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Pharmacogenetics research network and knowledge base.

The purpose of this RFA is to solicit applications for an open re-competition of the Pharmacogenetics Research Network and Knowledge Base ( This is a network of multidisciplinary, collaborative groups of investigators that contribute their data to the publicly available knowledge base PharmGKB, which is an open research tool accessible to all scientists.

The research groups in the network have interests across a range of biological processes: drug metabolism, small molecule transport, target receptors, and biological pathways involved in the drug treatment of cardiovascular diseases, asthma, cancer, and depression; other areas are welcome consistent with the interests of the funding institutes. The groups are collecting comprehensive, integrative information about specific proteins and gene families important to the field of pharmacogenetics. Some groups are using a genotype-to-phenotype approach starting with the detection of all possible variants, while other groups are employing a phenotype-to-genotype approach beginning with well-characterized clinical samples. All investigations are converging on the association of single nucleotide polymorphisms (SNPs) and haplotypes with drug responses. The results are confirmed by studies of the mechanistic and clinical consequences of the molecular changes, The database groups in the network are working towards the goal of creating a centralized public knowledge base, PharmGKB ( is designed to categorize four types of phenotype information--functional assays, pharmacokinetics, pharmacodynamics, and clinical outcomes--correlated with genotype information. The knowledge base uses standardized drug, disease, and generic vocabularies and is linked to existing databases.

The plans are to continue funding this network as a series of cooperative groups conducting studies to address a wide variety of common research problems in pharmacogenetics. This initiative will further emphasize development of the PharmGKB knowledge base; it is envisioned as an information resource that will be useful to the entire pharmacogenetics research community to enable future hypothesis-driven research. This competition is open to both new and renewal research and database groups.

Pharmacogenetics can be defined as the influence of human genetic variation on drug responses. It has long been known from family studies that variations found in enzymes of drug clearance have profound effects on the efficacy and duration of drug action, sometimes with significant adverse consequences. Genetic variations in drug metabolizing enzymes can lead to the excessive build-up of a drug with a narrow therapeutic index (e.g., thiopurine methyl-transferase and 6-mercaptopurine), or the lack of a therapeutic effect where metabolic activation is required (e.g., cytochrome P450 2D6 and codeine), Likewise, studies have shown that variations in target receptors can lead to a lack of beneficial effects of a drug, for example by increased desensitization (e.g., beta-2 adrenoreceptor and albuterol).

Another mechanism impacting drug efficacy is altered binding kinetics (e.g., serotonin 1B receptors and fluoxetine). Recent studies have shown that genetic variants can be linked to the susceptibility and progression of disease as well as to a response to a drug treatment (e.g., cholesterol ester transfer protein, atherosclerosis, and statins; or apolipoprotein E, Alzheimer's disease, and tacrine). There are multiple genetic mechanisms, including alterations in transcript stability, splice sites, or promotor binding regions, all of which can alter expression levels. The impact of these changes on functional protein levels such as reduced amounts or stability, or compromised enzymatic function, requires further study, Furthermore, how this fits into protein-protein interactions (e.g., coupling to second messengers) and biological pathways (e.g., redundant, competing, or complementary routes of clearance or signaling) needs to be understood in order to predict clinical consequences.

With advances in genomic technology, large-scale accumulation of information on drug pathways (sometimes called pharmacogenomics) is possible. These profiling studies can be DNA-based, transcript-based, or protein-based. Both pharmacogenetics and pharmacogenomics studies are of interest under this solicitation. It is essential to completely understand the significance of genetic variation at the molecular level, and the implications of the diverse genetic contexts present in different human populations. The incidence of SNPs (singly and in combinations of haplotypes) and gene duplication or deletion events must be interpreted correctly to associate genetic variation with the prediction of drug effects, and this may require development of new analytical tools. Population-based studies that examine the interactions between genetic predisposition for disease and the generic factors determining medication responses are also of interest for this initiative.

Ultimately, both a mechanistic understanding and robust statistical validation of putative pharmacogenetics effects are sought, and the translation in clinical impact is highly desirable, The goal of the field is to be able to predict the effects of a medication in an individual based upon his/her genome, but much research must be performed before that is possible in a comprehensive manner. Accurate descriptions of drug response phenotypes are challenging and difficult, and further research is required to define these phenotypes. The Pharmacogenetics Research Network is intended to address this need to acquire basic research results and store the information in a knowledge base, which will lead to a more complete understanding of drug actions, clinical translation of the information, and future drug development.

