Finding genes for alcohol-related behaviors and risk for alcoholism.

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) solicits research proposals to identify and characterize genes that contribute to individual susceptibility to alcoholism and alcohol-related behaviors. This PA encourages multidisciplinary studies using advanced genetic and genomics technologies to find and characterize candidate genes in humans and animal models.

Genetic linkage and association studies have identified many chromosomal regions and quantitative trait loci (QTL) associated with complex phenotypes related to alcohol induced behaviors and/or alcoholism. However, the large number of genes residing in those previously identified chromosomal regions/QTLs remain undefined, due to the lack of power and sensitivity of previously available methodology and technology. The completion of the sequences of the human and mouse genomes, and the development of new genomics technologies, have the potential for rapidly advancing the discovery of genes associated with alcoholism and alcohol-related behaviors.

NIAAA seeks research applications that will explore and develop innovative computational, statistical, and molecular approaches to increase the power of gene discovery. Areas of emphasis include utilizing advanced technologies such as high-throughput SNP genotyping, haplotype pattern mining, admixture linkage disequilbrium mapping, and DNA pooling for fine mapping. Currently, haplotype maps for both human and mouse genomes are being developed and these maps will provide an additional resource for finding genes. Once fine mapping has further characterized a previously identified QTL or chromosomal region, candidate nucleotide variants within the locus can be identified. Some methods that could be used for fine mapping include high-throughput sequencing, RAGE, SAGE, DNA microarrays, protein arrays, and other high-throughput approaches.

Many genes are predicted to reside within a QTL, and multiple polymorphisms are likely to be located in both coding and regulatory regions. Functional tests of candidate genes are needed to determine if the polymorphism(s) or genetic variants are relevant to the alcohol-induced trait. These tests may include the development of transgenic animals, such as BAC and YAC transgenics carrying chromosomal regions that contain large regulatory sequences.

This PA specifically seeks applications that propose human or animal studies to identify and characterize genes associated with alcoholism and alcohol-related behaviors. Behaviors include alcohol consumption, tolerance/dependence, sensitivity/sedation, withdrawal, reinforcement, craving, and relapse. Genes identified may be used to develop markers for alcohol vulnerability and dependence. In addition, these genes may also be used to identify potential therapeutic targets and to predict individual responses to medications that treat alcoholism. Examples of research areas appropriate to this announcement include, but are not limited to: 1) identification and characterization of genes associated with alcoholism and alcohol-related behaviors in the chromosomal regions previously identified in humans or animal models; 2) identification of genetic variants (SNPs/haplotpes) of associated with alcoholism and alcohol-related behaviors among the different populations, which will have high potential as targets for developing pharmacotherapeutic agents; 3) discovery of new genes associated with alcoholism and alcohol-related behaviors and determination of functional relevance of the candidate genes and their polymorphic variants.

This PA will use the NIH R01 and Exploratory/Developmental Research Grant (R21) award mechanisms (see http://grants.nih. gov/grants/guide/pa-files/PA-03-107.html).

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 to $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.govl 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, 301-435-0714, email: [e-mail].

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.

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: Lisa A. Neuhold, Program Director for Genetics, 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], email: Lneuhold@ willco.niaaa.nih.gov; Zhaoxia Ren, Program Director for Human Genetics, Genetics and Proteomics Research Branch, Division of Basic Research, NIAAA, 6000 Executive Blvd, Suite 402, MSC 7003, Bethesda, MD 20892-7003 USA, 301-443-5733, fax: [phone], email: [e-mail]; Q. Max Guo, Program Director, Genetics and Proteomics Research Branch, Division of Basic Research, National Institute on Alcohol Abuse and Alcoholism, 6000 Executive Blvd, Suite 402, MSC 7003, Bethesda, MD 20892-7003 USA, 301-443-0639, fax: [phone], email: [e-mail]. Reference: PA No. PA-03-162