD
• NIH RESEARCH HIGHLIGHTS
• NIAAA COMMUNICATIONS ACTIVITIES

NIAAA BUDGET

Fiscal Year (FY) 2017

NIAAA operated under H.R. 2028, a Continuing Resolution (CR), until April 28, 2017.  Following the National Institutes of Health (NIH) policy under the CR, all grants were funded at 90 percent. This is consistent with NIH practice during the CRs of FY 2006–2016. Upward adjustments to awarded levels may be considered after the FY 2017 appropriations are enacted, but NIH expects awardee institutions to monitor their expenditures carefully during this period. All legislative mandates that were in effect in FY 2016 remained in effect under the CR. 

FY 2018

The President released his FY 2018 budget Blueprint in March requesting $25.9 billion for NIH, a $5.8 billion decrease from the FY 2017 CR level.  A more detailed budget request is expected later in May.   

Late-breaking News: 

Budget Update

Late on April 28, 2017 Congress passed and the President signed a one-week extension of the Continuing Resolution (CR) until May 5 to allow more time to complete the omnibus package.

On May 1, 2017, Congress introduced an FY2017 Omnibus Appropriations bill that would provide funding through the end of the fiscal year, September 30, 2017, if enacted. 

CRAN UPDATE

Adolescent Brain and Cognitive Development (ABCD) Study  

The ABCD study continues in the enrollment phase. As of April 20, 2017, 2,152 subjects had enrolled and completed baseline neuroimaging and neuropsychological assessments. New sites at the University of Wisconsin-Milwaukee, the Medical University of South Carolina, and the University of Maryland-Baltimore have joined the study and are enrolling subjects.

The ABCD Study Newsletter is emailed monthly to families participating in the ABCD Study, as well as to educators and other stakeholders. Each issue includes news and other information about the study, a highlight from one of the 21 ABCD study sites, quotes and artwork from student participants, and fun facts about the brain. To see the newsletter and updates on ABCD media coverage, visit https://abcdstudy.org/.

The ABCD Informatics Workgroup is collaborating with the National Institute of Mental Health (NIMH) Data Archive on the transfer and storage of raw imaging data and basic demographic information in preparation for first ABCD data release to the research community. Although the data use agreement is still in development, the first data release is anticipated this spring. The workgroup is also strategizing effective mechanisms for targeted outreach to the scientific community, e.g., listservs and scientific conferences such as the annual meeting of the Organization for Human Brain Mapping (OHBM), which is the primary international organization dedicated to the use of neuroimaging to discover the organization of the human brain.

DIRECTOR'S ACTIVITIES

NIAAA Director Dr. George F. Koob, made a number of important presentations in February 2017 and March 2017. 

• He presented at the Frontiers in Chemistry Symposium at Scripps University in San Diego, California, on February 3, 2017. His talk was titled “What the Neurobiology of Addiction Tells Us about the Neurobiology of Emotion.” 


• He spoke at the 27^th Annual Leadership Forum of the Community Anti-Drug Coalitions of America (CADCA) at National Harbor, Maryland, on February 7, 2017. His presentation was titled “Vision for the Next 5 Years of Alcohol Research (and the current state of NIAAA in particular).”


• He was a plenary speaker at the Pre-Conference Overview of the Seventh International Conference on Fetal Alcohol Spectrum Disorder (FASD) in Vancouver, Canada, on March 1, 2017. His presentation was titled “The Neuroscience of Addiction: Is it a Choice?”
• He spoke at the Cellular and Molecular Basis of Disease (CMBD) Seminar Series at the University of New Mexico in Albuquerque, New Mexico, on March 10, 2017. His talk was titled “The Role of Stress in Addiction: Evidence-based Science for Diagnosis, Treatment and Prevention of Alcohol Use Disorders.”
• He organized and spoke at a plenary session titled “The Dark Side of Addiction: Neurocircuitry, Molecular-Epigenetic and Clinical Translational Insights” at the Spring Brain Conference in Sedona, Arizona, on March 18, 2017.
• He spoke at the Gordon Research Conference, “Alcohol-Induced End Organ Disease” in Ventura, California, on March 29, 2017. His talk was “Alcohol-Induced Organ Injury: Current and Future NIAAA Priorities.”

NIAAA WELCOMES NEW COUNCIL MEMBERS

NIAAA welcomes six new members of the National Advisory Council on Alcohol Abuse and Alcoholism.

• Louis Baxter, Sr., M.D., is President and Executive Medical Director of the Professional Assistance Program of New Jersey, Inc., Princeton.
• Daniel J. Calac, M.D., is Chief Medical Officer of the Indian Health Council, Inc., Valley Center, California, and Principal Investigator (PI) of the California Native American Research Centers for Health.
• Alex Dopico, M.D., Ph.D., is Distinguished Professor and Chair of the Department of Pharmacology at the University of Tennessee Health Science Center.
• Robert J. Hitzemann, Ph.D., is Professor in the Department of Behavioral Neuroscience, School of Medicine, Oregon Health Sciences University, Portland. 
• Vijay H. Shah, M.D., is Professor of Medicine and Physiology at the Mayo Clinic College of Medicine, Rochester, Minnesota, where he also serves as Chair and Consultant in the Division of Gastroenterology and Hepatology.
• Susan Smith, Ph.D., is Professor Emeritus at the University of Wisconsin in Madison, and Professor in the Department of Nutrition, David H. Murdoch Nutrition Research Institute, University of North Carolina at Chapel Hill.

Photo, shown left to right: Louis Baxter, Sr., M.D.; Vijay H. Shah, M.D.; Robert J. Hitzemann, Ph.D.; Patricia Powell, Ph.D., Acting NIAAA Deputy Director; George F. Koob, Ph.D., NIAAA Director; Alex Dopico, M.D., Ph.D.; Susan Smith Ph.D.; Daniel J. Calac, M.D.

