Kenneth R. Warren, Ph.D. Acting Director National Institute on Alcohol Abuse and Alcoholism

1. Strategic Planning and Priorities of the National Institute on Alcohol Abuse and AlcoholismAmerican Recovery and Reinvestment Act of 2009 (ARRA) and Other Research Opportunities Kenneth R. Warren, Ph.D. Acting Director National Institute on Alcohol Abuse and Alcoholism NIAAA Training Director’s Meeting and Trainee Workshop New Orleans, Louisiana March 13, 2009

2. History 1970 - Created as the U.S. Government’s principal agency for programs to understand, prevent, and treat alcohol abuse and alcoholism 1993 - Became one of 27 science Institutes and Centers of the National Institutes of Health (NIH) Mission:To support and promote the best science on alcohol and health for the benefit of all including: understanding how alcohol use impacts normal and abnormal biological functions and behavior improving the diagnosis, prevention, and treatment of alcohol-induced health disorders including alcohol dependence reducingtheharm caused by high-risk alcohol use Thereby enhancing the quality of overall health care

3. Why a Special Focus on Problems that Arise from Alcohol? • Alcohol is a part of the legal social contextin many countries and cultures and is used on many ceremonial occasions such as marriage, birth, and death, and to enhance the enjoyment of social gatherings • And it is used by most individuals without posing harm to themselves or others • Nonetheless, alcohol’s misuse is a leading risk factor for morbidity and mortality in the United States and worldwide

4. Harmful Drinking is a Leading Risk Factor for Disease Burden in the U.S. • 18 million Americans (8.5% of the population age 18 and older) suffer from alcohol abuse or dependence • Alcohol problems cost U.S. society an estimated $185 billion annually • Alcohol consumption is among the top ten leading causes of DALYs* • Among Actual Causes of Death Alcohol ranks 3rd with an estimated 85,000 annually *Disability-adjusted life years (years of potential life lost due to death plus years of healthy life lost to disability)

5. acute consequences including: unintentional death and injury homicide and violence suicide attempts particularly prevalent among adolescents and young adults chronic consequences including: liver cirrhosis cardiovascular diseases pancreatitis dementia alcohol dependence Two Distinct Patterns of Drinking Produces the Most Harm Binge Drinking (too much, too fast) 5+/4+ drinks/2 hours Heavy Drinking (too much, too often) frequent 5+/4+ drinks/day

6. Research Priorities from the NIAAAStrategic Plan

7. NIAAA Strategic Planning • In 2006, NIAAA initiated a new Planning process to develop a Strategic Plan that would reflect priorities across all age categories and all scientific disciplines that impact upon alcohol science. • Given that science is moving at a greater pace than ever before a decision was made that the Plan would not be static but rather updated on a yearly basis to be always current. • The format was a life-course perspective graphically represented with the life-course rainbow:

8. Alcoholic Family Environment Alcohol Dependence Medication Interactions Organ Damage Binge Drinking Prenatal Alcohol Exposure NIAAA’s Alcohol Research Programs Are Addressing Alcohol Issues Throughout The Lifespan • Lifespan Transcending Themes • Metabolism • Epigenetics • Epidemiology • AUD Diagnosis • Neurobiology • Health Services Research

9. It is now well recognized that neither genes nor environment alone explains why an individual develops alcohol dependence or pathologies (FAS, ALD). Rather, it is the interplay of GxE. Many genes in Alcohol Dependence already identified (GABRA2, GABRA6, COMT, OPMR1, etc.) Opportunities include: Whole Genome Association Studies Lymphoblastoid Cell Lines – gene identification from the many existing genetic studies on alcoholism (COGA, etc.) Lifespan Transcending Theme: Genes & Environment

10. We know that alcohol is an epigenetic effecter agent. Shown thus far: Increase DNA methylation of the promoter region of -synuclein gene associated with alcohol dependence and craving in humans (Chronic) demethylates genes for the NMDA receptor subunit NR2B Differentially suppress ADH1A, 1B, 1C in human hepatoma cell line via histone methylation. More evidence accumulating Lifespan Transcending Theme:Epigenetics

11. Opportunities: Enhance understanding of the pharmacokineticsof alcohol to explain individual differential responses to alcohol as they relate to biological/behavioral vulnerabilities to harm from alcohol use Understanding role of alcohol in generation of ROS, and impairment of oxidative defense mechanism to gain a better understanding of alcohol pathology Metabolomics: To understand metabolic effects of alcohol and its potential use as Biomarkers Lifespan Transcending Theme: Metabolism

