2011 Grant Project Profiles
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. Recently funded research projects which are described below offer an exciting opportunity to view the future through the studies currently underway by Foundation grantees.
Behavioral and Social Advisory Council
Dingcai Cao, Ph.D., The University of Chicago, "Alcohol effects on visual processing in at-risk social drinkers."
One of the most severe consequences of excessive drinking among young adults is unintentional injury or accidents. In 2009, 43% of drunk drivers that were involved in fatal vehicle crashes were aged between 21-34 years. Alcohol-related injury/fatalities likely involve many systems, including impairments in ocular-motor function, information processing or psychomotor function. The role of the visual system in all these processes cannot be underscored enough, since the majority of sensory information that reaches the central nervous system in humans comes through the eyes. Visual impairment caused by alcohol therefore has a large impact on alcohol-related injury. For instance, most heavy drinking in young adults occurs during evening or early morning hours and there are four times as many drunk-driving fatalities during those hours than during daylight hours. This may be due to alcohol producing greater visual processing impairments in night vision (processed by rod photoreceptors) than day vision (processed by cone photoreceptors). Moreover, different visual information (i.e., luminance, color, motion, shape, spatial location) is represented and processed in parallel visual pathways. In this study, we will conduct a placebo-controlled investigation of the acute effects of alcohol on fundamental aspects of visual processing produced by different photoreceptors (rods and cones) and by different visual pathways in moderate to heavy social drinkers. We will further examine the relationship of these alcohol-induced visual impairments to other objective and subjective responses. The outcome will provide a better understanding of mechanisms underlying the visual function changes caused by alcohol consumption, which likely play a large role in alcohol-related injury and premature death. The goal is to bolster harm reduction and risk reduction efforts to improve public health, education and safety related to alcohol misuse.
Tara Chaplin, Ph.D., Yale University, "Responses during parent-child interactions and alcohol-use behaviors in adolescents."
Adolescence is a period of risk for alcohol use and problem use. One important factor in adolescents' problem alcohol use is their family environment. Several questionnaire-based studies have found that poor self-reported parenting is a risk factor for teens' alcohol use. However, laboratory studies have not been done to examine how adolescents respond to family conflict interactions and if adolescents' emotional and physiological responses to these interactions have implications for their alcohol use. If adolescents are overly aroused by family interactions about difficult topics, they may avoid such talks and consequently have a less close family relationship, which may lead to decreased monitoring, increased involvement with deviant peers, and increased alcohol use. The proposed laboratory study will observe parent-adolescent conflict interactions in 60 14-16 year olds and their parents. Parenting behaviors during the interaction, including parental warmth, structuring, criticism, and negative emotion will be coded. Before the interaction and at repeated time-points after the interaction, adolescents' and parents' emotional, physiological (HR, BP), and neuroendocrine (cortisol) arousal will be assessed. Adolescents will complete assessments of alcohol use/problem use at the time of the laboratory session and 9 months later. The hypothesis is that adolescents who show high levels of emotional and physiological arousal in response to the family conflict interaction will show greater alcohol use and alcohol problems currently and at the 9 month follow-up. In addition, adolescents who experience more negative parenting, including lower parental warmth and structure and higher criticism and negative emotion, will show greater alcohol use/problem use, particularly if they show high arousal to the conflict interaction. The proposed study will contribute to the field by identifying specific family interaction responses that are associated with risk for or resilience from alcohol use in adolescents. These responses could then be targeted in family-based alcohol abuse prevention programs.
Emma Childs, Ph.D., The University of Chicago, "Location, location, location: Associations between alcohol drinking and the environment."
Alcohol drinkers form powerful associations with the places where drinking occurs e.g., bars and restaurants. These learned associations, called contextual conditioning, influence all stages of alcohol abuse and addiction. The processes of contextual conditioning represent a unique target for treatment, but they have not been studied in detail in humans. This project will use methods based upon a well-established animal paradigm to examine how contextual conditioning between alcohol and the places where drinking occurs is established in humans and its influence upon drinking behavior. This will contribute to a better understanding of how contextual conditioning influences drinking in alcohol-paired environments and will inform treatment strategies that focus upon breaking these associations in an effort to reduce problematic drinking.