STAFF TRANSITIONS

New Staff

Li Lin, Ph.D., joined NIAAA in January 2017 as a Program Officer in the Division of Metabolism and Health Effects (DMHE). Previously, Dr. Lin was Head of the Receptor Unit in the Laboratory of Cardiovascular Sciences, National Institute on Aging, studying vascular inflammation and receptor signaling.  Dr. Li was a recipient of a 2009 NIH-Department of Defense (DoD) biodefense award and a winner of 2015 NIH Neuro Startup Challenge. In her role as Assistant Professor in the graduate program of Immunology at Johns Hopkins University School of Medicine, she was co-PI of Johns Hopkins’ Immunology NIH T32 Program.  She earned a doctorate in biochemistry and molecular biology from the State University of New York at Stony Brook and received postdoctoral training in immunobiology at Yale University School of Medicine (as a Howard Hughes Medical Institute fellow), and at the Gladstone Institute of Virology and Immunology/University of California San Francisco. Dr. Li holds three patents in protein engineering.
   

Internal NIAAA Transitions

Mohammed Akbar, Ph.D., joined the Division of Neuroscience and Behavior (DNB) as a Program Officer, in February 2017 after serving for more than a year in that same capacity in DMHE. Dr. Akbar came to NIH in 1998 joining NIAAA’s intramural research division, where he studied fatty acids and alcohol in neuronal cells and rodents. During that time, he was also engaged in studying the role of dietary supplements and natural products in neurodegenerative diseases, oxidative stress and metabolic syndromes. Dr. Akbar received his Ph.D. from the Institute of Endocrinology, Gunma University, Maebashi, Japan, where he investigated the signal transduction mechanisms of purinergic receptors in endocrine organs.

Bridget Grant, Ph.D., Ph.D., retired in January after more than 29 years of federal service. Dr. Grant served in the tenured position of Chief, Laboratory of Epidemiology and Biometry, since 2004. Prior to this, starting in 1987, she served as Branch Chief of NIAAA’s extramural biometry branch. Most recently, she served as Chief, Epidemiology and Biometry Branch, NIAAA. Since 2001, Dr. Grant has directed the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), the largest and most ambitious psychiatric comorbidity study conducted to date. She has authored more than 500 publications and reports and is the recipient of numerous awards including the Jellinek Memorial Award for Epidemiology and Population Studies. Although retired, Dr. Grant has returned to NIAAA as a contractor.  

 

Departing Staff

Lindsey Grandison, Ph.D. will retire this spring after fourteen years at NIAAA.  Prior to joining NIAAA, Dr. Grandison had a 24-year academic career in the Department of Physiology and Biophysics at Robert Wood Johnson Medical School in Piscataway, New Jersey.  His research there focused on neuroendocrine regulation.  Dr. Grandison brought his expertise to NIAAA in 2002 where he managed the stress portfolio including the Integrative Neuroscience Initiative on Alcoholism-Stress consortium.  Over the past few years he led the NIAAA initiative on post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) comorbidity, and coordinated activities with the DoD and the Cohen Veterans Bioscience Foundation.  His interest in stress and resilience led to his leadership of the NIH's Basic Behavioral and Social Science Opportunity Network (OPPNET) working group on resilience which resulted in a notice of funding opportunity (NOFO for a Resilience Consortium.  In addition, since 2008, he co-led the NIAAA Centers and Training working group, which is responsible for operation of the Alcohol Research Centers and NIAAA’s training activities. 

Jessica Ryan left NIAAA to join the National Eye Institute (NEI) as a Supervisory Management Analyst in February 2017. During her seven years with NIAAA, she worked as a management analyst in the Ethics and Management Analysis Branch (EMAB), where her responsibilities included performance management, NIAAA’s training programs, NIAAA’s employee web page, and employee awards and recognition programs. Jessica will be working on similar programs at NEI, as well as overseeing a portfolio of management analysis projects.

 

In Memoriam - Sandra Camman

Ms. Sandra Camman, a long-time employee of NIAAA, passed away on March 26, 2017.  During her nearly 20-year career at the Institute, Ms. Camman worked in the former Office of Scientific Affairs as a Grants Technical Assistant, in the Administrative Services Branch as an Administrative Officer, and in the Intramural Research Program as a Purchasing Agent. Everyone who worked with Ms. Camman appreciated her diligence and positive attitude.  We will miss her.

HONORS & AWARDS

Abraham Bautista, Ph.D., Director of the Office of Extramural Activities, NIAAA, was awarded the Distinguished Service Award for Extraordinary Service by the Society on Neuroimmune Pharmacology on April 1, 2017, in Philadelphia, Pennsylvania.

NEW REQUESTS FOR APPLICATIONS (RFAs) AND PROGRAM ANNOUNCEMENTS (PAs)

Notice of Funding Opportunities (NOFO) Issued by NIAAA

Alcohol-PTSD Comorbidity: Preclinical Studies of Models and Mechanisms (R01) RFA-AA-17-016 - This NOFO, issued by NIAAA in collaboration with Cohen Veterans Bioscience, encourages Research Project Grant (R01) applications that will further the development, validation and/or application of animal models for mechanistic studies on the comorbidity of PTSD and alcohol use disorder AUD. 

Mechanisms of Alcohol-Associated Cancers (R01) PA-17-220 - This NOFO invites applications investigating the cellular and molecular mechanisms by which alcohol increases cancer risk. 

Nutrition and Alcohol-Related Health Outcomes (R01) PA-17-211,  (R03) PA-17-212, (R21) PA-17-213  - This NOFO encourages applications that propose to examine associations between nutrition and alcohol-related health outcomes in humans and animal models. The goal is to stimulate a broad range of research on the role of nutrition in the development, prevention, and treatment of a variety of alcohol-related health outcomes, including AUD and chronic disease.

Alcohol Research Resource Awards (R24) PAR-17-170 - This NOFO encourages non-hypothesis-driven grant applications to support investigator-initiated research projects that will maintain and expand the availability of resources to serve biomedical research within NIAAA’s priority areas, as described in the Strategic Plan 2017–2021.