12. Lifespan Transcending Theme: Neuroscience • Identify the neurocircuits, neuropharmacology, and neurochemistry that underlies alcohol’s physiological and behavioralactions including the development of compulsive alcohol use (alcohol seeking, reinforcement, relapse) • Explore alcohol effects with the CNS at many levels from molecularand cellular to structural and cognitive – to understand actions includinglearning, memory, tolerance, dependence

13. Alcohol and the Embryo and Fetus • Despite our knowledge on FASD many questions remain: • At the molecular level, the role of gene expressions and epigenetics • Contributions to pathology from other risk factors: e.g., stress and nutrition • Role of protective agents: choline, NAP, SAL • Improvement in diagnosis: 3-D facial imaging coupled to self-educating (machine learning) computer technology • Determining the true prevalence of FAS in the U.S. • Development of Interventions for FASD children

14. Early to Middle Childhood: The Interval of Emerging Risk • In early childhood, the interplay of biologicaland environmental factors shape normal development, as well as risk and resilience for abnormal development • There is an opportunity to pursue an enhanced understanding of the contributions of: • biology(e.g., hormonal development) • environment, GxE (epigenetics) as underlying factors for risk and resilience to harmful alcohol use and Alcohol Dependence across the FULL lifespan

15. Critical period; risk of dependence increases inversely with age of onset of drinking A time of heightened risk-taking for many. Brain continues to mature through adolescence into perhaps the early or mid-20’s Scientific opportunities include: Adolescent decision-making Alcohol’s effects on brain structures and behavioral regulatory systems through imaging (dtMRI, fMRI) and neurobehavioral assessment Identifying endophenotypicandintermediate phenotypic markers of drinking risk Establishing the extend of vulnerability of the adolescent brain to alcohol’s acute and chronic effects Youth/Adolescence

16. Young Adult • (~Age 18-29) Period with the highest prevalence of Alcohol Abuse and Alcohol Dependence • Many will transition out of dependence without treatment; Important to understand WHY and how i.e., what is different in biology, personality, environment • Opportunity to determine functional differences through imaging (electrophysiology, fMRI, etc.) in those who will continue to be alcohol dependent and those who will transition out

17. Midlife: Organ Pathology • Period when most organ pathologies become clinically significant • Important potential initiatives around metabolic effects on organs, liver and others • Important co-morbidity with Hepatitis C andHIV

18. Midlife: Behavior & Treatment • Period when most individuals will seek treatment • Even for those who enter treatment, major contributors to “change” may occur before entering treatment • Uncoveringmechanisms of behavior change, and adapting that knowledge, will improve recoveryfor all

19. Many promising agents under test Opportunities exist to: Develop animal models better reflecting endophenotypes in alcohol dependence Develop improved human laboratory paradigms withsurrogate outcome markers Identify through basic research target sites for lead compounds Expand pharmacogenetic research (Predictiveand Personalized medicine) Develop collaborative networks with industry and academia Midlife: Medications Development

20. Senior Adult • Only 0.5% of population reported past-year dependence; 1.4% abuse • Greater potential for medications interactions • Growing population • Trans-NIH longitudinal research studies can provide important information of alcohol problems in seniors in a cost efficient manner

21. The American Recovery and Reinvestment Act of 2009 (ARRA) • On February 17, 2009 President Obama signed the American Recovery and Reinvestment Act of 2009 (ARRA) • Among its many goals, the ARRA seeks to preserve and create jobs, promote economic recovery, and increase economic efficiency by spurring technological advances in science and health  • As part of the ARRA, NIH will receive $10 billion for use in 2009 and 2010 including: • $1 billion for extramural construction • $800 million to the Office of the NIH Director for extending and developing appropriate programs (e.g., challenge grants) • $400 million for Comparative Effectiveness Research • $7.4 billion will be provided to the NIH institutes and centers (proportional to their appropriations) 

22. The American Recovery and Reinvestment Act of 2009 (ARRA) • The ARRA impact is expected to extend beyond the immediate scientists who will receive funds, to allied health workers, technicians, students, trade workers, etc. • Beyond the immediate economic stimulus, the science funded by the Recovery Act will positively impact upon the health of the nation for years to come  • Information about these critical projects and their impact on the economy will be posted on HHS/RECOVERY.gov

23. What Funding Mechanisms Will Be Supported Under The ARRA? In general, NIH will focus scientific activities in several areas: • Recently peer reviewed, highly meritorious R01 and similar mechanisms capable of making significant advances with a two-year grant • Administrative and competitive supplements to current grants.  • Shared Instrumentation Grants: $100K – $500K (from NCRR) • High-End Instrumentation $600K - $8M (from NCRR) • Other Programs to be announced once approved • NIH Challenge Grant program – RFA OD-09-003 – due April 27. -- A new program that will support research which addresses specific scientific and health research challenges in biomedical and behavioral research that will benefit from significant 2-year jumpstart funds.