Blas Espinoza-Varas, Ph.D., University of Oklahoma Health Sciences Center, "Auditory-information conflict and alcohol-use disorder in the adolescent."
Research on the inhibition or activation of inappropriate behaviors prompted by conflicting verbal commands (i.e., auditory inhibitory control) is critically important in the prevention and treatment of alcohol-use disorders (AUD) in adolescents. In this age group, drinking alcohol is a behavioral self-control failure that occurs most often in settings in which the peer pressure is strong, and the psychosocial interaction is mainly through verbal communication; that is, through verbal commands that encourage or discourage the adolescent's choices and actions. Peer pressure, the main cause of adolescent AUD, exerts largely through verbal commands, and decisions to abstain or to drink alcohol depend heavily on auditory verbal information. Some teenagers can be "talked into" drinking alcohol with relative ease, but others desist under compelling verbal pressure, pointing to large individual differences in the ability to inhibit inappropriate behavior prompted by conflicting commands such as "have a drink" versus "just say no." In late adolescents, this project will assess AUD-risk effects on inhibitory control for conflicting information conveyed by verbal commands that are used habitually to control actions (e.g., "quit"). The voice tone and the speaking rate of these commands are critical task-relevant dimensions because they encode how strict or firm a command is. Thus, the experiments will assess classification of impeding (e.g., "quit") or instigating commands (e.g., "do it"), along the lenient/stern task-relevant dimension, and classification of speed up (e.g., "hurry") or slow down (e.g., "wait") commands along the slow/fast speaking-rate relevant dimension; in both cases, the conflicting task-irrelevant dimension is laterality or left/right ear presentation. This study is innovative because, in adolescents, there are no studies of AUD-risk effects on self-control for conflicting auditory information. The study could unveil basic mechanisms involved in the processing of conflicting auditory information, and help understand the transition from normal to disordered alcohol use.
Panagiota Kitsantas, Ph.D., George Mason University, "Determinants of alcohol reduction and cessation during pregnancy."
Despite widespread public health initiatives to inform women about the harmful effects of alcohol exposure on the developing fetus, recent estimates indicate that 12% of pregnant women aged 18-44 years report consuming alcohol during the past month and 3.1% report binge drinking. In order for public health officials, policymakers and clinicians to effect a positive change in current rates of alcohol use during pregnancy, the identification of subgroups of women most at-risk for alcohol consumption during pregnancy is necessary. Further, given the need for careful allocation of scarce health care resources for prevention and treatment programs, the identification of women most in need of support is critical. The proposed study will seek to identify and describe groups of women in the U.S. who are most at risk for alcohol use during pregnancy (reduction, no reduction, resumption, and cessation) using an innovative statistical approach (classification and regression trees) and the nationally-representative data set, Pregnancy Risk Assessment Monitoring System (PRAMS). The proposed study will add to current evidence by examining prenatal alcohol use within the context of a broader range of both individual risk factors (including psychosocial factors) and combinations of factors that have not been studied by previous research. Findings from this study will provide important information about subgroups of women most at-risk, a necessary first step for the design of intervention and prevention programs targeting pregnant women at risk of alcohol intake during pregnancy.
Ty W. Lostutter, Ph.D., University of Washington, "Alcohol's impact on academic success of OEF/OIF college students."
Educational success leads to many positive individual outcomes, including financial security, healthier lifestyle choices, and personal fulfillment later in life. Postsecondary education is beneficial to society as greater educational attainment is related to lower unemployment and poverty rates. The Post-9/11 Veterans Educational Assistance Act of 2008 (the 9/11 GI Bill) provides over 2 million veterans who served in Afghanistan (Operation Enduring Freedom, OEF) and Iraq (Operation Iraqi Freedom, OIF) with the opportunity to attain a college degree. While the 9/11 GI Bill gives OEF/OIF veterans access to educational benefits and many veterans are able to attend college without experiencing difficulties, other veterans will return from deployment with physical and psychological challenges that may impede their academic success. In particular, research suggests OEF/OIF veterans have high rates of alcohol use and psychiatric disorders that could potentially interfere with class attendance, decrease grades and tests scores, and/or could lead to withdrawal/dropout from college. Relatively little research has actually examined the relationship of alcohol use and psychiatric symptoms with academic success among OEF/OIF veterans. The current study will conduct a longitudinal web-survey comparing OEF/OIF veteran college students to a randomly-selected, stratified-matched sample of non-veteran college students on alcohol use, psychiatric symptom severity, coping, social support, and objective measures of academic performance. The project also aims to evaluate theoretical moderators (coping, social support, TBI status) and mediators (alcohol use, psychiatric symptom severity, study skills) of the relationship between OEF/OIF status and academic performance. The current proposal seeks to address this gap in the literature and inform future alcohol prevention/intervention efforts in this population.