The Pharmacogenetics Research Network will continue to be comprised of a series of multidisciplinaty research and database groups, each of which is performing state-of-the-art studies in pharmacogenetics, either independently or in conjunction with other network groups.

While pursuing the highest quality research studies, each network group must agree to meet the following expectations: 1) to further develop the knowledge base, PharmGKB, which is a database with accurate and derailed definitions of pharmacogenetic phenotypes linked to genotypes; 2) to advance the research field, by defining common goals and needs, and contributing to solving problems of the field through discussions and workshops; 3) to produce and share resources, such as biological reagents, and experimental and computational tools, to be disseminated rapidly and with minimal restrictions; and 4) to communicate with scientists both within and outside the network, and to foster translation and application of this knowledge. These requirements are further detailed below, and are included in the specific review criteria.

A research group should be organized around a unifying theme, for example, a family of proteins with which drugs interact, a set of drug pathways leading to the site of action, or drug treatments for a particular disease. The group should be comprised of a multidisciplinary team of investigators, minimally including personnel with backgrounds in cellular/molecular pharmacology, genetics/genomics, and clinical expertise. Individuals from the fields of pharmacology, pharmaceutics, physiology, genetics. genomics, clinical medicine, medicinal chemistry, epidemiology, statistics, bioinformatics, and computational biology may be incorporated and must demonstrate that they can work together. This research team should propose current, cutting-edge pharmacogenetics studies. They should be "driven by the science" to produce the highest quality research results for deposition into PharmGKB and for publication. The research groups will be responsible for serving as interactive resources for the developers of PharmGKB in their self-described areas.

Applications should not simply be proposed as a series of projects from all investigators working in pharmacogenetics at an institution. Careful thought should be given to the definition of a research group's goals, and the steps to be taken to accomplish those goals. The best core or project teams to accomplish the research goals should be assembled; applications that cross multiple institutions are acceptable, An application should discuss how existing databases were used to design and approach the solution of a pharmacogenetic problem, and how PharmGKB can better serve its users in the future. The assembled group must justify their choice of a research area as the most appropriate, demonstrate their study design and power, and employ state-of-the-art technical approaches, including statistics and analyses. The selected research problem in pharmacogenetics could be conceived starting with the identification of all possible variants (a genotype-to-phenotype approach) or beginning with well-characterized patient materials (a phenotype-to-genotype approach). The applicant group should stare the advantages and disadvantages of the approach chosen, and where convergence is expected with other studies ongoing in the field.

Correct and complete descriptions of phenotypes and association with genotypes form the core organizing principle underlying the Pharmacogenetics Research Network. The research groups being funded are required to produce meaningful data sets suitable to populate PharmGKB. Scientifically valid research questions should be constructed to yield data that contribute to advancing the understanding in the field, and that am appropriate for deposition into the knowledge base. The types of data deposits that are expected should be described in detail, along with the time frame for their submission. Both human and animal data, as well as non-mammalian systems, will be accepted. Where animals or cell lines or model organisms are being examined, they should be justified as the appropriate reference models, consistent with the goal of identifying and interpreting human genetic drug response variants.

Research groups should address how the pharmacogenetic researchers outside of the network can be positively impacted. Useful sample sets should be offered to established repositories (e.g., the National Institute of General Medical Sciences [NIGMS] Human Genetic Cell Repository at the Coriell Institute, http:// for immortalization and distribution. Useful reagents (e.g., antibodies, primers) should be made easily available. Software tools should be shared freely whenever possible.

Current papers representative of the research field being studied should be deposited by the research groups into the community submissions project in PharmGKB. Evidence of these steps taken will attest to the desire of the research group to serve in a scientific network and to share their findings with the scientific community, and should be presented in the application.

A database group applying to continue PharmGKB should present a plan to further develop the knowledge base as a research resource that will store, organize, present, and integrate pharmacogenetic knowledge. PharmGKB must display a variety of data types: genetic variants, haplotypes, population frequencies, summary statistics, oligonucleotide and cDNA microarray data, molecular and functional screening assays, pharmacokinetic data, pharmacodynamic data, and, where appropriate, clinical data demonstrating the consequences of genetic variation. It should have in place user-friendly methods to accept these data deposits of diverse forms and sizes. In all cases, the data should be described using the standard nomenclature of the respective fields. The knowledge base should have reciprocal links to other established databases, such as GenBank, dbSNP, PDB, etc.

