ABMRF/The Foundation for Alcohol Research has played a major role in shaping the early careers of the most prominent alcohol researchers across North America. Since our founding in 1982, we have maximized our impact as a relatively small foundation by centering the grant program on novel research proposals put forth by the most promising investigators. The new research projects funded in 2007, which are described below, offer an exciting opportunity to view the future through the studies currently underway by Foundation grantees.

Arpana Agrawal, Ph.D., Washington University School of Medicine, “Gene x environment influences on quantitative indices of alcohol consumption.” 

A refined understanding of the bio-behavioral underpinnings of alcoholism will be achieved through identifying candidate genes that are associated with alcoholism, and more importantly, by understanding their interactions with the childhood psychosocial environment. These gene – environment interactions provide a doorway to the complex cascade of biological and environmental pathways that contribute directly and via interactions to risk for alcoholism. Using two related Australian adult samples, we propose to test the important contributions of genes (e.g., GABRA2) and the critical role of interactions between the childhood psychosocial environment (e.g., parental separation) on alcohol consumption and vulnerability to alcohol dependence. Isolating such genetic sensitivity to environmental adversity will aid us in identifying individuals with an increased vulnerability to alcohol-related problems, and may help clinicians and prevention scientists cater more targeted efforts at them.

Dee Harrison-Findik, Ph.D., University of Nebraska Medical Center, “Molecular mechanisms of short-term, moderate alcohol exposure-mediated regulation of hepcidin and iron metabolism in vivo.” 

Iron is required for an array of vital biological processes.  Hower, due to its chemical properties, iron can also cause cellular injury.  Patients with alcoholic liver disease frequently exhibit elevated levels of serum iron and liver iron.  Increased liver iron content is associated with greater mortality from alcoholic cirrhosis, suggesting a pathogenic role of iron in alcoholic liver disease.  Moderate alcohol consumption has also been shown to increase the prevalence of iron overload.  However, the underlying mechanisms are unknown. 
We have recently demonstrated that short-term, moderate alcohol exposure-mediated oxidative stress reduced the synthesis of a liver-specific hormone, hepcidin.  Hepcidin is well-known to play a central role in the regulation of body iron balance.  Interestingly, the alcohol-induced decrease in liver hepcidin synthesis resulted in elevated intestinal iron transport, which was reversed by the injection of hepcidin in vivo.  Hence, the main goal of this study is to further understand how moderate alcohol exposure regulates liver hepcidin synthesis and body iron stores.  Understanding these underlying mechanisms is of considerable clinical importance, because iron acts as a secondary risk factor in alcoholic liver disease.  These studies may therefore lead to the development of therapeutic strategies or diagnostic tools to prevent alcohol-induced liver injury at earlier stages, before it develops into a chronic disease with irreversible liver damage.

Ian N. Hines, Ph.D., The University of North Carolina at Chapel Hill, “Modulation of hepatic natural killer T cell function by ethanol.” 

Chronic alcohol consumption is a known inducer of liver injury including the development of scarring, a process referred to as fibrosis.  It is not clear, however, how repeated exposure to ethanol can induce scar formation within the liver.  Previous studies have identified certain immune cells including the T lymphocyte as an important component of this process.  The liver is home to a number of different lymphocyte populations including the natural killer T (NKT) lymphocyte.  NKT cells produce a number of mediators thought to be involved both in causing fibrosis (T helper 2 cytokines) as well as mediators known to inhibit or slow the process (T helper 1 cytokines).  The current study is conducted with the hypothesis that alcohol consumption promotes the production of pro-fibrotic T helper 2 cytokines and suppresses the production of inhibitors of this response (T helper 1 cytokines) by NKT cells within the liver.  Using a rodent model of alcohol administration, the effects of both acute (6 hours following alcohol administration) and chronic (1, 2, or 4 weeks of continuous alcohol exposure) on liver NKT cell cytokine responses will be evaluated.  Moreover, the effects of ethanol on NKT cells in a fibrotic liver will also be investigated.  Together, findings from the current study will provide new information and mechanisms by which ethanol may promote fibrosis and scarring within the liver and potentially aid in the development of therapies to slow or prevent its occurrence.     