NIH-Wide NOFOs with NIAAA’s Participation

 Intensive Longitudinal Analysis of Health Behaviors: Leveraging New Technologies to Understand Health Behaviors (U01) RFA-OD-17-004, (U24) RFA-OD-17-005

 Blueprint Neurotherapeutics Network (BPN): Small Molecule Drug Discovery and Development for Disorders of the Nervous System (UG3/UH3) PAR-17-205

 National Cooperative Drug/Device Discovery/Development Groups (NCDDG) for the Treatment of Mental or Substance Use Disorders or Alcohol Addiction (U01) PAR-17-185, (U19) PAR-17-186

NIAAA Policy Notice

NIAAA Policy for Submission of Applications Containing Genome-Wide Association Studies:  NOT-AA-17-002. This Notice communicates the NIAAA Policy regarding grant applications seeking to identify common variants conferring genetic risks for AUD and related phenotypes. The policy is based on recommendations from the Genetics and Genomics Advisory Meeting NIAAA convened on October 26, 2016. Dr. Hemin Chin (DNB) is the scientific contact. 

NOTABLE NIAAA STAFF ACTIVITIES -- FEBRUARY 2017 - MARCH 2017

Dr. Bin Gao, Dr. Andras Orosz, and Dr. Laura Nagy (Cleveland Clinic) co-organized a new Gordon Research Conference on “Alcohol-Induced End Organ Diseases” the first of which took place March 26–31, 2017, in Ventura, California. This series of conferences will be held every second year and will provide an important forum for discussions of the tissue and organ damage caused by alcohol misuse. Dr. George Kunos and Dr. Pal Pacher and Dr. George F. Koob were invited speakers.

Dr. Raye Z. Litten made a presentation to the DoD Alcohol and Substance Abuse Disorders Program Research Group at Fort Detrick in Frederick, Maryland, on March 27, 2017. His talk was titled “NIAAA’s Medications Development Program for Alcohol Use Disorder.”

Dr. Mariela Shirley served as a senior mentor at the Collaborative Perspectives on Addictions (CPA) Early Career Professional Mentoring Event, which occurred at the CPA meeting, held March 24–25, 2017, in Albuquerque, New Mexico. CPA is the annual mid-year meeting of the Society of Addiction Psychology (Division 50) of the American Psychological Association that is devoted to the education and training of research and treatment addiction psychologists.

Dr. Kenneth Warren gave the Geoffrey Robinson Memorial Lecture, which was the lead presentation at the opening plenary session of the Seventh International Conference on Fetal Alcohol Spectrum Disorders (FASD) on March 2, 2017, in Vancouver, Canada. He provided an overview of current knowledge about the prevalence of FASD in countries around the world. He then introduced the two lead investigators from NIAAA’s Collaborative Initiative on FASD Prevalence (CoFASP), who discussed their respective FASD active case ascertainment prevalence studies across four major geographical areas of the United States.

Dr. Deidra Roach gave a presentation titled “Women and Alcohol” at the CADCA annual conference at National Harbor, Maryland on February 9, 2017. Her presentation highlighted recent changes in the epidemiology of harmful drinking among women and the need for more research on gender-specific approaches to the treatment of AUD Dr. Roach presented an abbreviated version of this talk to the Substance Abuse and Mental Health Services Advisory Council on Women’s Services, Rockville, Maryland, also in February 2017.

WHAT'S AHEAD? 

• NIAAA Strategic Plan:  NIAAA has launched its Strategic Plan 2017-2021, now available online at https://www.niaaa.nih.gov/about-niaaa/our-work/strategic-plan

• NIAAA and the Division of Treatment and Recovery Research (DTRR) are sponsoring a research track at the annual meeting of the American Psychiatric Association, to be held May 20–24, 2017, in San Diego, California. The research track will focus on how alcohol research can inform and improve the “Treatment of Alcohol Use and Co-occurring Psychiatric Disorders Across the Life Span.” The track is made up of symposia, workshops, and lectures including such sessions as updates on the science of stress and its impact on alcohol use disorder, screening and discussion of the HBO/NIAAA Documentary Film Risky Drinking, Using Mobile Phone and Web-Based Technology to Enhance Treatment and Support Recovery, Helping Patients Who Drink Too Much: Using the NIAAA’s Clinician’s Guide, and Medications for the Treatment of Alcohol Use Disorder in Patients with Co-Occurring Psychiatric Disorders. In addition, our efforts in relating adolescent neurodevelopment and drug and alcohol exposure will be highlighted in a symposium featuring the NIAAA-supported National Consortium on Alcohol and Neurodevelopment in Adolescence or NCANDA project, which focuses on the effects of alcohol exposure on the adolescent brain, and in a workshop highlighting an exciting multi-Institute effort called the Adolescent Brain Cognitive Development or ABCD study, which will study brain development of about 10,000 youth ages 9 to 10 over the course of 10 years. 


• At the Annual Scientific Meeting of the Research Society on Alcoholism (RSA) in Denver, Colorado, NIAAA Director Dr. George F. Koob will present the NIAAA Update on June 25, at 8:05 a.m. Also at RSA, NIAAA staff are organizers, moderators, or presenters in more than 35 symposia and workshops, 2 satellite meetings, and several grantsmanship training activities. For the full program and latest schedule updates, please consult the RSA website at http://www.rsoa.org/.


• The Fourth International Congress on Alcoholism and Stress will take place in Volterra, Italy on May 9-12, 2017.  Dr. George F. Koob will be a plenary speaker on the first day of the meeting which is titled “Alcoholism and Stress: Framework for Future Treatment Strategies.” Several NIAAA staff as well as a number of NIAAA grantees are organizers, moderators, or presenters at the meeting.  In addition, NIAAA is a cosponsor of the conference. For the full program go to: http://volterraconference.com/

NIAAA RESEARCH HIGHLIGHTS

ALCOHOL ABUSE AND CARDIAC DISEASE 

Significance: The association between alcohol consumption and heart disease has been assessed in multiple epidemiological studies and meta-analyses, with varying results. In this study, researchers performed a retrospective longitudinal analysis of over 14 million California residents to investigate the associations among alcohol abuse (as defined in the International Classification of Diseases, 9th Revision) and cardiac conditions. A diagnosis of alcohol abuse increased the relative risk of three types of cardiac conditions—atrial fibrillation, myocardial infarction, and congestive heart failure—more prominently in those individuals without traditional cardiovascular risk factors. 