The knowledge base should describe gene-protein-drug-disease relationships, with each object layer completely represented. Relationships between these different data types should be displayed visually, and reflect the opinions and agreement of researchers working in these fields. Raw data should be stored wherever possible, so that PharmGKB can be mined to learn of new correlations. This is intended to be a hypothesis-generating tool. Moreover, data should also be summarized and interpreted so that the information in the knowledge base is accessible to all scientist-users. Given the long history of the field of pharmacogenetics, there should be a current and complete literature archive linked to complete publications wherever possible. Existing high value data sets outside of the network research groups should be sought to populate PharmGKB, to ensure complete and even-handed representation across the field of pharmacogenetics. Methods to establish credit and provide practical scientific incentives for submitters should be proposed.

Applications to continue the knowledge Base PharmGKB should reflect the current status of the project, and describe how the design aspects, implementation, and maintenance will be continued or improved upon. Careful attention should be paid to issues of curation, and delineating who has the responsibility to format, abstract, and check the different kinds of data sets for completeness and accuracy. Comparisons should be made to other successful ongoing database efforts. Future major design directions should be presented and discussed, with prototypes. Discussion of accomplishments, challenges, and obstacles should be provided, and/or external observations and alternative strategies on how to overcome problem areas. There should be evidence of the practical ability to work with the research groups in the network. If a new database group is funded, copies of the existing datasets and data tables will be provided at the time of award, according to the prior negotiated terms and conditions regarding future portability.

Taken together, the research and database groups of the Pharmacogenetics Research Network and Knowledge Base should encompass a range of ongoing studies and original data on pharmacologically important genes, proteins, and pathways. This will be accomplished by funding a balanced series of research groups that are studying different gene families, drug treatments, and diseases of significance to human health. The scope of the Pharmacogenetics Research Network will likely continue to include enzymes of drug metabolism, small molecule transporters, and target receptors and pathways involved in drug treatment of cardiovascular diseases, asthma, cancer, and depression, and may broaden somewhat in reflection of the participating NIH institutes' interests.

This network will be continued as a trans-NIH effort; the institutes' specific interests: NIGMS is interested in studies identifying robust, statistically valid correlations between pharmacogenetic responses (phenotypes) and genetic variation (genotypes, haplotypes) using stare-of-the-art approaches and technologies, and in the deposition of this knowledge into a database designed to be accessible by the entire research community.

The National Cancer Institute (NCI) is interested in projects that can potentially lead to meaningful improvements in clinical and survival endpoints, and in studies of genetic variability in human populations that may influence risk of preneoplastic conditions or primary and secondary malignancies after exposure to medications, including cancer therapies.

The National Heart, Lung, and Blood Institute (NHLBI) is interested in studies of the role of genetic polymorphisms and their functional consequences in modulating treatment responses in heart, lung, blood, and sleep diseases.

The National Human Genome Research Institute (NHGRI) supports research on how databases represent phenotypes, particularly related to genetic variation, and encourages the use and extension of standardized ontologies, as well as rapid data release.

The National Institute on Drug Abuse (NIDA) is interested in the influence of genetic variation on metabolic, homeostatic, neurocognitive, and physiological responses to abused drugs, as well as the safety and efficacy of drugs used for the treatment of addiction, dependence, and withdrawal, and in drug-drug interactions (e.g., antiretrovirals and drugs of abuse).

The National Institute of Environmental Health Sciences (NIEHS) is interested in identifying the response genes that are important to understanding genetic susceptibility to environmental exposures (see the Environmental Genome Project at

The National Library of Medicine (NLM) is interested in knowledge representation and the design and management of databases with medical data.

The Office of Research on Women's Health (ORWH) is interested in evaluating the importance of gender differences in genetic polymorphisms of proteins important in the pharmacokinetics and pharmacodynamics of drugs and drug reactions, and the role of hormones and other factors.

This RFA will use the NIH U01 award mechanism. The applicant is solely responsible for planning, directing, and executing the proposed project. The RFA is a one-time solicitation. The anticipated award date is on or after 1 July 2005. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application.