Rael T. Lange, Ph.D., British Columbia Mental Health and Addiction Services, “Neuropsychological and neuropathological effects of acute versus chronic alcohol consumption: Outcome from traumatic brain injury.” 

Traumatic brain injury (TBI) is one of the leading causes of death and disability in persons under the age of 50 years. Alcohol misuse is a significant risk factor for TBI. The prevalence of alcohol intoxication in hospital patients presenting to the Emergency Department (ED) with head trauma range from 37% to 53%. Patients who are intoxicated at the time of TBI have been found to be more difficult to manage and treat, have worse recovery, and consequently, place an increased economic burden on the health care system. However, it is unclear whether poor recovery following an intoxicated-TBI is due to the deleterious effects of acute alcohol intoxication at the time of injury or due to the consequences of pre-injury alcohol misuse common in this population. Past research is characterized by many methodological problems that limit our understanding of these issues. The purpose of this study is to employ a well-controlled, prospective research methodology to examine the relative contributions of acute versus chronic alcohol factors on outcome and recovery from TBI. This study will recruit patients who have sustained a TBI from a Level 1 trauma center in Vancouver, BC, Canada. Participants will undergo magnetic resonance imaging (MRI) scanning and neuropsychological testing at 6-weeks post-injury. Diffusion Tensor Imaging will be used to examine microstructural white matter integrity in the corpus callosum; the largest white matter tract in the brain. It is hypothesized that day-of-injury alcohol intoxication will have a greater impact than pre-injury alcohol consumption in determining neuropathological abnormalities and neuropsychological deficits. The results of this study will identify the most salient aspects of alcohol misuse that negatively impact outcome and recovery from TBI; and will serve as the impetus for researchers and clinicians to understand more specifically how alcohol misuse may affect the diagnosis, management, treatment, and rehabilitation of TBI patients whose clinical presentation is complicated by the presence of alcohol.

Melissa A. Lewis, Ph.D., University of Washington, “Personalized alcohol and related risky sexual behavior feedback intervention project.” 

Heavy alcohol use among college students remains a concern, as it continues to be both prevalent and problematic. Findings from research studies continually demonstrate that not only are college students engaging in heavy drinking but that they also experience negative consequences, such as engaging in risky sexual behavior. The proposed study involves a longitudinal prevention intervention for sexually-active, heavy drinking college students. This research will assess the unique and combined contribution of providing personalized information on normative peer behavior and personalized protective tips for reducing negative consequences of high-risk drinking and alcohol-related risky sexual behavior. Students who receive the prevention intervention will receive (1) personalized information regarding normative peer drinking and alcohol-related sexual behavior, (2) protective tips that students can use in order to reduce negative consequences from drinking and alcohol-related sexual behavior, or (3) both of these personalized pieces of information. Students who do not receive the intervention will be provided information about general student behavior in a format similar to the intervention information. Personalized normative peer comparisons and protective tips are often included in brief personalized interventions for college student drinking but seldom evaluated independently. This research will provide a deeper understanding of how lowering normative perceptions for high-risk peer behavior and increasing use of protective behaviors can result in decreased negative consequences from drinking and related risky sexual behavior among college students. The present study is important because it will provide knowledge as to what is necessary and/or sufficient to reduce harm from high-risk drinking and related sexual behavior; in particular, information about “why” someone might want to reduce harm from high-risk drinking and related sexual behavior (i.e., personalized information on normative comparisons), the tools for “how” someone could reduce harm from high-risk drinking and related sexual behavior (i.e., personalized protective tips), or both the “why and how” someone might want to or could reduce harm from high-risk drinking and related sexual behavior. Because of the frequency and seriousness of consequences of drinking behavior and alcohol-related risky sexual behavior, an effective intervention of this type has the potential to reduce harm and be readily disseminated to college campuses elsewhere.