Background: Understanding the relationship between alcohol abuse, a common and theoretically modifiable condition, and the most common cause of death in the world, cardiovascular disease, may inform potential prevention strategies. Objectives: The study sought to investigate the associations among alcohol abuse and atrial fibrillation (AF), myocardial infarction (MI), and congestive heart failure (CHF). Methods: Using the Healthcare Cost and Utilization Project database, we performed a longitudinal analysis of California residents ≥21 years of age who received ambulatory surgery, emergency, or inpatient medical care in California between 2005 and 2009. We determined the risk of an alcohol abuse diagnosis on incident AF, MI, and CHF. Patient characteristics modifying the associations and population-attributable risks were determined. Results: Among 14,727,591 patients, 268,084 (1.8%) had alcohol abuse. After multivariable adjustment, alcohol abuse was associated with an increased risk of incident AF (hazard ratio [HR]: 2.14; 95% confidence interval [CI]: 2.08 to 2.19; p < 0.0001), MI (HR: 1.45; 95% CI: 1.40 to 1.51; p < 0.0001), and CHF (HR: 2.34; 95% CI: 2.29 to 2.39; p < 0.0001). In interaction analyses, individuals without conventional risk factors for cardiovascular disease exhibited a disproportionately enhanced risk of each outcome. The population-attributable risk of alcohol abuse on each outcome was of similar magnitude to other well-recognized modifiable risk factors. Conclusions: Alcohol abuse increased the risk of AF, MI, and CHF to a similar degree as other well-established risk factors. Those without traditional cardiovascular risk factors are disproportionately prone to these cardiac diseases in the setting of alcohol abuse. Thus, efforts to mitigate alcohol abuse might result in meaningful reductions of cardiovascular disease. (Whitman IR, Agarwal, V, Nah G, Dukes, JW, Vittinghoff, Dewland, E, Marcus, GM. Journal of the American College of Cardiology 2107, 69, 13–24, doi: 10.1016/j.jacc.2016.10.048)

ALCOHOL CONSUMPTION, LEFT ATRIAL DIAMETER, AND ATRIAL FIBRILLATION

Significance: In this study, researchers examined the correlation between atrial fibrillation (AF) and alcohol consumption using Offspring and Original Framingham Heart Study participants. The results show that with every 10 g increase in daily alcohol consumption, risk of new-onset AF increases 5 percent. This increase is associated with enlargement of the left atrium, a possible intermediate phenotype to the development of AF.
 
Background: Alcohol consumption has been associated with atrial fibrillation (AF) in several epidemiologic studies, but the underlying mechanisms remain unknown. We sought to test the hypothesis that an atrial myopathy, manifested by echocardiographic left atrial enlargement, explains the association between chronic alcohol use and AF. Methods and Results: We evaluated the relationship between cumulative alcohol consumption and risk of incident AF in 5220 Offspring and Original Framingham Heart Study participants (mean age 56.3 years, 54% women) with echocardiographic left atrial size measurements. The incidence of AF was 8.4 per 1000 person‐years, with 1088 incident AF cases occurring over a median 6.0 years (25th–75th percentiles 4.0–8.7 years) of follow‐up. After multivariable adjustment for potential confounders, every additional 10 g of alcohol per day (just under 1 drink per day) was associated with a 0.16 mm (95% CI, 0.10–0.21 mm) larger left atrial dimension. Also in multivariable adjusted analysis, every 10 g per day of alcohol consumed was associated with a 5% higher risk of developing new‐onset AF (hazard ratio, 1.05; 95% CI, 1.01–1.09). An estimated 24% (95% CI, 8–75) of the association between alcohol and AF risk was explained by left atrial enlargement. Conclusions: Our study of a large, community‐based sample identified alcohol consumption as a predictor of left atrial enlargement and subsequent incident AF. Left atrial enlargement may be an intermediate phenotype along the causal pathway linking long‐term alcohol consumption to AF.  (McManus DD, Yin X, Gladstone R, Vittinghoff E, Vasan RS, Larson MG, Benjamin EJ, and Marcus GM. J Am Heart Assoc. 2016 Sep; 5(9): e004060.  Published online 2016 Sep 14. doi: 10.1161/JAHA.116.004060)

INFLAMMATION IS INDEPENDENT OF STEATOSIS IN A MURINE MODEL OF STEATOHEPATITIS

Significance: Obesity and excessive alcohol consumption promote the development of various liver diseases including steatohepatitis, cirrhosis, and hepatocellular carcinoma. Signaling of peroxisome proliferator-activated receptor-gamma (PPARγ), a transcription factor, has a role in stimulating lipid storage in the liver and is thus a contributing factor for the development of liver diseases. This study reveals the paradoxical nature of PPARγ, insofar as PPARγ signaling promotes fatty liver, but also down-regulates liver inflammation. It also reveals the complex interplays between diet, alcohol, and liver pathology, and has important clinical implications: pharmacological blocking of PPARγ as a treatment for alcohol-related liver diseases may result in unintended liver injury that ultimately leads to pathological consequences.

Background: Obesity and excessive alcohol consumption promotes the development of various liver diseases and PPARγ signaling is known to be a contributing factor. The molecular mechanism and signaling pathways of PPARγ, however, is unclear. Results: the new study dissected the signaling mechanism of PPARγ in steatohepatitis and liver inflammation, using a clinically relevant high fat diets and binge ethanol (HFD-plus-binge ethanol) murine model. HFD feeding plus a single binge ethanol results in severe steatohepatitis in mice. However, under the same experimental model, mice lacking PPARγ in their livers showed a significant increase of inflammation marked by massive infiltration of neutrophils in the liver and elevation of liver injury indexes, despite of a reduction of steatosis and fibrosis. These results suggest that PPARγ signaling promotes fatty liver but paradoxically down-regulates liver inflammation. This observation also implies that, in contradiction to the conventional view, inflammation is independent of steatosis in the context of HFD and binge drinking. Using combined experimental approaches, the team also delineated the PPARγ signaling pathway: HFD alone activates PPARγ that blocks the NF-κB-CxCL1/Il-8 axis, and the activated PPARγ relates the signal to fat-specific protein 27 to promote steatosis. Under HFD-plus-binge ethanol, however, ethanol inhibits PPARγ and releases the NF-κB-CxCL1/Il-8 axis that enhances neutrophil infiltration, leading to inflammation. (Wang W, Xu MJ, Cai Y, Zhou Z, Cao H, Mukhopadhyay P, Pacher P, Zheng S, Gonzalez FJ, Gao B. Hepatology. 2017 Feb 21. doi: 10.1002/hep.29129. [Epub ahead of print] PMID:28220523)