This RFA uses just-in-time concepts. It uses the nonmodular budgeting formats. Follow the instructions for nonmodular budget research grant applications and submit the detailed categorical budget information on the PHS 398 form. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at nihgps_2001/part_i_1.htm.

The NIH U01 is a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator as described under the section "Cooperative Agreement Terms and Conditions of Award." NIH makes no commitment to continue the cooperative agreement programs beyond the initially awarded period of performance.

Attendance at two Steering Committee meetings per year is required. These will likely rotate between the East and West coasts and central United States. Travel funds should be requested for this purpose for the Principal Investigator and for one to two other Observers. A plan for depositing data into PharmGKB is required. See the current submission methods at

This satisfies the NIH requirement for sharing research data for applications greater than $500,000 direct costs in any year of the proposed research. Funds should be requested to support individuals capable of submitting data to PharmGKB.

A letter should be included in the application, stating that the applicant research group members have read all of the existing policies of the Pharmacogenetics Research Network ( The letter should indicate that the group members will adhere to each of the policies and will contribute to the development of future policies that will guide the network's actions.

Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at in an interactive format. For further assistance contact GrantsInfo, 301-435-0714, e-mail:

Using the RFA label: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://

The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is, the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Letters of intent must be received by 19 July 2004. Applications are due 19 August 2004. The earliest anticipated start date is 1 July 2005.

Contact: Rochelle M. Long, Pharmacology, Physiology, and Biological Chemistry Division, NIGMS, NIH, Bldg 45, Rm 2AS.49G, MSC 6200, Bethesda, MD 20892-6200 USA, 301-594-1926, fax: 301-480-2802, e-mail: longr@; Richard A. Anderson, Genetics and Developmental Biology Division, NIGMS, NIH, Bldg 45, Rm 2AS.25B, MSC 6200, Bethesda, MD 20892-6200 USA, 301-594-0943, fax: 301-480-2228, e-mail: andersor@; Ken Kobayashi, Cancer Therapy Evaluation Program, NCI, NIH, 6130 Executive Bird, Ste 7131, MSC 7426, Rockville, MD 20852-4907 USA, 301-496-1196, fax: 301-402-0428; e-mail: kobayashik@ctep.nci.; J. Fernando Arena, Division of Cancer Control and Population Sciences, NCI, NIH, 6130 Executive Blvd, Executive Plz N, MSC 7395, Rm 5104, Rockville, MD 20852-4907 USA, 301-594-5868, fax: 301-402-4279, e-mail:; Susan Banks-Schlegel, Division of Lung Diseases, NHLBI, NIH, Rockledge Two, Rm 10220, 6701 Rockledge Dr, MSC 7952, Bethesda, MD 20992-0001 USA, 301-435-0202, fax: 301-480-3557, e-mail:; Dina Paltoo, Division of Heart and Vascular Diseases, NHLBI, NIH, Rockledge Two, Rm 9180, 6701 Rockledge Dr, MSC 7940, Bethesda, MD 20892-0001 USA, 301-435-1802, fax: 301-480-1336, e-mail:; Lisa D. Brooks, Genetic Variation Program, NHGRI, NIH, 31 Center Dr, Rm B2B07, Bethesda, MD 20892-2033 USA, 301-435-5544, fax: 301-480-2770, e-mail:; Joni L. Rutter, Division of Neuroscience and Behavioral Research, NIDA, NIH, 6001 Executive Blvd, Rm 5227, MSC 9555, Bethesda, MD 20892-9555 USA, 301-435-0298, fax: 301-594-6043, e-mail: jrutrer@; Kimberly Gray, Division of Extramural Research and Training, NIEHS, NIH, 111 T.W. Alexander Drive, PO Box 12233, MD EC-21, Research Triangle Park, NC 27709 USA, 919-541-0293, fax: 919-316-4606, e-mail:; Milton Corn, Extramural Programs, NLM, NIH, 6705 Rockledge Dr, Bldg 1, Ste 301, Bethesda, MD 20892-0001 USA, 301-496-4621, fax: 301-402-2952, e-mail:; Lisa Begg, Research Programs, ORWH, OD, NIH, One Center Dr, Rm 201, MSC 0161, Bethesda, MD 20892-0001 USA, 301-496-7853, fax: 301-402-1798, e-mail:

Reference: RFA No. RFA-GM-04-002
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Title Annotation:Fellowships, Grants, & Awards
Publication:Environmental Health Perspectives
Date:May 15, 2004
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