Chiang-shan Ray Li, M.D., Ph.D., Yale University School of Medicine, “Inhibitory control and alcohol dependence.”  

Alcohol dependence is a chronic, relapsing disorder. Patients with alcohol dependence oftentimes report that they understand the serious consequences of using alcohol, but they are not able to “control” their behaviors. One of the major goals of addiction neuroscience is thus to understand how our brain exercises inhibitory control and monitor our behaviors and how these processes are altered in the patients of alcohol dependence. The goal of this proposal is to combine functional brain imaging with a behavioral task as a cognitive proxy to examine these issues. The results gathered from the proposed projects will help us understand the “alcohol-dependent brain” and facilitate the development of novel therapeutic strategies to treat patients with alcohol dependence.

Hongbo R. Luo, Ph.D., Children’s Hospital Boston, “Molecular basis of alcohol-induced neutrophil chemotaxis defect.” 

Alcohol is the most commonly abused substance in the United States.  An increased susceptibility to infectious diseases due to alcohol-induced immunosuppression was often found in alcoholic patients as well as in cases of acute alcohol consumption (binge drinking).  Impairment of neutrophil chemotaxis, an essential cellular process in innate immunity, plays an essential role in alcohol-induced immunosuppression.  The ultimate goal of this research is to gain insight into the molecular basis underlying alcohol-induced neutrophil chemotaxis defect.  One of signaling pathways mediating neutrophil chemotaxis is PtdIns(3,4,5)P3 pathway.  Our preliminary data show that this pathway can be deactivated in alcohol treated cells.  Accordingly, we hypothesize that PtdIns(3,4,5)P3 signal deactivation is a causal mediator of alcohol-induced impairment of neutrophil chemotaxis.  In this study, we will continue to elucidate the molecular mechanism leading to alcohol-induced deactivation of PtdIns(3,4,5)P3 signaling.  Experiments proposed in this application will provide insight into the mechanism of action of alcohol in suppressing neutrophil chemotaxis, with the ultimate goal of solidifying PtdIns(3,4,5)P3 and related pathways as novel therapeutic targets for treatment of alcohol-induced immunosuppression and infection (in both chronic and acute alcohol consumption).  In addition, these studies will advance our knowledge of the effect of alcohol on PtdIns(3,4,5)P3 signaling in general and assist us to understand alcohol-induced cellular defects in other types of cells or tissues.

James MacKillop, Ph.D., Brown University, “Understanding craving for alcohol via behavioral economics.” 

The role of craving has been increasingly controversial in alcoholism research. This is in part because of ambiguous findings connecting craving to actual alcohol use or post-treatment relapse. Such ambiguity may be related to measurement limitations in the assessment of a purely subjective experience. From a behavioral economic perspective, craving may reflect a transient increase in the relative value of alcohol and may be best understood using objective measures of value. This project seeks to test the hypothesis that craving can be directly translated into measures of relative value using a human laboratory paradigm. In addition, recent research suggests that genetic factors may contribute to the expression of craving. A second goal of this research is to examine whether possession of a specific genetic characteristic contributes to craving. Findings from this research will have the potential to clarify the nature of craving for alcohol and genetic factors that may contribute to its expression.     

Krisztina Malisza, Ph.D., National Research Council Canada, Institute for Biodiagnostics, “Stop, look and remember – Neuroimaging cognitive function in children with ARND and ADHD.” 