PARP INHIBITION PROTECTS AGAINST ALCOHOLIC AND NON-ALCOHOLIC STEATOHEPATITIS

Significance: Poly(ADP-ribose) polymerases (PARP) are the most abundant nuclear enzymes involved in regulation of DNA repair, cell death, and inflammation. This study shows that PARP is overactivated in livers of subjects with alcoholic liver disease and that pharmacological inhibition of this enzyme with structurally distinct PARP inhibitors, including the recently FDA approved olaparib (Lynparza), attenuates high fat or alcohol-induced liver injury, abnormal metabolic alterations, fat accumulation, inflammation, and fibrosis in multiple preclinical models of liver disease. These results suggest that PARP inhibition is a promising therapeutic strategy in the treatment of alcoholic and non-alcoholic liver disease, and hepatic fibrosis.

BACKGROUND & AIMS: Mitochondrial dysfunction, oxidative stress, inflammation, and metabolic reprograming are crucial contributors to hepatic injury and subsequent liver fibrosis. Poly(ADP-ribose) polymerases (PARP) and their interactions with sirtuins play an important role in regulating intermediary metabolism in this process. However, there is little research into whether PARP inhibition affects alcoholic and non-alcoholic steatohepatitis (ASH/NASH). METHODS: We investigated the effects of genetic deletion of PARP1 and pharmacological inhibition of PARP in models of early alcoholic steatohepatitis, as well as on Kupffer cell activation in vitro using biochemical assays, real-time PCR, and histological analyses. The effects of PARP inhibition were also evaluated in high fat or methionine and choline deficient diet-induced steatohepatitis models in mice. RESULTS: PARP activity was increased in livers due to excessive alcohol intake, which was associated with decreased NAD+ content and SIRT1 activity. Pharmacological inhibition of PARP restored the hepatic NAD+ content, attenuated the decrease in SIRT1 activation and beneficially affected the metabolic-, inflammatory-, and oxidative stress-related alterations due to alcohol feeding in the liver. PARP1-/- animals were protected against alcoholic steatohepatitis and pharmacological inhibition of PARP or genetic deletion of PARP1 also attenuated Kupffer cell activation in vitro. Furthermore, PARP inhibition decreased hepatic triglyceride accumulation, metabolic dysregulation, or inflammation and/or fibrosis in models of NASH.

CONCLUSION: Our results suggest that PARP inhibition is a promising therapeutic strategy in steatohepatitis with high translational potential, considering the availability of PARP inhibitors for clinical treatment of cancer. LAY SUMMARY: Poly(ADP-ribose) polymerases (PARP) are the most abundant nuclear enzymes. The PARP inhibitor olaparib (Lynparza) is a recently FDA-approved therapy for cancer. This study shows that PARP is overactivated in livers of subjects with alcoholic liver disease and that pharmacological inhibition of this enzyme with 3 different PARP inhibitors, including olaparib, attenuates high fat or alcohol induced liver injury, abnormal metabolic alteration, fat accumulation, inflammation and/or fibrosis in preclinical models of liver disease. These results suggest that PARP inhibition is a promising therapeutic strategy in the treatment of alcoholic and non-alcoholic liver diseases. (Mukhopadhyay P, Horváth B, Rajesh M, Varga ZV, Gariani K, Ryu D, Cao Z, Holovac E, Park O, Zhou Z, Xu MJ, Wang W, Godlewski G, Paloczi J, Nemeth BT, Persidsky Y, Liaudet L, Haskó G, Bai P, Boulares AH, Auwerx J, Gao B, Pacher P. J Hepatol. 2017 Mar;66(3):589-600)

IN VIVO IMAGING OF TRANSLOCATOR PROTEIN, A MARKER OF ACTIVATED MICROGLIA, IN ALCOHOL DEPENDENCE

Significance: This study used positron emission tomography with a radiotracer that binds to the translocator protein (a protein expressed on the outer mitochondrial membrane of microglia) to measure microglia activation in vivo in the brain of alcohol-dependent individuals. The results show that there were significantly lower levels of activated microglia along with a lower or blunted peripheral immune response (as measured by cytokine expression in monocytes) in alcohol-dependent individuals compared to healthy controls. This study provides an important assessment of innate immune function in alcohol dependence, and the results suggest that the neuroimmune system may be a potential target for medications development. 

Neuroinflammation may be a critical component of the neurobiology of alcohol use disorders, yet the exact nature of this relationship is not well understood. This work compared the brain and peripheral immune profile of alcohol-dependent subjects and controls. Brain levels of 18-kDa translocator protein (TSPO), a marker of microglial activation and neuroinflammation, were measured with [11C]PBR28 positron emission tomography imaging in 15 healthy controls and 15 alcohol-dependent subjects. Alcohol-dependent subjects were imaged 1-4 days (n = 14) or 24 days (n = 1) after their last drink. Linear mixed modeling of partial-volume-corrected [11C]PBR28 data revealed a main effect of alcohol dependence (P = 0.034), corresponding to 10% lower TSPO levels in alcohol-dependent subjects. Within this group, exploratory analyses found a negative association of TSPO levels in the hippocampus and striatum with alcohol dependence severity (P < 0.035). Peripheral immune response was assessed in a subset of subjects by measuring cytokine expression from monocytes cultured both in the presence and absence of lipopolysaccharide. Peripheral monocyte response to lipopolysaccharide stimulation was lower in alcohol-dependent subjects compared with controls for the proinflammatory cytokines interleukin-6 and interleukin-8. Thus, alcohol-dependent individuals exhibited less activated microglia in the brain and a blunted peripheral proinflammatory response compared with controls. These findings suggest a role for pharmaceuticals tuning the neuroimmune system as therapeutics for alcohol dependence. (Hillmer AT, Sandeigo CM, Hannestad J, Angarita GA, Kumar A, McGovern EM, Huaung Y, O’Connor KC, Carson RE, O’Malley SS, Cosgrove KP. Molecular Psychiatry epub ahead of print February 28, 2017)
 

OXYTOCIN REDUCES ETHANOL SELF-ADMINISTRATION IN MICE

Significance: Accumulating evidence suggests that the oxytocin system may represent a promising target for the treatment of alcohol use disorder (AUD). This study investigated the effects of systemic administration of oxytocin on alcohol self-administration in a binge-like drinking model, in a 2-bottle choice paradigm, and using operant conditioning procedures. Oxytocin selectively decreased alcohol consumption in these models at doses that did not affect sucrose consumption under similar testing conditions. These results support the therapeutic potential of oxytocin as a treatment for AUD.