Linda McEvoy, Ph.D., University of California, San Diego, "25-year trajectories of alcohol use and health in an older community cohort."
Individuals over the 65 years of age are the most rapidly growing segment of the population, yet few studies focus on alcohol use in the elderly. National surveys indicate that adults today drink more than they did in the past, and that a large proportion of elderly adults regularly consume alcohol. Physiological changes with age make older adults less tolerant of the effects of alcohol, and many older adults take medications that can interact adversely with alcohol. Thus if drinking patterns established in younger adulthood are maintained throughout late life, society may be faced with an increase in alcohol-related problems in the elderly as the baby-boom generation reaches late adulthood. We will examine whether and how alcohol use changes with age over a 25 year period among 1684 community-dwelling participants (mean age at baseline 69 years) of a longitudinal study of healthy aging, the Rancho Bernardo Study (RBS), initiated in 1972. We will examine whether men and women differ in patterns of drinking over time; whether changes in alcohol intake relate to changes in physical or mental health; and whether any relations observed between health and alcohol use differ between men and women. We expect to find that in healthy individuals, alcohol intake will remain stable with increasing age but that declining health status, as reflected in increased number of diagnosed chronic illnesses, will be associated with decreased or discontinued alcohol use. We also expect that increases in depressed mood will be associated with increased alcohol intake over time, indicating that depression is a risk factor for increased drinking among the elderly. Findings from this study will increase awareness of potential problematic drinking among the elderly and inform health campaigns aimed at reducing deleterious effects of drinking in the elderly.
Paola Pedrelli, Ph.D., Massachusetts General Hospital, "Toward developing a positive and negative reinforcement framework of binge drinking among college students."
Heavy alcohol use is prevalent among college students and binge drinking (BD) is associated with severe negative consequences such as motor vehicle accidents, suicide, poor classroom performance and increased risk to develop alcohol dependence or abuse later in life. Knowledge of mechanisms underlying BD is critical for the development of prevention strategies and treatment programs for this high-risk behavior. Reinforcement-based processes have been largely examined to explain alcohol consumption. Negative reinforcement processes are at the bases of drinking to cope, defined as the consumption of alcohol to avoid aversive negative states. Thus, low distress tolerance, defined as the ability to withstand distress, may be one mechanism explaining BD among college students. Positive reinforcement processes are at the bases of alcohol consumption for appetitive motives, namely to experience its rewarding effect. High sensitivity to rewards (SR) and to the rewarding qualities of alcohol (ASR) are associated with higher alcohol use, and enhancement motives, and thus may also explain BD in college students. Among BD college students, a model including both positive and negative reinforcement processes has not yet been examined with multi-methods approach, including laboratory-based instruments as well as self-report questionnaires. Similarly, the influence of positive and negative reinforcement processes on alcohol-related problems is unclear. The proposed study will use a multitrait-multimethod framework to investigate distress tolerance and coping motives, consistent with a negative reinforcement paradigm, and sensitivity to rewards and enhancement motives, corresponding to a positive reinforcement paradigm, among 51 BD college students relative to 51 matched Non-Binge drinking peers (NBD). Finally, we will examine the association of alcohol-related problems and distress tolerance, coping motives, sensitivity to rewards and enhancement motives. Results of the proposed project will provide critical information that will guide prevention strategies and treatment development for BD behaviors.
Linda Skaal, Ph.D., University of Limpopo, "Screening and brief intervention for alcohol problems in HIV outpatients in PHC settings: A single-blinded randomized controlled trial."