Fetal alcohol syndrome (FAS), partial FAS and alcohol related neurodevelopmental disorders (ARND) are collectively referred to as fetal alcohol spectrum disorders (FASD).  The diagnosis of FASD, in particular ARND, is frequently difficult due to symptom similarities associated with other disorders, such as Attention Deficit Hyperactivity Disorder (ADHD).  We will use a technique called functional magnetic resonance imaging (fMRI) to detect possible differences in brain function between individuals diagnosed with ARND, who do not show the facial features typically associated with FAS, and children with ADHD and healthy controls.  The children in this study will perform several different computer-based tests while they are in the MRI.  These tasks are specially designed to examine how the brain works during tests of attention, spatial working memory and response inhibition.  In this way, we can determine if there are different patterns of brain activity for children with different diagnoses.  In order to design possible treatments it is necessary to characterize and understand the effects of alcohol on the developing brain; fMRI provides a means to do this.  Very little is understood about functional brain activity in people with FASD, so neuroimaging studies are particularly useful.  Behavioural testing and brain activity patterns may provide an indication of deficits in selective attention or working memory in individuals; this can enhance a physicians’ ability to make accurate clinical diagnoses.  Accurate diagnosis of the condition will help increase the likelihood of early and successful intervention.  This will contribute to a better understanding of the effects of alcohol on the health and behaviour of children who were prenatally exposed.

James G. Murphy, Ph.D., The University of Memphis, “Behavioral economic moderators of brief alcohol interventions in a diverse sample of college students.” 

An estimated 31% of the 8 million U.S. college students meet criteria for alcohol abuse.  College students often drink large quantities of alcohol over relatively brief time periods, which can result in dangerously high blood alcohol concentrations.  These patterns of heavy drinking place college students at high risk for alcohol-related health and social problems.  Alcohol use contributed to over 1,700 deaths among U.S. college students in 2001.  The goal of this project is to compare two interventions designed to reduce risky drinking in diverse samples of college students.  Students who report risky drinking during visits to the student health center will be invited to participate in this study and randomly assigned to complete either a computerized alcohol education program or an individual motivational counseling session that includes personalized feedback on their alcohol use and risks.  All students will complete follow-up assessments one and six months after the interventions.  In addition to determining the relative effectiveness of these brief intervention formats, this study will identify characteristics of students who do not respond to these brief interventions and may require further intervention.  This could ultimately lead to more efficient treatment assignment and stepped-care approaches to reducing heavy drinking among college students. 

Ralph Radach, Ph.D., Florida State University, “Visuomotor impairments due to acute alcohol intoxication.” 

The most important way humans navigate in and communicate with the environment is through visual perception. Virtually all complex cognitive tasks like driving, searching for objects or reading a text rely on visual input, obtained via the planning and execution of rapid eye movements. While adverse effects of alcohol on visual performance have been acknowledged for a long time, there is little research on where exactly in the machinery of perception, attention, and eye movement control these impairments occur. The planned work represents the first attempt to examine this issue through a programmatic series of experiments. 
In these studies, participants are asked to execute eye movements in response to simple stimuli shown in the visual periphery. One group of experimental tasks is intended to systematically map the influence of alcohol on a hierarchy of processing levels. These include simple automatic reactions, well learned visuomotor routines, and responses involving a more complex and deliberate level of cognitive control. Another group of experimental tasks will elucidate the critical question of when and how alcohol compromises the ability to inhibit or redirect responses when the task or context calls for it.
Our research also aims to make a major methodological contribution to the field by clarifying the role of alcohol expectancy in research on cognitive control. To this end, each experiment will test differences between acute alcohol intoxication and both placebo and simple no-alcohol conditions. These comparisons will show how participant’s efforts to compensate for anticipated alcohol effects may influence experimental results.
Taken together, we expect this project to provide a more comprehensive picture of how acute alcohol intoxication affects visuomotor performance and its underlying cognitive processes and perceptual mechanisms. 

Jennifer Read, Ph.D., State University of New York at Buffalo, “Trauma, PTSD, and alcohol information processing in college students.”   