24. Challenge Grants • Each NIH Institute, Center, and Office has selected specific Challenge Topics within the broad Challenge Areas related to its mission that have been accorded the highest priority by the NIH • Institute specific information available on each Institutes Web-Site.

25. Behavior, Behavioral Change, and Prevention* Bioethics * Biomarker Discovery and Validation * Clinical Research * Comparative Effectiveness Research (CER) * Enabling Technologies * Enhancing Clinical Trials * Genomics* Health Disparities * Information Technology for Processing Health Care Data Regenerative Medicine * Science, Technology, Engineering and Mathematics Education (STEM) Smart Biomaterials – Theranostics Stem Cells * Translational Science * Broad Challenge Areas *Challenge Areas with NIAAA Topics

26. Challenge Areas and Challenge Topics Examples of high priority topics for NIAAA include: • Identifying Phenotypic Markers for Positive Behavior Change • Capturing Social Network Information for Groups at High Risk for Negative Health Behaviors • Ethical Issues in the Translation of Genetic Knowledge to Clinical Practice • Developing high-throughput biomarker assays from finger-stick dried blood spots • Medication Development for Hepatic Fibrosis • Innovative Analyses of Existing Clinical Datasets Detailed information on NIH Challenge Areas, Topics and Grants can be found on the NIH Website (http://grants.nih.gov/grants/funding/challenge_award/)

27. Comparative Effectiveness Research (CER) • Recovery Act funds allocated to NIH specifically for comparative effectiveness research (CER) will be available to support additional grants • Projects receiving these funds will need to meet the definition of CER: “a rigorous evaluation of the impact of different options that are available for treating a given medical condition for a particular set of patients. • Such a study may for example compare similar treatments, analyze very different approaches, such as surgery and drug therapy, or include the development and use of clinical registries, clinical data networks, and other forms of electronic health data that can be used to generate or obtain outcome data as they apply to CER

28. Thank you Kenneth R. Warren, Ph.D. Acting Director National Institute on Alcohol Abuse and Alcoholism http://www.niaaa.nih.gov

29. Animal Rights ¹Animal Welfare 1980’s - a movement to defend the “rights” of animals begins. Tenet 1:“Animals should not be used for clothing, food, entertainment, or experiments.” Tenet 2: “Animals should have legal rights and the status of personhood.”

30. NIH’s Proactive Animals in Research Agenda To meet Immediate challenges: • Give our staff tools to assist their grantees. • Provide better support to our investigators. • Work with funded institutions. To address long-term challenges: • Improve communications. • Document health impact. • Mobilize the stakeholders.

31. The use of animal models in biomedical research is facing major challenges … I. Immediate challenge: Guard the public’s investment in biomedical research from threats & violence • against institutions • against investigators and their families • against others who support research institutions II. Long term challenges: • Improve public’s understanding of the role of animal research to advance medicine and health • Change in societal views of relationship between humans and other animals • Change in the legal status of animals

32. Who should respond to this challenge? • Government • Funding Agencies • Research Institutions • Grantees • Biomedical and Pharmaceutical Industries • Professional Organizations • Advocates for Biomedical Research • The Public

33. What we advise you to do. • Learn about the laws to protect research animals. • Be diligent about careful preparation of the sections of the grant application about animals. • Know where to get advise about animal research protocols: your institution’s Animal Care and Use Committee, the NIH Office of Laboratory Animal Welfare (OLAW), and your NIAAA project officer. • Understand how results of your research may contribute to the advancement of medicine and improvements in human health.

34. What we advise you to do,continued. • Understand when you must have changes in your research approved by your Animal Care and Use Committee, your NIAAA Project Officer, and/or NIAAA Grants Management. • Assess your vulnerabilities. Goggle yourself. • Know the preparedness plan and phone numbers to call for emergencies at your lab, office, and home. • Develop good relationships with you neighbors and the larger community where you live.

35. Some Web sites with useful information and resources about the use of animals in research: A National Institutes of Health (NIH) Web site: http://grants.nih.gov/grants/policy/air/index.htm Federation of American Societies for Experimental Biology (FASEB): www.animalrightsextremism.org Society for Neuroscience: http://www.sfn.org/index.aspx?pagename=gpa_AnimalsinResearch see Animals in Research Resources

36. Universal Message for Alcohol Use Across The Lifespan Col. Evan Hoapili USAF (ret.), Francis E. Warren Air Force Base, Cheyenne, Wyoming