Both alcohol dependence and HIV infection are major problems in South Africa. Prior studies showed that these problems are closely related and that the consequences for individuals with HIV infection who use alcohol are negative in a broad spectrum, including increased sexual risk behavior, psychosocial and adherence problems. Therefore there is a need for action to reduce alcohol use among patients diagnosed with HIV. In this trial a brief intervention for alcohol problems among outpatients diagnosed with HIV in clinics in Ga-Rankuwa in South Africa will be evaluated. Five hundred fifty two patients with moderate alcohol use will be included in the study. These patients will be randomized in which one group will receive a brief intervention session aimed at reducing alcohol use. The intervention is based on the World Health Organization's brief intervention package for hazardous and harmful drinking. The other group will only receive a health leaflet. Patients will be followed up at three and 12 months. The objectives of this trial will be to assess the prevalence of alcohol use among HIV positive patients at baseline and to compare the two groups regarding drinking patterns, health status, quality of life, sexual behavior and level of adherence to antiretroviral therapy at three months and 12 months after the inclusion in the study. If the intervention proves to be successful in reducing alcohol use among HIV positive patients, the intervention could be incorporated in the standard care guidelines for HIV treatment.
Elena Stepanova, Ph.D., University of Missouri, Columbia, "Effects of exposure to alcohol-related cues on prejudice, stereotyping and discrimination."
This research will investigate the extent to which the mere presence of alcohol-related stimuli in the environment affects the expression of bias and discrimination against racial minorities. Previous research has shown that drinking alcohol increases the expression of bias, but the possibility that merely seeing alcohol-related cues (such as advertisements for alcohol) could affect racial bias has wide-ranging implications for public health and policy. Three major goals of this work are to determine: (1) whether brief exposure to alcohol-related cues affects attitudes, stereotypes, and discrimination towards Blacks; (2) the underlying mechanisms of these effects, that is, how brief exposure to alcohol-related cues affects racial biases (for example, by increasing automatic activation of racial attitudes; by decreasing inhibition of race-based responses; by activation of general negative evaluations); and (3) factors moderating these effects, such as motivation to control prejudice, explicit racial attitudes and the strength of pre-existing alcohol-related expectancies. In a series of five experiments, participants will be primed with alcohol-related cues or neutral cues, and their affective, cognitive and behavioral responses related to racial biases will be measured. The most important implication of this research is that consumption, or even purported consumption of alcohol might not be necessary for alcohol to increase expression of racial biases. This work would suggest that people could be more likely to act upon their prejudices simply for having entered a bar, watched an alcohol advertisement, or passed a billboard on the freeway. Such findings will have important implications for social engineering campaigns designed to limit the likelihood of alcohol-related harm, going beyond considerations of limiting consumption. Identifying the mechanism by which these effects occur will help design intervention techniques for reduction of bias.
Ryan Trim, Ph.D., University of California, San Diego, "Desistance from alcohol-use disorders and problems in adulthood."
Prior research has shown that individual characteristics, including a family history of alcoholism and the genetically-influenced low level of response (or low sensitivity) to alcohol, increase the risk for developing alcohol-related problems and alcohol-use disorders (AUDs) over time. Many people who report problematic drinking early in life recover from alcohol-related problems and disorders as they progress through adulthood. However, some high-risk individuals will continue to drink at high levels consistent with chronic alcohol dependence across their lifetime. Less is known about which factors (measured both early in life and across adulthood) may promote recovery, or failure to recover, from alcohol-related problems in adulthood. The current study proposes to examine longitudinal data from more than 400 men enrolled in the San Diego Prospective Study and studied for over 30 years (from age 20 to age 50) to identify characteristics that impact the recovery from alcohol-use disorders and problems. First, predictors of recovery will be examined for those subjects who reported alcohol-related problems or AUDs at ~age 30. We hypothesize that having no family history of alcoholism and a higher sensitivity to alcohol, as well as a late onset of drinking, will be associated with earlier recovery from AUDs and problems. In addition, we will test for time-specific effects of characteristics measured throughout adulthood (such as treatment, peer support, and social roles), on the recovery from AUDs and alcohol problems. Second, we will utilize data on all participants to identify common patterns of drinking throughout adulthood, as well as determine what characteristics are associated with transitioning into a lower-risk drinking pattern. Findings from the current study will provide a better understanding of how and when individual characteristics impact recovery from alcohol problems and AUDs in adulthood.
