Intramural research program
The intramural research component of NIAAA is a single Division, the Division of Intramural Clinical and Biological Research (DICBR). In terms of number of personnel DICBR is the largest division in NIAAA, but its budget is about only about 10% of the Institute total. An intramural research budget of about 10% of an Institute’s budget is roughly average for those NIH Institutes that have intramural programs. The DICBR is comprised of 10 laboratories, most of which are divided further into sections/units. The chief of each laboratory is a doctoral-level scientist who is tenured at NIH. Sections/units within laboratories are also headed by doctoral-level scientists, some of whom have achieved tenure (and are section/unit chiefs) and some of whom are not yet tenured but are on tenure track (and are section/unit acting chiefs). The process of achieving tenure at NIH involves rigorous review by a board of outside scientists expert in the relevant field(s) and, unlike extramural grant review, past scientific achievement is weighted much more heavily than future plans in reaching the tenure decision.
The DICBR has as its overall goals understanding the biological basis of alcohol use disorders and alcohol-induced morbidities, and developing novel strategies and tools for the prevention and treatment of these disorders. Research is conducted at multiple levels: cellular/molecular, animal studies in rodents and non-human primates, human studies of the genetics and epidemiology of alcoholism and comorbidities and validation of novel molecular targets for alcohol use disorders. Collaborations among the various units and between these units and investigators from other NIH institutes or extramural institutions reflect the integrative, multi-disciplinary nature of ongoing research. Research into the causes and consequences of alcoholism is not a discipline in its own right; rather, it relies upon and employs the tools of a wide range of biological disciplines. The outstanding scientists heading the various research units of our intramural program are recognized for their contributions to their chosen research fields, be it molecular biology, neuroscience, biochemistry, physical chemistry, physiology, genetics, epidemiology or psychiatry, and apply their expertise to answer questions related to alcohol use disorders.
The Laboratory of Clinical and Translational Studies (LCTS) is the primary clinical laboratory of our intramural program. It focuses upon developing novel pharmacological treatments for alcohol use disorders through a combination of pre-clinical studies aimed at discovering and validating new molecular targets using rodent and primate models, and clinical proof-of-concept studies that test these novel targets through the use of therapeutic agents directed against such targets. This work also takes advantage of state-of-the-art functional brain imaging techniques. Through agreements with industry partners, LCTS has been able to leverage government dollars and gain access to compounds of interest that would otherwise have been unattainable. None the less, due to budgetary constraints, the NIAAA contribution to NIH’s long-standing primate research program had to be ended in FY 2007.
The Laboratory of Membrane Biochemistry and Biophysics (LMBB) explores the relationship between alcohol-induced changes in membrane structure and function and investigates the biological functions of polyunsaturated fatty acids, with special emphasis on docosa-hexaenoic acid (DHA). This laboratory utilizes diverse methodological approaches, ranging from spectroscopy to biochemistry and nutritional neuroscience to psychiatry.
The Laboratory of Neurogenetics (LNG) aims to identify genes that predispose to or protect from alcoholism and comorbid disorders. Their approach combines functional genomics in in vitro systems, large-scale analyses of gene expression and linkage analyses, including both candidate gene and genome-wide approaches.
The Laboratory of Epidemiology and Biometry (LEB) designs, conducts and analyzes the collected data from national epidemiological surveys on alcohol use disorders and related conditions, in order to gain insight into their prevalence, comorbidities, prevention, treatment needs and societal costs.
The unifying theme of research in the Laboratory of Integrative Neuroscience (LIN) is forebrain mechanisms of cognition and behavioral control that play a role in addiction, which are investigated using a combination of electrophysiological, cell and molecular biological and whole animal behavioral techniques and paradigms.
The Laboratory of Molecular Signaling (LMS) explores the signaling pathways involved in the effects of poly-unsaturated fatty acids on neuronal survival and their modulation by ethanol, using a combination of cell biological and mass spectrometry-based proteomic approaches.
Research in the Laboratory of Physiologic Studies (LPS) focuses upon neuroendocrine mechanisms that regulate appetitive functions, including alcohol drinking behavior, on liver biology and on mechanisms of oxidative and nitrosative stress. A shared interest among the three sections of this laboratory is the role of the endocannabinoid system in the above functions.
The Laboratory of Metabolic Control (LMC) studies how the flux through various metabolic pathways is involved in controlling cellular energy status, with particular emphasis on the metabolism of ketone bodies and its therapeutic implications.
The Laboratory of Molecular Physiology (LMP) investigates cellular, subcellular and molecular mechanisms underlying synaptic transmission in the nervous system, using electrophysiological and advanced cellular imaging techniques, as well as zebrafish genetics.
Finally, the Laboratory of Neuroimaging (LNI) uses in vivo brain imaging to gain insight into the neurochemical basis of addictive disorders, including drug-seeking behavior, alcoholism and alcohol dependence. It is unusual that the chief of the LNI is the Director of another NIH Institute (NIDA); NIH requires that an Institute Director’s intramural laboratory be located administratively in another Institute to avoid a potential for conflict of interest. As is common among all NIH research institutes, LNI staff interacts scientifically with other DICBR and NIH researchers.
NIH, including NIAAA, is very much engaged in the training of future scientific leaders. In addition to its primary research role, the NIAAA Intramural Program has an active training program with trainees at undergraduate, post-baccalaureate, graduate and postdoctoral levels. Trainees come from throughout the US and many other countries through a variety of training mechanisms; at any given time, there are a 100 or more trainees working in DICBR laboratories.
After a period of rapid budgetary growth (‘the doubling’) the NIH budget has been flat for a number of years, with budget growth less than inflation. The DICBR budget has paralleled that of NIH. Despite the budgetary pressure, research productivity has reached new highs in the intramural program. Recent significant scientific advances illustrate this fact, and also the broad and interdisciplinary scope of the research:
- pre-clinical and clinical validation of the neurokinin 1 receptor (NK1R) as a novel target for the treatment of alcoholism ;
- the identification of gene variants that affect the expression of neuropeptide Y, with implications for the regulation of appetite, weight, resiliency to stress and emotional responsiveness ;
- data showing a molecular (CAMKIIα) switch mechanism that is perhaps a basis of memory ;
- evidence that endocannabinoid action in the liver is critical for the development of alcoholic fatty liver ;
- evidence that elevation of the ethanol metabolite, acetate, may be responsible for the decrease in brain glucose utilization observed in human subjects consuming alcohol ;
- presentation of nationally representative findings on socio-demographic and psychopathological predictors of first incidence of DSM-IV substance, mood and anxiety disorders ;
- discovery of the contribution of the hepatic endocannabinoid system not only to the development of diet-induced fatty liver, but also to the associated insulin resistance and dyslipidemias ;
- epidemiological evidence that maternal seafood consumption during pregnancy promotes neural and cognitive development in children ; and
- evidence that chronic stress biases decision-making strategies, affecting the ability of stressed animals to perform actions on the basis of their consequences .
The key to continued success in the DICBR lies in the creative ingenuity and hard work of our investigators who are guided by the principle enunciated by the Nobel laureate, Albert Szent-Györgyi: ‘Discovery consists in seeing what everyone else has seen and thinking what no one else has thought’.