College students are at risk for both trauma and resulting traumatic stress sequelae (TSS), as well as for heavy drinking and its negative consequences. The proposed research examines pathways through which environmental (cue) and individual trauma stimuli affect alcohol-related information processing in individuals with and without posttraumatic stress disorder (PTSD). The study consists of two parts, an initial diagnostic interview session and an experimental session. In the experimental session, participants (N=160, 80 females) will be assigned randomly to either personalized trauma or neutral primes in a 2 (PTSD status) X 2 (trauma cue) design. The effects of PTSD and exposure to a trauma cue on processing of alcohol information will be examined. Findings from this study will help to identify cognitive pathways affecting drinking. This information ultimately can inform preventive interventions for individuals at risk for heavy alcohol use and associated problems, during the important developmental transition into adulthood.

Donita L. Robinson, Ph.D., University of North Carolina at Chapel Hill, “Neurophysiological adaptations in the nucleus accumbens to chronic and repeated ethanol exposure.” 

The nucleus accumbens is a brain area that plays an important role in long-term alcohol use, in that it is involved in the rewarding effects of the drug, in learning that specific cues can predict alcohol availability, as well as the link between those cues and subsequent craving and seeking the drug.  Accordingly, understanding neural activity in the nucleus accumbens during alcohol use is a key goal not only to work out the mechanisms by which excessive alcohol use develops, but also to provide biological targets for drug therapies to treat alcoholism.  The purpose of this study is to determine changes in nucleus accumbens activity that are associated with alcohol dependence and withdrawal.  To accomplish this, we use an animal model of  alcohol drinking in which rats are trained to press one lever for alcohol or another lever for water.  This model allows us to monitor brain activity while the animal experiences key aspects of alcohol use:  sensing cues that are associated with alcohol, seeking the alcohol, and finally drinking.  We obtain a real-time measure of brain activity by recording the rate of action potentials generated by neurons in the nucleus accumbens.  These action potentials are driven by input from other areas providing emotional, physiological, and contextual information; thus, firing rates of these neurons provide a fascinating window onto brain mechanisms directing drinking behavior.  Neural changes associated with chronic alcohol exposure are thought to result from both duration of exposure as well as the number of withdrawal episodes.  Therefore, this study will also compare different patterns of alcohol exposure and withdrawal and will characterize neuronal firing rates both during the exposure period and the withdrawal phase.  In summary, the study of nucleus accumbens function during alcohol drinking and its alteration by chronic alcohol exposure is a crucial step in understanding biological adaptations underlying the transition from moderate drinking to alcohol dependence. 

Gregg Roman, Ph.D., University of Houston, “The neuromodulation of ethanol sedation by heterotrimeric G proteins in Drosophila.” 

In trying to understand why some people move from alcohol use to alcohol abuse and finally addiction, it is apparent we need to better understand the effects of alcohol on the nervous system. Many excellent molecular studies have identified many proteins located in the nervous system that are affected by alcohol levels. A major challenge has been to assign the roles of these affected proteins to different alcohol related behaviors. We are taking a whole organism approach to this problem by modulating specific proteins and neurons, and determining the effect of these changes on the behavioral sensitivity to alcohol. These experiments will be performed with the fruit fly Drosophila melanogaster, the premier genetic model system for behavioral neurobiology. Although the Drosophila brain is different in structure, it contains the same classes of proteins and has neurons that act essentially identical to our own.  Furthermore, Drosophila will get drunk at about the same blood alcohol levels as we do, displaying a similar behavior sensitivity to alcohol. In Drosophila, we can specifically express different genes within almost any set of neurons within the living fly under the experimenters’ control. Using these genetic tools we will express transgenes that disrupt the heterotrimeric G protein signaling pathways within a particular group of neurons known to affect the sedative properties of ethanol. One such transgene is the S1 subunit of pertussis toxin, which will irreversibly inhibit the activity of heterotrimeric G(o) proteins. Heterotrimeric G proteins are responsible for the neruomodulatory activities of serotonin, dopamine, and many other neurochemicals. Heterotrimeric G(o) is especially interesting as it is the most abundant membrane protein within our brain, yet relatively little is known about its functions within the nervous system.  We will further disrupt the molecular events that modulate the activities of the G protein-coupled receptors.   After disrupting these singling pathways, we will determine the effect of alcohol on the loss of postural control (the ability to remain standing) and on sedation. Thus we will be able to determine if any of these pathways operating within a specific cluster of neurons with the brain is responsible for modulating the negative effects of alcohol.  