Medical Advisory Council
Anita Bechtholt-Gompf, Ph.D., Harvard Medical School-McLean Hospital, "Kappa-opioid mechanisms in escalating ethanol intake and acute withdrawal-induced anxiety."
Alcoholism is a chronic relapsing disorder that involves drinking larger and larger amounts of alcohol. It is thought that opioids that are found naturally in the body play an important role in the rewarding value of alcohol because drugs that non-selectively interfere with all opioids improve outcomes in alcoholics and reduce alcohol intake in animals. Much effort has gone into determining the specific role of different types of opioid receptors in the efficacy of drugs that non-selectively interfere with all opioids, and this work has resulted in substantial data suggesting a critical involvement of mu- and delta-opioid receptors. However, recent evidence points to a potential influence of the kappa-opioid receptor in alcohol reward, but the data are divergent with findings supporting that kappa-opioid receptor activation can contribute to or diminish alcohol reward. This inconsistency might be resolved if the state of the animal relative to alcohol exposure, withdrawal, and anxiety were carefully considered. Repeated cycles of alcohol exposure and withdrawal are associated with increased withdrawal severity, alcohol intake and anxiety. Since kappa-opioid receptors are expressed in key brain areas involved in alcohol reward and anxiety and their activation is associated with anxiety and aversive states, our guiding hypothesis is that kappa-opioid receptor activation is involved in increasing alcohol intake and acute alcohol withdrawal (hangover) induced anxiety. These experiments have the potential to inform the development of new drug treatments by providing insight about the role of kappa-opioid receptor activation in specific brain areas in the transition to alcohol abuse and alcohol withdrawal induced anxiety.
Kirsty Donald, Ph.D., University of Cape Town, "Alcohol and methamphetamine exposure: Imaging and neurobehavioral correlates."
Prenatal exposure to alcohol and stimulants may negatively affect the developing brain with long term effects on development and behaviour. As drugs of abuse become more readily available and affordable, the problem of polysubstance abuse has become increasingly significant. South Africa has a high prevalence of alcohol abuse and associated fetal alcohol spectrum disorders. Researchers have largely relied on animal models in the past to study the effects of drugs of abuse on brain development. However advances in neuroimaging methods over the last decade have allowed researchers to study structural, metabolic, and functional abnormalities resulting from prenatal exposure to drugs of abuse in infants. Both basic and clinical research have begun to implicate a number of neurotransmitter and neuroendocrine systems as underlying the association between maternal alcohol, methamphetamine and polysubstance abuse and subsequent negative behavioural outcomes in offspring. In particular, the glutamatergic system, the most widespread excitatory neurotransmitter system in the brain, appears to be disrupted in offspring of rodent mothers exposed to stress. There has been relatively little work, however, on the glutamatergic system during early life in humans. Magnetic resonance spectroscopy (MRS) allows an assessment of both neuronal integrity, and of particular neurotransmitter concentrations (such as glutamate/glutamine). This study aims to assess the effects of maternal alcohol and methamphetamine use on infant neuronal integrity and glutamatergic function, as assessed by magnetic resonance spectroscopy and correlate with early neurobehavioural measures. This research aims to advance understanding of the relevant mechanisms resulting in the neurological effects of alcohol and stimulant exposure, as this may ultimately drive therapeutic approaches.
Nirelia Idrus, Ph.D., San Diego State University, "Fetal alcohol effects and vitamin D."
