ERYTHROID LINEAGE MOLECULAR TOOLBOX RELEASE DATE: July 8, 2003 PA NUMBER: PA-03-150 March 2, 2006 (NOT-OD-06-046) Effective with the June 1, 2006 submission date, all R03, R21, R33 and R34 applications must be submitted through using the electronic SF424 (R&R) application. Accordingly, this funding opportunity expires on the date indicated below. Replacement R21 (PA-06-170) and R01 (PA-06-169), funding opportunity announcements have been issued for the submission date of June 1, 2006 and submission dates thereafter. See NOT-OD-06-048 for information on May 1, 2006 Submission Date for AIDS and AIDS-related R03 and R21 Applications. EXPIRATION DATE: March 2, 2006 National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) ( CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.849 THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanism(s) of Support o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PA The National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) announces a new program designed to stimulate research in erythroid cells. The aim of this program is to contribute to a complete description of expressed erythroid molecular biological components and to create reagents useful for study of the erythroid cell lineages. Components include genes that are expressed in erythroid cells, either during development or during differentiation, and the proteins that are translated in erythroid cells, potentially with post-translational modifications or subcellular localizations that are unique to erythroid cells. A long range goal of this program is to unify genetics and the study of function by facilitating characterization of the structure-function relationships between the expressed genes in the erythroid lineages and cell morphology, physiology, and disease phenotypes. Development of new technologies to facilitate applications of this genomic information is also encouraged. Applicants are encouraged to refer to the NIDDK's Progenitor Cell Genome Anatomy Projects at to find current resources that are available. Synergy with existing Progenitor Cell Genome Anatomy Projects is encouraged. RESEARCH OBJECTIVES Background For many years, the erythroid cell has been used as a model system to understand molecular genetics, biochemistry, structural membrane biology, cell physiology and gene expression. Given the fact that erythroid cells are easy to obtain and that there are relatively few genes expressed, these cells provide a model system with which to characterize exactly how the genetic program specifies the formation of a particular cell type. The erythroid cell exists as a single, suspended cell, eliminating the complicating factors of teasing it away from other cell types and purifying it out of a solid matrix. Likewise, the sheer number of erythroid cells available to harvest from a single individual makes it an ideal system to study. Finally, the precursor cells are available through bone marrow harvest and cell purification schemes for particular stages of the erythroid lineages have been developed for human, rabbit, goat, mouse and most other mammalian species. The relatively lower numbers of expressed sequences in erythroid cells facilitate studies to measure basic molecular biological processes, to develop mathematical models for quantitating the dynamic process of cell differentiation, to identify genes necessary for the successful formation of a mature red blood cell and to apply these principles to eukaryotic cells, in general. In the latter stages of erythropoiesis before nuclear extrusion, 90% of the mRNA transcription results in translation products necessary for hemoglobin production. These studies have led the way for a generalized understanding of the transcription process itself. In addition, the fact that each red blood cell must squeeze itself through a narrow capillary allows quantitation of biophysical parameters to be made. The frequency with which red blood cell-related diseases affect humans is a public health issue and another focus of this program. Samples, easily obtained from patients, allow performance of multiple tests to monitor disease and to develop new therapies for treatment. In addition, the molecular basis of hemoglobinopathies provides a useful teaching and education tool. Objective and Scope The ultimate goals of this program will be to use erythroid cells at different stages of development and differentiation to assemble the complete collection of genes expressed, describe how they are expressed and elucidate physical parameters, including subcellular localization of the proteins translated during erythropoiesis. These reagents may then be used to discover the structure-function relationships that exist in erythroid cells with possible application to other cell types. Appropriate topics for R21 projects would include, but are not limited to the following: o Expansion of cell purification and culture procedures to facilitate rapid isolation of morphologically pure stages of erythroid differentiation. o Characterization of specific classes of proteins in erythroid cells. o Development of antibodies to specific proteins that may be used as reagents for cell biology studies. o Identification of genes that are expressed during development (i.e., embryonic, fetal liver and adult stages) and differentiation (i.e., committed CFU-E, pronormoblast, orthochromatophilic erythroblast, polychromatophilic erythroblast, and reticulocyte stages) of red blood cells. o "Data mining" of molecular genetics to discover functionally important biological themes. o Identification of alternative splicing products and characterization of function consequences. o Testing of novel technologies to evaluate global gene or protein expression. Appropriate topics for the R01 grant mechanism include, but are not limited to: o Development of molecular genetic descriptions of erythroid cells at various stages of development (i.e., embryonic, fetal liver and adult stages) and differentiation (i.e., committed CFU-E, pronormoblast, orthochromatophilic erythroblast, polychromatophilic erythroblast, and reticulocyte stages and red blood cells). Such global descriptions are needed as standards for the entire scientific community. This includes a determination of which sets of genes are expressed at the various stages of erythropoiesis and their function in the red blood cell lineages. o "Data mining" of these above mentioned descriptions to discover functionally important biological themes. o Generation of gene expression profiles that are standardized by use of a common set of microarrays, possibly from single cells. In addition, expression profiles need to be developed in cells with specific gene knockouts or knockdowns. o Generation of proteomic profiles. Some proteins may be present, but not active because of post-translational modification. Included in this may be: 1) an analysis of the sub-cellular localization of proteins in the erythroid proteome, 2) a protein-protein interaction map of the erythroid proteome, and 3) a comprehensive phenotypic map of loss-of-function of genes encoding the erythroid proteome. Results could be stored as maps, made widely available on the Internet. o Application of molecular knowledge to human diseases. Among inherited disorders of the red blood cell, sickle cell anemia and the thalassemias are the most prevalent worldwide. While the molecular bases of these diseases are known, more is needed to learn about the contribution of other genes to the clinical course of these illnesses and their overall severity. o Development of computational biologic programs capable of integrating data from all levels of biology, namely DNA, mRNA, protein-protein interactions and others. The goal is to develop mathematical models and graphical displays of the red blood cell. o Comparisons of genomes or sections of genomes that reveal highly conserved motifs in erythroid cell development and differentiation. It is expected that research tools developed will be made readily available to the rest of the scientific community. MECHANISMS OF SUPPORT This PA will use the NIH R21 or R01 award mechanisms. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. Applicants are encouraged to contact program staff for advice about choosing the appropriate grant mechanism. This PA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see 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. Applications requesting $500,000 or more in direct costs for any year must follow instructions provided in section on SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR below. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at R21 (Exploratory/Developmental) grants (see The R21 mechanism is intended to encourage new exploratory/developmental research projects by providing support for the early stages of their development. Awards are made to demonstrate feasibility of a subsequent project and to obtain preliminary data testing innovative ideas. Therefore, these grants are not renewable. Continuation of projects developed under this program will be through the regular research project grant mechanism (for example, R01). These grants are not intended to support or supplement ongoing funded research of an established investigator, or to serve as an alternative mechanism of support for projects not receiving funding as competitive continuation applications. The NIH Grants Policy statement applies to these awards. An R21 application should have a research plan that does not exceed 15 pages. A two-year project period is the maximum period of support. You may request a project period of up to two years with a combined budget for direct costs up to $275,000 for the two year period. For example, you may request $100,000 in the first year and $175,000 in the second year. The request should be tailored to the needs of your project. Normally, no more than $200,000 may be requested in any single year. Little or no preliminary data are required. Up to five relevant published articles may be included as Appendix material, if desired. 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 R01 (Research) grants The R01 award represents an investigator-initiated research grant designed to support a discrete, specified research project performed by a principal investigator. ELIGIBLE INSTITUTIONS You may submit an application if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign o Faith-based or community-based organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS Plan for Dissemination of Data and Biomaterials Sharing of biomaterials, data, and software in a timely manner has been an essential element in the rapid progress that has been made in the genetic analysis of human diseases. PHS policy requires that investigators make unique research resources available for research purposes to qualified individuals within the scientific community when they have been published (see the NIH Grants Policy Statement at In addition, NIH recently released a statement on the sharing of research data that applies to all investigator-initiated applications with direct costs greater than $500,000 in any single year ( All applicants who respond to this PA must propose plans for sharing data and biomaterials generated through the grant. Applicants should explain how funds for the storage and distribution of data and biomaterials will be obtained, and may request such funds in the budget of the application. It is expected that the information to be shared will include clinical, diagnostic, and pedigree structure information. Biomaterials to be shared should include patient DNA and cell lines. When possible, data and biomaterials should be placed in databases or repositories that will permit their efficient distribution to investigators throughout the scientific community. Rapid sharing of data and biomaterials is strongly encouraged. The Initial Review Group will evaluate the proposed sharing plan and comment on its adequacy in an administrative note in the summary statement. Reviewers will not factor the proposed data-sharing plan into the determination of scientific merit or priority score. NIH staff will consider the adequacy of the plan and determine whether the grant shall be awarded. The sharing plan as approved, after negotiation with the applicant when necessary, will be a condition of the award. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research, and financial or grants management issues: o Direct your questions about scientific/research issues to: Terry Rogers Bishop, Ph.D. Hematology Genomics Program Director; Training and Careers Program Director Division of Kidney, Urologic, and Hematologic Diseases National Institute of Diabetes, Digestive, and Kidney Diseases 6707 Democracy Blvd., Room 619 Bethesda, MD 20892-5458 Telephone: (301) 594-7726 Email: o Direct your questions about financial or grants management matters to: Donna Huggins Grants Management Specialist National Institute of Diabetes, Digestive, and Kidney Diseases 6707 Democracy Blvd., Room 711 Bethesda, MD 20892-5456 Telephone: (301) 594-8848 Email: SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted at the standard application deadlines, which are available at Application deadlines are also indicated in the PHS 398 application kit. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: All investigator- initiated R21 applications must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: Applications requesting $500,000 or more in direct costs for any year must include a cover letter identifying the NIH staff member within one of the NIH institutes or centers who has agreed to accept assignment of the application. Applicants requesting more than $500,000 must carry out the following steps: 1) Contact the IC program staff at least 6 weeks before submitting the application, i.e., as you are developing plans for the study; 2) Obtain agreement from the IC staff that the IC will accept your application for consideration for award; and, 3) Identify, in a cover letter sent with the application, the staff member and IC who agreed to accept assignment of the application. This policy applies to all investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended or revised version of these grant application types. Additional information on this policy is available in the NIH Guide for Grants and Contracts, October 19, 2001 at SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the checklist, and five signed photocopies in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) APPLICATION PROCESSING: Applications must be mailed on or before the receipt dates described at 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. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. PEER REVIEW PROCESS Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. An appropriate scientific review group convened in accordance with the standard NIH peer review procedures ( will evaluate applications for scientific and technical merit. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score o Receive a second level review by the appropriate national advisory council or board. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning the application's overall score, weighting them as appropriate for each application. The application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. SIGNIFICANCE: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITEIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. SPECIFIC R21 REVIEW CRITERIA: The NIH R21 exploratory/developmental grant is a mechanism for supporting novel scientific ideas or new model systems, tools or technologies that have the potential to significantly advance our knowledge or the status of health-related research. Because the research plan is limited to 15 pages, an exploratory/developmental grant application need not have background material or preliminary information as one might normally expect in an R01 application. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Reviewers will place less emphasis on methodological details and certain indicators traditionally used in evaluating the scientific merit of R01 applications including supportive preliminary data. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator- generated data. Preliminary data are not required for R21 applications ADDITIONAL CONSIDERATIONS DATA SHARING: The adequacy of the proposed plan to share data. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. AWARD CRITERIA Applications submitted in response to a PA will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program priorities REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at and at Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see It is the responsibility of the applicant to provide the official NIH identifier(s) for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as "covered entities") must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website ( provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284)and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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