Gene-environment interactions influencing alcohol-related phenotypes and diseases.

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is seeking research grant applications on the role of gene-environment interactions underlying susceptibility to alcohol-related phenotypes including alcohol dependence, relapse, withdrawal; alcohol-induced organ damage including neurodegeneration, cirrhosis and other liver diseases, pancreatitis, cardiomyopathy, immune disorders, cancers, and alcohol-induced birth defects. This solicitation specifically encourages multidisciplinary approaches to study how environmental conditions, such as chemical, infectious, physical, nutritional, and social behavioral factors, impact genetic predisposition to alcohol-related diseases. Identification and characterization of gene-environment interactions will offer better opportunities to effectively target prevention, intervention and treatment strategies. The National Institute of Environmental Health Sciences (NIEHS) is collaborating on this PA and is seeking research grant applications on interactions between alcohol effects and environmental agents.

Alcoholism and alcohol-related diseases are the result of complex interactions of multiple genetic and environmental factors. Several genetic factors have been associated with alcohol-related behaviors, alcohol-induced birth defects, and alcohol-induced organ damage; however, the role of environmental factors in modifying the risk of developing alcohol abuse, alcoholism, and/or organ damage remains undefined.

Genetic factors leading to differential risk for alcoholism were demonstrated using twin and family studies. In addition, functional polymorphisms of alcohol dehydrogenase (ADH2) and aldehyde dehydrogenase (ALDH2) genes have been shown to have a significant impact on alcohol metabolism in the liver, and thus, may contribute to vulnerability to alcohol abuse and dependence, alcohol-related liver diseases and cancers.

Genetic and environmental interactions modulate an individual's susceptibility to certain diseases/disorders. For example, male children who have a polymorphism in the monoamine oxidase A gene conferring low enzyme activity show non aggressive behavior when raised in a non-abusive environment. However, male children with the same polymorphism show aggressive and antisocial behavior when raised in an abusive environment. Males with normal enzyme activity do not become violent offenders when raised in the same abusive/maltreated environment. Similar results have been found in animals. For example, mice lacking a functional corticotroping-releasing hormone 1 receptor do not differ from wild-type mice in alcohol intake under stress-free conditions; however, after repeated stress, the knockout mice increase their alcohol consumption. Also, monkeys with a polymorphism in the regulatory region of the serotonin transporter gene show no differences from the wild-type monkeys when reared with their mothers. However, monkeys with the polymorphism that were nursery raised have attention and orientation deficits.

The dynamic multi-level interactions between genetic and environmental components are responsible for the heterogeneity and complexity of alcohol dependence phenotypes. Therefore, it is necessary to use multi-disciplinary approaches to decipher the underlying mechanisms for alcohol abuse, alcohol dependence and alcohol related disorders. Comprehensive designs and methodologies for both human and animal studies of gene-environment interactions are of crucial importance to identify alcohol-related genes and environmental factors, and their interrelationships. Human studies using informative populations such as twins, multi-generation families and migrants, as well as children at high risk or low risk to develop alcohol dependence can provide unique opportunities and advantages to study neurobiological and behavioral consequences of gene-environment interaction. In addition, animal models can be used to study gene-environment interactions requiring genetic and environmental manipulations that are impractical or ethically impossible in humans. Controlled genotypes can be devised in genetically modified or chemical-induced mutant animals. Therefore, animal models can also offer unique opportunities to explore the role of gene-environment interactions as the means of understanding the pathways to alcohol-induced diseases.

There are several approaches for analyzing the effects of environmental factors in experimental animals, including differential gene expression using cDNA microarrays, RAGE, and SAGE; as well as proteomic methods to determine changes in protein levels and protein modifications. The rote of genes implicated in the response may be further studied by developing transgenic and gene-targeted animals, as well as, by using other gene expression strategies including RNA interference (RNAi) and retroviral-mediated gene transfer techniques.

Epigenetic changes are known to be involved in the etiology of a large number of diseases such as schizophrenia, cancer, and alcohol dependence. Recent evidence shows that there is an association between the GABAA receptors and alcohol dependence that is modulated by genetic imprinting. There are numerous types of epigenetic modifications on both DNA and nucleosomes, including methylation and acetylation, which could affect the expression and regulation of alcohol-related genes. NIAAA seeks proposals that will examine environmental factors that alter the epigenetic status of genes that may affect gene expression leading to alcohol-induced diseases.

The purpose of this PA is to encourage multidisciplinary research that will investigate gene-environment interactions influencing susceptibility to alcohol abuse and dependence, alcohol-related behaviors, and alcohol-induced organ damage in both animals and humans. NIAAA seeks research projects that include, but are not limited to:

1) studies of changes in gene or protein expression by investigating animal models such as knock-out and other genetically modified animals under a variety of environmental conditions to identify candidate genes, or their corresponding proteins, that may be associated with susceptibility to alcohol abuse and dependence, relapse, withdrawal, alcohol-induced organ damage including neurodegeneration, cirrhosis and other liver diseases, pancreatitis, cardiomyopathy, immune disorders, cancers, and alcohol-induced birth defects; 2) studies to identify allelic variants (polymorphisms) and determine the functional relevance of an identified gene or protein for increasing or decreasing susceptibility to alcohol abuse and dependence, alcohol-related phenotypes, and other alcohol-induced diseases under different environmental conditions; 3) studies using genetic epidemiological, psychiatric and behavioral genetic and molecular genetic methods to determine the interaction of genetic, biological, and social factors in the development of risk to alcohol abuse and dependence; 4) studies to develop and/or utilize statistical modeling approaches to identify the contributions of genetic and environmental factors to the individual risk, their interrelationship and their developmental trajectories; 5) studies to determine the genetic and environmental risk and protective factors that influence individual drinking behaviors including children and adolescent underage drinking across populations, socio-cultural, backgrounds, and environmental exposures; 6) studies to determine the environmental factors that alter the epigenetic status of genes, thus increasing vulnerability to alcohol abuse and dependence, alcohol-associated behaviors, and alcohol-induced organ damage; 7) studies to determine the functional relevance of candidate genomic markers associated with an increased susceptibility to alcohol abuse and dependence, alcohol-related phenotypes, and alcohol-associated medical conditions; 8) studies to identify potential links between alcohol exposure and expression of functional polymorphisms of neurotransmitters and their receptors under various environmental conditions such as stress and cross-fostering, to understand the development of excessive drinking behaviors; 9) studies to determine how genetic variations between individuals and among various populations impact on how environmental influences may differentially alter alcohol metabolism.

NIEHS seeks research grant applications in which the goals are to determine gene-environment effects on disease susceptibility in response to specific exposures or which involve Environmentally Responsive Genes, for example, as defined in the Environmental Genome Project (http://egp.gs.washington.edu/). NIEHS seeks applications that focus primarily on exposure to environmental agents and in which attention to alcohol abuse is secondary or minor.

This PA will use the NIH R01 and Exploratory/Developmental Research Grant (R21) award mechanisms. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. Applications using the R21 mechanism may request a project period of up to two years with a combined budget for direct costs of up $275,000 for the two year period. For example, the applicant may request $100,000 in the first year and $175,000 in the second year. The request should be tailored to the needs of the project. Normally, no more than $200,000 may be requested in any single year.

This PA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/ funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Otherwise follow the instructions for non-modular research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/ policy/nihgps_2001/part_i_1.htm. Exploratory/ developmental grant support is for new projects only; competing continuation applications will not be accepted. Two revisions of a previously reviewed exploratory/developmental grant application may be submitted as defined in NIH Policy at http://grants.nih.gov/grants/policy/ amendedapps.htm.

Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/ phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone [phone], Email: [e-mail].

Application Receipt Dates: Applications submitted in response to this PA will be accepted at the standard application deadlines, which are available at http://grants.nih.gov/grants/ dates.htm. Application deadlines are also indicated in the PHS 398 application kit.

Application Processing: Applications must be mailed on or before the receipt dates described at http://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR will not accept any application in response to this PA that is essentially the same as one currently pending initial review unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique.

Contact: Zhaoxia Ren, Program Director, Genetics and Proteomics Research Branch, Division of Basic Research, NIAAA, 6000 Executive Boulevard, Suite 402, MSC 7003, Bethesda, MD 20892-7003 USA, 301-443-5733, fax: [phone], e-mail: [e-mail]; Lisa A. Neuhold, Program Director, Genetics and Proteomics Research Branch, Division of Basic Research, NIAAA, 6000 Executive Boulevard, Suite 402, MSC 7003, Bethesda, MD 20892-7003 USA, 301-594-6228, fax: [phone], e-mail: [e-mail]; Ellen Witt, Program Director, Neuroscience and Behavior Research Branch, Division of Basic Research, NIAAA, Willco Bldg, Suite 402, 6000 Executive Bird, MSC 7003, Bethesda, MD 20892-7003 USA, 301- 44345545, fax: [phone], e-mail: [e-mail]; Vivian B. Faden, Chief, Epidemiology Branch, Division of Biometry and Epidemiology, NIAAA, 6000 Executive Boulevard, Suite 402, MSC 7003, Bethesda, MD 20892-7003 USA, 301-592-6232, fax: [phone], e-mail: [e-mail]; Leslie Reinlib, Scientific Program Administrator, Susceptibility and Population Health Branch, Division of Extramural Research and Training, NIEHS, PO Box 12233, MD-EC-21, Research Triangle Park, NC 27711-0001 USA, 919-541-4998, fax: [phone], e-mail: [e-mail]. Reference: PA No. PA-03-141