Despite preventative measures, some women continue to drink alcohol while pregnant. The range of effects that result from developmental alcohol exposure include cell loss, hyperactivity and problems with learning and memory, and is referred to as fetal alcohol spectrum disorders (FASD). One percent of the U.S. population is thought to be affected, with 40,000 new FASD cases estimated each year; the estimated lifetime cost of one child with FASD being $1-2 million. It is therefore important that we identify effective interventions that can reduce the severity of FASD. One potential intervention is vitamin D. Alcohol exposure can decrease vitamin D levels in both humans and animals, including pregnant females, indicating that alcohol-induced vitamin D deficiencies may contribute to FASD. Vitamin D deficiency also disrupts development in a manner remarkably similar to those seen with developmental alcohol exposure. However, even in the absence of a deficiency, vitamin D has neuroprotective properties and can promote brain development. I will be examining whether vitamin D can mitigate alcohol-related neuropathology and behavioral alterations using a rat model of FASD. Vitamin D will be given prior to, during, and after 3rd trimester equivalent alcohol exposure and then subjects will be run through a battery of tasks that test behavioral functioning. Cell numbers in key brain regions will be estimated to determine whether vitamin D is neuroprotective. Preliminary results indicate that vitamin D reduces hyperactivity, motor and cognitive deficits associated with developmental alcohol exposure. These data will provide important information on a potential treatment for FASD.
Inna Kruman, Ph.D., Texas Tech University Health Sciences Center, "Alcohol-induced neurotoxicity and one-carbon metabolism."
Nearly 100 million people worldwide have alcohol use disorders, yet the fundamental mechanisms underlying alcohol-mediated brain damage remain poorly understood. Increased homocysteine levels is common in most alcoholics and at the same time, is a risk factor for various neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Homocysteine is part of normal metabolism involved in vital cellular functions and its increase is associated with impairment of normal metabolism and disturbance of cellular functions, including biosynthesis of DNA precursors, essential for DNA repair. Defects in DNA repair lead to the accumulation of DNA damage, genome instability and cell death. A mild deficiency in methylenetetrahydrofolate reductase (MTHFR) induced by inherited polymorphisms of corresponding gene, involved in homocysteine metabolism is common in human population (10-15% in Caucasians). The mild MTHFR deficiency may be influenced by ethanol exposure, creating an additional risk factor for ethanol-induced neurotoxicity. Using a mouse model of MTHFR deficiency, this proposal explores how the impairment of homocysteine metabolism contributes to alcohol-induced neurotoxicity. We, therefore, will determine the impact of MTHFR deficiency on alcohol-induced brain damage. The proposed studies offer a new concept for understanding the mechanisms of alcohol-related pathological changes in the brain based on the key role of genome instability conveyed by the impairment of homocysteine metabolism. These studies will help to develop new therapies for preventing its adverse effects.
Anna Lee, Ph.D., Ernest Gallo Clinic and Research Center, "PKC epsilon regulation of nicotinic acetylcholine receptors is a novel mechanism in co-morbid alcohol and nicotine addiction."
Alcohol and nicotine addiction often occur together, and currently there are no drugs available that simultaneously treat both addictions. Although genetic screening has identified common genes in both addictions, the molecular pathways that contribute to both addictions are unclear. It has been seen that protein kinase C epsilon (PKCε) is part of a common molecular pathway that underlies both alcohol and nicotine addiction. Mice lacking PKCε (PKCε knockout mice) do not consume as much alcohol or nicotine as normal mice do, and show less reward from alcohol and nicotine administration compared with normal mice. The PKCε knockout mice have decreased levels of a6 and b3 nicotinic acetylcholine receptor subunit mRNA in the ventral striatum, a key brain region involved in addiction and reward signaling. We hypothesize that PKCε regulates the function of these nicotinic receptors in the striatum, which modulates reward signaling leading to alcohol and nicotine addiction. In this project, we will test if directly reducing PKCε expression in the striatum can decrease alcohol consumption in wild type mice. We will also test if inhibiting a6 containing nicotinic receptors in the striatum can reduce the rewarding effects of alcohol in wild type mice. These studies will help better understand why alcohol and nicotine addiction occur together so frequently, and help identify new targets for the development of new drug therapies.
Yongke Lu, Ph.D., Mount Sinai School of Medicine, "Ethanol induction of CYP2A5 and its toxicological significance."