Tuan D. Tran, Ph.D., East Carolina University, “Critical periods of fetal alcohol exposure and effects on cerebellar-dependent learning and neuroanatomy.” 

Women who use or abuse alcohol during pregnancy may have children that are severely afflicted with life-long brain, behavior, and cognitive disabilities. Animal research using rodent models of fetal alcohol exposure have been instrumental in elucidating the many factors that interplay in contributing to the teratology and neuropathology associated with maternal alcohol abuse. One of the primary factors that has reliably predicted the extent of neurobehavioral deficits resulting from developmental alcohol exposure in rats, is heavy (high alcohol dose) binge-like exposure during the equivalent of the third trimester (with respect brain growth) in humans. Studies using this “3rd trimester” model have demonstrated that certain brain regions, such as the cerebellum, are highly vulnerable to alcohol exposure during this period and the subsequent behavioral or learning deficits appear to be highly associated with the early cerebellar deficits. The cerebellum is important for maintaining motor function such as balance and coordination, but is also involved in simple associative learning — an idea that was championed  through the work of the 1904 Nobel Prize winner, Ivan Pavlov.

One specific form of associative learning is “eyeblink classical conditioning” (ECC) and this model has perhaps received the most attention in mammalian neuroscientific research over the past several decades. Briefly stated, delay ECC is mediated by a discrete brain circuit that involves the cerebellum and brain stem. Therefore, studies can employ ECC to assess the learning deficits and neurpathology associated with maternal alcohol consumption with much higher resolution than many other types of learning procedures can. The majority of the fetal alcohol work involving ECC has been limited to the 3rd trimester model. In this project, the primary aim is to investigate whether alcohol exposure during the prenatal period in rats (which is equivalent to the first, second, and/or both trimesters) produces similar or different learning and neuroanatomical deficits to the already established 3rd trimester model. Learning will be assessed using ECC and the neuroanatomical correlates will be assessed using unbiased cell counts (stereology) in key cerebellar neuron populations known to be essential for ECC  (Purkinje cells and Interpositus neurons). Both the learning and neuroanatomical procedures will be conducted in young and adult rats to determine whether the impact of developmental alcohol exposure during any discrete exposure period is temporary or permanent. Additionally, we will examine whether these measures are differentially affected by the dose of alcohol that is administered. The question of critical windows for alcohol’s effect on the brain and behavior is important to pose, as women who do consume alcohol during their pregnancy, tend to do so most likely during the early stages (first or second trimesters) whether they know that they are pregnant or not. Furthermore, there may be no threshold for alcohol’s effects on the developing human fetus, and examining dose-related changes resulting from any single period of exposure in rats may bolster our understanding of how this drug compromises human brain development. The results from this project may allow future research that examines the potential for therapeutic approaches (chemical or behavioral) in ameliorating fetal alcohol spectrum disorders.

Karmen K. Yoder, Ph.D., Indiana University, “Imaging the dopamine response to alcohol in nontreatment-seeking alcoholics.” 

The actions of alcohol on the neurotransmitter dopamine (DA) are thought to be a critical component of alcohol addiction, yet very little is known about how alcohol affects the human DA system. Positron emission tomography (PET), which uses very small amounts of radioactively labeled compounds to “trace” biological processes, provides us with a unique, non-invasive method for studying the in vivo neurochemistry of the human brain. Using PET and a radiotracer that binds to the DA D2 receptor, [11C]raclopride, we can quantify the DA response to alcohol administration in human subjects.