BACKGROUND: Excessive ethanol (EtOH) consumption remains an important health concern and effective treatments are lacking. The central oxytocin system has emerged as a potentially important therapeutic target for alcohol and drug addiction. These studies tested the hypothesis that oxytocin reduces EtOH consumption. METHODS: Male C57BL/6J mice were given access to EtOH (20% v/v) using a model of binge-like drinking ("drinking in the dark") that also included the use of lickometer circuits to evaluate the temporal pattern of intake as well as 2-bottle choice drinking in the home cage. In addition, EtOH (12% v/v) and sucrose (5% w/v) self-administration on fixed- and progressive-ratio schedules were also evaluated. A wide range of systemically administered oxytocin doses were tested (0 to 10 mg/kg) in these models. RESULTS: Oxytocin (0, 0.3, 1, 3, or 10 mg/kg) dose dependently reduced EtOH consumption (maximal 45% reduction) in the binge drinking model, with lower effective doses having minimal effects on general locomotor activity. Oxytocin's effect was blocked by pretreatment with an oxytocin receptor antagonist, and the pattern of contacts (licks) at the EtOH bottle suggested a reduction in motivation to drink EtOH. Oxytocin decreased 2-bottle choice drinking without altering general fluid intake. Oxytocin also reduced operant responding for EtOH and sucrose in a dose-related manner. However, oxytocin decreased responding and motivation (breakpoint values) for EtOH at doses that did not alter responding for sucrose. CONCLUSIONS: These results indicate that oxytocin reduces EtOH consumption in different models of self-administration. The effects are not likely due to a general sedative effect of the neuropeptide. Further, oxytocin reduces motivation for EtOH at doses that do not alter responding for a natural reward (sucrose). While some evidence supports a role for oxytocin receptors in mediating these effects, additional studies are needed to further elucidate underlying mechanisms. Nevertheless, these results support the therapeutic potential of oxytocin as a treatment for alcohol use disorder. (King CE, Griffin WC, Luderman LN, Kates MM, McGinty JF, Becker HC Alcohol Clin Exp Res. 2017 Feb 17. doi: 10.1111/acer.13359. [Epub ahead of print])
 

OXYTOCIN BY INTRANASAL AND INTRAVENOUS ROUTES REACHES THE CEREBROSPINAL FLUID IN RHESUS MACAQUES: DETERMINATION USING A NOVEL OXYTOCIN ASSAY

Significance: With recent interest in oxytocin as a therapeutic target for central nervous system (CNS) disorders, a large number of basic and clinical studies deliver oxytocin via the intranasal route. However, cerebrospinal fluid (CSF) penetrance of systemically administered oxytocin (via either the intranasal or intravenous routes) has not been demonstrated. It is not known whether the intranasal route bypasses the blood brain barrier. In addition, the possibility of a ‘feed-forward’ effect of administered oxytocin on endogenous oxytocin levels in CSF has been posited but never demonstrated. We have addressed these questions, which are central to developing oxytocin as a therapeutic modality for numerous neuropsychiatric disorders, by developing a sensitive and specific assay that distinguishes between administered (deuterated) and endogenous oxytocin in CSF and plasma. This approach allowed us to demonstrate, definitively, that oxytocin crosses the blood-brain barrier.

Oxytocin (OT) is a potential treatment for multiple neuropsychiatric disorders. As OT is a peptide, delivery by the intranasal (IN) route is the preferred method in clinical studies. Although studies have shown increased cerebrospinal fluid (CSF) OT levels following IN administration, this does not unequivocably demonstrate that the peripherally administered OT is entering the CSF. For example, it has been suggested that peripheral delivery of OT could lead to central release of endogenous OT. It is also unknown whether the IN route provides for more efficient entry of the peptide into the CSF compared to the intravenous (IV) route, which requires blood-brain barrier penetration. To address these questions, we developed a sensitive and specific quantitative mass spectrometry assay that distinguishes labeled (d5-deuterated) from endogenous (d0) OT. We administered d5 OT (80 IU) to six nonhuman primates via IN and IV routes as well as IN saline as a control condition. We measured plasma and CSF concentrations of administered and endogenous OT before (t=0) and after (t=10, 20, 30, 45 and 60 min) d5 OT dosing. We demonstrate CSF penetrance of d5, exogenous OT delivered by IN and IV administration. Peripheral administration of d5 OT did not lead to increased d0, endogenous OT in the CSF. This suggests that peripheral administration of OT does not lead to central release of endogenous OT. We also did not find that IN administration offered an advantage compared to IV administration with respect to achieving greater CSF concentrations of OT. (Lee MR, Scheidweiler KB, Diao XX, Akhlaghi F, Cummins A, Huestis MA, Leggio L, Averbeck BB. Mol Psychiatry. 2017 Mar 14. doi: 10.1038/mp.2017.27. [Epub ahead of print])
 

PREFRONTAL CORTEX KCA2 CHANNELS REGULATE MGLU5-DEPENDENT PLASTICITY AND EXTINCTION OF ALCOHOL-SEEKING BEHAVIOR
 
Significance: This study provides evidence of how functional coupling of small conductance calcium activated potassium (KCa2+) channels and mGluR5 regulates extinction of alcohol seeking behavior in a prefrontal cortex sub-region dependent manner. The long-lasting (three week) effect of apamin, an allosteric inhibitor of KCa2+ channels, on attenuation of alcohol seeking behavior suggests that KCa2+ may be a novel therapeutic target for relapse prevention.

Identifying novel treatments that facilitate extinction learning could enhance cue-exposure therapy and reduce high relapse rates in alcoholics. Activation of mGlu5 receptors in the infralimbic prefrontal cortex (IL-PFC) facilitates learning during extinction of cue-conditioned alcohol-seeking behavior. Small-conductance calcium-activated potassium (KCa2) channels have also been implicated in extinction learning of fear memories, and mGlu5 receptor activation can reduce KCa2 channel function. Using a combination of electrophysiological, pharmacological, and behavioral approaches, this study examined KCa2 channels as a novel target to facilitate extinction of alcohol-seeking behavior in rats. This study also explored related neuronal and synaptic mechanisms within the IL-PFC that underlie mGlu5-dependent enhancement of extinction learning. Using whole-cell patch clamp electrophysiology, activation of mGlu5 in ex vivo slices significantly reduced KCa2 channel currents in layer V IL-PFC pyramidal neurons, confirming functional down-regulation of KCa2 channel activity by mGlu5 receptors. Additionally, positive modulation of KCa2 channels prevented mGlu5 receptor-dependent facilitation of long-term potentiation in the IL-PFC. Systemic and intra-IL-PFC treatment with apamin (KCa2 channel allosteric inhibitor) significantly enhanced extinction of alcohol-seeking behavior across multiple extinction sessions; an effect that persisted for 3 weeks, but was not observed after apamin treatment in the prelimbic PFC. Positive modulation of IL-PFC KCa2 channels significantly attenuated mGlu5-dependent facilitation of alcohol cue-conditioned extinction learning. These data suggest that mGlu5-dependent facilitation of extinction learning and synaptic plasticity in the IL-PFC involves functional inhibition of KCa2 channels. Moreover, these findings demonstrate that KCa2 channels are a novel target to facilitate long-lasting extinction of alcohol-seeking behavior. (Cannady R, McGonigal JT, Newsom RJ, Woodward JJ, Mulholland PJ, Gass JT. J Neurosci. 2017 Mar 20. pii: 2873-16. doi: 10.1523/JNEUROSCI.2873-16.2017. [Epub ahead of print])
 

TRAJECTORIES OF SUBSTANCE USE FREQUENCY AMONG ADOLESCENTS SEEN IN PRIMARY CARE: IMPLICATIONS FOR SCREENING

Significance: Adolescents who do not use substances are more likely to have parents, peers, and siblings who also abstain. Adolescents whose substance use increases between annual primary care visits are more likely to have substance-using peers. These findings support asking youth about peer substance use as an indicator of substance use risk as recommended in NIAAA’s Alcohol Screening and Brief Intervention for Youth: A Practitioner's Guide. In addition, understanding adolescents’ typical use trajectories may help physicians decide whether to schedule additional follow-up visits between annual routine health exams. 

The purpose of this study was to identify trajectories of substance use in a prospective cohort of adolescent primary care patients one year after a clinic visit. The authors recruited 12- to 18-year-olds from 9 New England practices between 2005 and 2008 and identified 5 trajectories of substance use. Trajectory A distinguished adolescents with no past-year use at a baseline clinic visit and at 12-month follow-up. The remaining 4 trajectories involved adolescents who used substances, and considered frequency of use in the past 90-days at baseline and followup. Trajectories included less than monthly use at both timepoints (trajectory B), less than monthly use increasing to monthly or more often (trajectory C), monthly or more often use decreasing to less than monthly (trajectory D), and monthly or more often use at both timepoints (trajectory E). Multiple logistic regression was used to examine associations with substance-involved parents, siblings, and peers. Among 860 adolescents (mean age 15.4 years; 60.9% female; 65.6% non-Hispanic white), more than one-half (52.7%) abstained (trajectory A). The remainder were classified into trajectories B (23.8%), C (9.5%), D (5.7%), and E (8.3%). Those who abstained were least likely to have substance-involved parents (aOR 0.58; 95% CI 0.46-0.72), siblings (aOR 0.49; 95% CI 0.40-0.60), or peers (aOR 0.44; 95% CI 0.37-0.52). Those increasing from less than monthly use to using monthly or more often were more likely to have substance-involved siblings (aOR 1.58; 95% CI 1.23-2.03) or peers (aOR 1.51; 95% CI 1.06-2.17). Most adolescent primary care patients remained abstinent or infrequent users over 1 year, but 1 in 5 showed frequent use, with substance-involved siblings and peers predicting escalation of use. (Hadland SE, Copelas SH, Harris SK. J Pediatr. 2017 Feb 10. pii: S0022-3476(17)30143-9. doi: 10.1016/j.jpeds.2017.01.033 [Epub ahead of print])
 

TRENDS IN ALCOHOL CONSUMPTION AMONG OLDER AMERICANS: NATIONAL HEALTH INTERVIEW SURVEYS, 1997– 2014

Significance: This study found upward trends in the prevalence of drinking among adults 60 years of age and older between 1997 and 2014. Although men continue to drink more than women, the prevalence of current drinking trended upward over time more strongly among women than men, narrowing the gender gap by about 5% between 2006 and 2014. The gender gap in binge drinking also narrowed. These findings indicate a need for alcohol-related public-health education, screening, and treatment for the growing older population, with an increasing focus on women.

The majority of US older adults consume alcoholic beverages. The older population is projected to almost double by 2050. Substantially more drinkers are likely. METHODS: We described gender-specific trends (1997–2014) in prevalence of drinking status (lifetime abstention, former drinking, current drinking [including average volume], and binge drinking) among US adults ages 60+ by age group and birth cohort. In the 1997–2014 National Health Interview Surveys 65,303 respondents ages 60+ (31,803 men, 33,500 women) were current drinkers; 6,570 men and 1,737 women were binge drinkers. Prevalence estimates and standard errors were computed by age group (60+, 60–64, 65–69, 70–74, 75-79, 80+) and birth cohort (<1925, 1925–1935, 1936–1945, 1946–1954). Trends were examined using joinpoint regression and described as average annual percent change (AAPC: overall change 1997–2014) and annual percent change (APC: in-between infection points). Primary analyses were unadjusted. All analyses (unadjusted and adjusted for demographics/lifestyle) were weighted to produce nationally representative estimates. Statistical procedures accounted for the complex survey design. RESULTS: Among men ages 60+, unadjusted prevalence of current drinking trended upward, on average, 0.7% per year (AAPC, p=0.02); average volume and prevalence of binge drinking remained stable. Adjusted results were similar. Among women age 60+, unadjusted prevalence of current drinking trended upward, on average, 1.6% per year (AAPC, p<0.0001) but average volume remained stable; prevalence of binge drinking increased, on average, 3.7% per year (AAPC, p<0.0001). Adjusted results were similar. Trends varied by age group and birth cohort. Among men born 1946-1954 unadjusted prevalence of current drinking trended upward, on average 2.4% per year (AAPC, p=0.02); adjusted results were non-significant.

CONCLUSIONS: Our finding of upward trends in drinking among adults ages 60+, particularly women, suggests the importance of public health planning to meet future needs for alcohol-related programs. (Breslow RA, Castle I-JP, Chen CM, Graubard BI. Alcohol Clin Exp Res. 2017 March 24 April doi: 10.1111/acer.13365. [Epub ahead of print])

 Press and Publications Activities:

Recent News Media Interviews: Dr. Koob and other NIAAA experts continue to speak with a variety of national and international news outlets on timely topics related to NIAAA’s research portfolio and its impact on prevention and treatment of alcohol misuse and AUD. Interviews occurring since December include The Washington Post, The New York Times, The Christian Science Monitor, The Philadelphia Inquirer, and the Associated Press.

Dr. Koob has also done several interviews with the NBC Today Show for an upcoming segment on medications for alcohol problems.

Notable News Articles: 

• NPR Morning Edition

On February 27, 2017, Dr. Koob was featured in “A Medicine That Blunts the Buzz of Alcohol Can Help Drinkers Cut Back,” a story about using naltrexone and other medications as a strategy for harm reduction for heavy drinkers. The story was aired on NPR’s Morning Edition and widely shared from the NPR website. 

• Pharmaceutical Journal

On March 9, 2017, Dr. George F. Koob and Dr. Lorenzo Leggio of NIAAA were featured in an article published by the United Kingdom’s Pharmaceutical Journal. The article also highlighted medications development content from the NIAAA draft strategic plan.

 Press Release:

Study finds effective interventions to prevent alcohol use among American Indian and rural youth (March 1, 2017). (Orange on graphic indicates study location.)

Publication Statistics: 

As of March 7, there were 30,314 subscribers to Alcohol Research: Current Reviews (current impact factor 3.528); 20,873 to the NIAAA Spectrum; and 20,260 to receive general information.  

Partnerships, Outreach & Public Liaison Activities:

American Society of Addiction Medicine (ASAM)

• Twitter Chat: NIAAA partnered with ASAM for a Twitter chat on April 28, 2017. More details follow in the “Alcohol Awareness Month” section of Seasonal Outreach.  
• Infographic: To help promote the Twitter chat on social media, NIAAA and ASAM developed a co-branded infographic based on NIAAA-provided statistics about the treatment gap. ASAM created a banner from the infographic to exhibit at its annual conference and will continue to display the banner at upcoming events. 

Seasonal Outreach 

•  Super Bowl: Leading up to the Super Bowl on February 5, 2017, NIAAA promoted two alcohol-related social media images: “Don’t Get Sacked” and “Time to Punt.” The messages were shared by NBC News Health; “The Doctors” television show (including Twitter, Instagram, and Facebook); ABC News Chief Health and Medical Editor, Dr. Richard Besser; the International Alliance for Responsible Drinking; and several treatment organizations and bloggers, with a potential audience of 1.7 million people. In addition, People.com posted the web banner images through the Super Bowl weekend at no cost to NIAAA. 
• Valentine’s Day: NIAAA introduced a new social media image for Valentine’s Day. The “Love Your Liver” graphic was shared or liked by the American Association for the Study of Liver Diseases, the American Liver Foundation, several addiction and recovery groups, Guard Your Health (Army National Guard), the National Center on Addiction and Substance Abuse, a Denver Channel 2 news producer, and several bloggers. The graphic had a potential audience of 151,000 people.
•  St. Patrick’s Day: NIAAA tweeted St. Patrick’s Day-themed messages leading up to the holiday and participated in the National Highway Transportation Safety Administration’s #BuzzedDriving chat. Messages had a total potential audience of 447,000 people. Groups and individuals sharing the messages included “The Doctors” television show (including Twitter, Instagram, and Facebook); Washington Regional Alcohol Program (WRAP); campus alcohol education programs, such as Grand Valley State University’s Alcohol Campus Education Services, the Red Watch Band program, and Loyola University; the National Center on Addiction and Substance Abuse; ABC News Chief Health and Medical Editor, Dr. Richard Besser; The Washington Post data reporter, Christopher Ingraham; and numerous health professionals and addiction services organizations. In addition, People.com posted the web banner images during St. Patrick’s Day at no cost to NIAAA.
•  Alcohol Awareness Month: To recognize Alcohol Awareness Month, NIAAA tweeted messages on prevalence, symptoms, and treatment of AUD throughout April 2017, using the #AlcoholAwareness hashtag. NIAAA also partnered with ASAM for a Twitter chat on April 28, 2017, in coordination with ASAM’s annual conference in New Orleans, Louisiana. The chat topic was the “treatment gap,” or the large number of people with AUD who do not receive treatment. Lori Ducharme, Ph.D., DTRR, served as the NIAAA expert.

Presentation at Lycée Rochambeau: On March 15, Dr. Koob spoke before 150 students, parents, and faculty at Lycée Rochambeau, the French International School in Chevy Chase, Maryland. His presentation focused on neuroscience issues related to alcohol and teens, such as the effects on the developing brain, the dark side of addiction, and the nature of AUD. The talk was part of a series at the school on substance misuse. Dr. Koob was recognized by the school when he was awarded the French Legion of Honor in July 2016. A portion of his talk was delivered in French. 

Late Breaking News

Budget Update

Late on April 28, 2017 Congress passed and the President signed a one-week extension of the Continuing Resolution (CR) until May 5 to allow more time to complete the omnibus package.

On May 1, 2017, Congress introduced an FY2017 Omnibus Appropriations bill that would provide funding through the end of the fiscal year, September 30, 2017, if enacted.

 Strategic Plan Web Address

 The NIAAA Strategic Plan 2017-2021 is now available online at https://www.niaaa.nih.gov/about-niaaa/our-work/strategic-plan