Alcohol abuse is a significant global health problem. Every year, vast amounts of money and health care provisions are provided for patients with diseases related to alcohol abuse. Alcohol-induced liver injury is a leading cause of death worldwide. Many liver toxic effects of ethanol have been linked to its metabolism by various enzymes in the liver. In human liver, an enzyme called CYP2A6 is increased in patients with alcoholic liver diseases. But it is still unclear whether CYP2A6 plays a role in the development of alcoholic liver disease. Recently, we found that in mouse liver an enzyme called CYP2A5, which is similar to human CY2A6 and has same functions, can also be induced by chronic ethanol feeding. The mouse model will be used in this study. Alcohol and tobacco are frequently co-abused. Nicotine is inactivated to cotinine primarily by mouse CYP2A5 and human CYP2A6, and ethanol induction of nicotine oxidizing enzyme may have an impact on smoking behaviors. In addition, CYP2A5/6 also metabolizes and activates carcinogens such as aflatoxin B1, N-nitrosodiethylamine, and NNK to cause cancers. Therefore, to disclose the regulatory mechanisms of CYP2A5 induction by ethanol will be of toxicological significance. In this study, we will investigate how CYP2A5 is induced by ethanol. In addition, the CYP2A5 induction by ethanol was not observed in mice that don't express another important enzyme called CYP2E1, but when human CYP2E1 was introduced to these mice, the ethanol induction of CYP2A5 was restored. These results suggest that CYP2A5 induction by ethanol is CYP2E1 dependent. CYP2E1 is considered one of the causes of alcoholic liver disease. Therefore, we will also investigate whether CYP2E1 promotes alcoholic liver injury through CYP2A5. The proposed experiments will provide new mechanisms by which ethanol caused toxic effects and identify targets for therapeutic intervention.
Chitra D. Mandyam, Ph.D., University of California, San Diego, "Alcohol dependence inhibits medial prefrontal cortex gliogenesis."
The medial prefrontal cortex (mPFC) is one of the key brain regions implicated in reinforcing effects of alcohol and reinstatement of alcohol-seeking behaviors. New emerging evidence from our laboratory demonstrates that mPFC progenitors (progeny of stem cells that are characterized by limited self-renewal and can survive and mature into differentiating cells, such as glia) are involved in certain aspects of alcohol addiction, as behavioral tasks such as excessive drinking during chronic intermittent ethanol vapor exposure (CIE) inhibits the proliferation and reduces the survival of mPFC progenitors. The mechanisms underlying CIE-induced inhibition of proliferation of mPFC progenitors are unknown. The goal of this proposal is to investigate CIE-induced effects on cell cycle dynamics of mPFC progenitors and the components of gliogenic niche during alcohol dependence. Two specific aims will address the hypothesis that CIE alters specific components of the cell cycle of mPFC progenitors during alcohol dependence. The results will provide new information regarding the role of adult-generated glia in the mPFC in alcohol dependence.
Michelle Mellion, M.D., Rhode Island Hospital, "A pilot study on small fiber neuropathy in Alcohol Related Peripheral Neuropathy (ALN): Establishment of skin biopsy as a biomarker for diagnosis and determination of the pathogenesis of ALN."
Alcohol can affect the nerves in your body. The affect of alcohol on the nerves in your arms and legs can cause sensory changes such as pain, burning, pins and needles, weakness, and occasionally problems with the bladder and bowels; a disease called alcohol related peripheral neuropathy (ALN). This disease can lead to serious injuries and cause permanent disability. Nerve biopsies have traditionally been used to evaluate the effect of alcohol on nerve tissue. This procedure is invasive and can have complications such as sensory loss. Skin biopsies may be an alternative, minimally invasive method that is associated with little complications with which to measure the effect of alcohol on peripheral nerves. The purpose of this study is to establish that skin biopsy is a useful method to detect the effect of alcohol on peripheral nerves and to begin to understand the process by which alcohol affects peripheral nerves. This information could possibly provide information for better and more effective treatments of this debilitating disease. Eleven patients with no alcohol history and eleven patients who fulfill the diagnosis of alcohol dependence and who have participated in heavy drinking over the past year will be enrolled in this study. They will have a one-time visit with the research team. They will be evaluated for other causes of neuropathy with blood tests and nutritional assessment. A focused neurological examination and nerve conduction studies will assess for the severity of their neuropathy. Skin biopsies will be taken from the right lower leg and upper thigh. The number of nerve fibers in the skin and any abnormalities of the nerves in the skin will be analyzed. The results will be compared to assess if there is a difference between the two groups.