Studying nontreatment-seeking alcoholics is important in the quest to understand the neurobiological basis of alcoholism and the neurochemical consequences of chronic alcohol consumption. In this work, we will characterize the brain DA response to alcohol in nontreatment-seeking alcoholics. There are two major aims to this study. First, we will obtain test-retest data on the DA responses to alcohol in nontreatment-seeking alcoholics using new quantitative methods for analyzing PET receptor ligand data. The experimental design also allows us to assess the test-retest variability of striatal D2 receptors in this population. Second, we will relate the DA responses to alcohol to alcohol-related behavioral variables, including subjective responses to alcohol, alcohol expectancies, and drinking patterns. These immediate goals provide an important foundation for the design of future studies investigating how DA is involved in the development and maintenance of alcoholism. In addition, the results will provide preliminary data on how D2 receptor levels change as a function of years of chronic drinking. The ability to image the DA system of heavy drinkers in vivo will significantly advance our understanding of the neurochemistry of alcoholism.

Janice Zabolotny, Ph.D., Beth Israel Deaconess Medical Center, “Role of PTP1B overexpression in pathogenesis of alcoholic fatty liver disease.” 

Alcohol consumption and diet have important consequences for human health.  In some individuals, either alcohol consumption or obesity can cause fatty liver disease.  Because two-thirds of adults in the U.S. and Canada are now overweight or obese, understanding how moderate alcohol consumption affects individuals with existing fatty liver disease due to obesity is an important but underexplored area of alcohol research.  Fatty liver disease is characterized by excess fat accumulation in the liver, and can result in liver inflammation and dysfunction. The hormone insulin is an important regulator of fat storage in the liver and abnormal insulin function may contribute to the development of fatty liver disease.  In obesity, an overabundance of a protein called protein tyrosine phosphatase 1B (PTP1B) causes insulin dysfunction and is thought to stimulate fat accumulation in liver.  How PTP1B abundance is regulated is not well understood at present.  We recently found that inflammation occurring in obesity elevates PTP1B amount in liver.  Currently, it is not known whether PTP1B overabundance may occur in response to liver inflammation associated with alcohol consumption and may promote alcoholic fatty liver disease.  Likewise, it is unknown whether liver PTP1B overabundance occurring in obesity may increase the risk of developing alcoholic fatty liver disease.  Our studies will determine whether alcohol-induced liver inflammation elevates PTP1B amount in lean and obese animals, and whether PTP1B overabundance in liver of mice accelerates development of alcoholic fatty liver disease.  This work will identify whether the PTP1B phosphatase is an important therapeutic target to treat alcoholic fatty liver disease and advance understanding of how alcohol and obesity interact to affect health.

Huiping Zhang, Ph.D., Yale University School of Medicine, “Association study of a subfamily (Rz) of regulator of G-protein signaling (RGS) genes in alcohol dependence.”  

There is evidence that the rewarding effect of alcohol is mediated by several receptors (e.g., dopamine and opioid receptors), which are expressed in neurons related to the brain reward center. Interestingly, regulators of G-protein signaling (RGS) can negatively control the activation of these receptors. Presumably, variations in RGS genes could alter the function of RGS proteins, and consequently adjust the activity of the above receptors. The primary objective of the proposed research is to analyze whether variations in two important RGS genes (RGS17 and RGS20, which are closely related to opioid receptors in both gene location and protein function) are associated with alcohol dependence.

The association study will be performed in both African and European Americans, the two major populations in the United States. The study design will be both family- and case-control-based association analyses. In the family-based study, we will examine whether certain RGS variants are significantly more frequently transmitted from parents to affected children with alcohol dependence than by chance. In the case-control study, we will examine whether certain RGS variants are significantly more frequent in alcohol dependence cases than in normal controls. The over-transmitted variants identified in the family study and/or the significantly more frequent variants in cases identified in the case-control study may be genetic risk factors for alcohol dependence, although further functional study of these variants is needed.

We believe that the findings from the proposed study may help in developing new genetic testing methods for early prediction, diagnosis and prevention of alcohol dependence, and in the design of new drugs for treatment of alcohol dependence.