Igor Ponomarev, Ph.D., University of Texas at Austin-Waggoner Center for Alcohol and Addiction Research, "Molecular mechanisms of accumbal plasticity in a mouse model of excessive alcohol consumption."
Excessive alcohol drinking is a prerequisite for the development of alcohol dependence and alcoholism. To understand how controlled alcohol consumption transitions into alcohol abuse and alcohol dependence we need to study brain functions affected by high alcohol intake. The study will investigate molecular mechanisms of alcohol's effects on the brain and focus on two populations of neurons that play important roles in regulation of alcohol drinking. We will measure expression of multiple genes in these neurons using a mouse model of binge drinking and identify those genes regulated by high alcohol consumption. We hypothesize that these alcohol-responsive genes are important for cellular adaptation to alcohol and the transition to uncontrolled drinking. This knowledge may be used to develop drugs for treatment of alcoholism.
Sanjoy Roychowdhury, Ph.D., Cleveland Clinic, "RIP3-mediated necroptosis and ethanol-induced liver injury."
Excessive alcohol consumption leads to liver damage. There is no straightforward treatment available to date. Liver transplantation is the only possible option for the patient suffering from alcohol-induced liver damage. The project will help us to better understand the cause of alcoholic liver damage, as well as identify new therapeutic targets for prevention of alcoholic liver damage.
Bernd Schnabl, M.D., University of California, San Diego, "Analysis of the enteric microbiome associated with alcoholic liver disease."
Alcoholic liver disease affects several million people in the United States, and alcohol abuse is the most important cause of liver cirrhosis in industrialized countries. Gut-derived bacterial products are necessary for progression of alcoholic liver disease, but the exact mechanisms of intestinal bacterial overgrowth and translocation are poorly understood. Understanding the mechanisms by which alcohol results in intestinal bacterial overgrowth and promotes bacterial translocation by increasing intestinal permeability would greatly enhance our ability to design preventive and therapeutic interventions for patients with chronic alcohol abuse. We therefore will investigate the contribution of microbial and host factors to alcohol-induced liver disease.
Jun Xu, M.D., Ph.D., Keck School of Medicine of the University of Southern California, "Notch signaling in synergistic steatohepatitis induced by obesity and alcohol."
In the United States, about 7.5% of adults meet the DSM IV criteria of alcohol abuse and about 64% of adults are overweight or obese. Chronic alcohol drinking and obesity are two most common life-style causes of steatohepatitis (fat accumulation and inflammation in liver). Overweight or obese alcohol drinkers have two to four times higher risk of steatohepatitis than those with normal body weights. In patients of liver disease, 44% of all deaths are attributed to alcohol drinking. Thus, steatohepatitis caused by obesity and alcohol represents one of the most important public health issues. This proposal is to study how alcohol drinking in overweight/obese individuals aggravates liver damage. To do this, we have fed alcohol to obese mice (a synergism mouse model) and these mice develop severer steatohepatitis than regular mice, regular mice fed with alcohol, or obese mice without alcohol feeding. In this mouse model, the steatohepatitis is associated with increased numbers of macrophage cells in the liver. We find these macrophages (HM) having pro-inflammatory characteristics as evident by increased Nos2 gene expression, which is dependent on cellular Notch signaling because blocking Notch signaling with a chemical inhibitor DAPT abrogates the Nos2 induction. These results suggest a pivotal role of Notch in pro-inflammatory HM activation, Nos2 gene upregulation, and consequent aggravation of steatohepatitis in our model. We also find that glucose metabolism, especially in mitochondria is critical for HM activation, which provides novel evidence linking metabolism to gene expression and cell function. Based on these results, we propose to study the role of Notch in HM activation and in aggravation of steatohepatitis induced by obesity and alcohol, and to determine how glucose metabolism regulate HM activation and Nos2 expression using a metabolomic approach. This study may lead to novel findings that provide preventive and therapeutic targets for steatohepatitis.
Please refer to the links below for grants project profiles from previous years: