Systems Approach to Immunity and Inflammation (U19)

Systems Approach to Immunity and Inflammation (U19) is sponsored by National Institute of Allergy and Infectious Diseases (NIAID). Supports collaborative research projects that apply systems biology approaches to understanding immunity and inflammation.

Expired RFA-AI-11-017: Systems Approach to Immunity and Inflammation (U19) This notice has expired. Check the NIH Guide for active opportunities and notices. Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating National Institute of Allergy and Infectious Diseases ( NIAID ) Funding Opportunity Title Systems Approach to Immunity and Inflammation (U19) Research Program Cooperative Agreements May 26, 2016 - This RFA has been reissued as RFA-AI-16-050 .

Funding Opportunity Announcement (FOA) Number Additional Information on Eligibility .

Catalog of Federal Domestic Assistance (CFDA) Number(s) The primary objective of the program is to use a systems biology approach to develop a comprehensive understanding of innate or adaptive immune responses to infection with and/or vaccination against one or more pathogenic microbes, with a focus on NIAID Emerging/Re-emerging Pathogens of concern to human health.

The initiative will support quantitative analyses that will identify and measure dynamic networks regulating immune responses. The basis of the research program will be genome wide screens of mutant mice for identification of key regulatory immune response genes.

The studies will be complemented by detailed genomics, proteomics, computational biology and bioinformatics approaches that focus on transcriptional regulation and signaling mechanisms. Investigators will analyze a subset of the newly discovered murine immune regulatory genes in human correlation studies.

Letter of Intent Due Date AIDS Application Due Date(s) Required Application Instructions It is critical that applicants follow the instructions in Application Guide except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts ). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced.

While some links are provided, applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV . When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information Part 2. Full Text of Announcement Section I.

Funding Opportunity Description Section II. Award Information Section III. Eligibility Information Section IV.

Application and Submission Section V. Application Review Information Section VI. Award Administration Information Section VII.

Agency Contacts Section VIII. Other Information I.

Funding Opportunity Description The Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), promotes and supports a broad range of research projects focused on basic mechanisms of immune function, including studies of innate and adaptive immunity and the immunological basis of vaccines, adjuvants, and immune-based therapies.

As part of its research mission, DAIT announces a program to support a systems biology analysis of innate and/or adaptive immune responses to infection and/or vaccination with a focus on NIAID Emerging/Re-emerging Pathogens. (listed at http://www. niaid.

nih. gov/topics/emerging/pages/list. aspx ).

HIV studies are excluded from this FOA. The mammalian immune system has evolved to provide an efficient and effective host response during pathogen infection. Cells of the innate immune system are activated directly by recognizing conserved microbial products, such as pathogen DNA, RNA or components of bacterial cell walls.

Dendritic cells, natural killer cells, macrophages, and neutrophils are cells of the innate immune system with specialized functions against pathogens, such as the production of anti-microbial molecules or phagocytosis of the pathogen. The innate immune response to infection is very rapid and is instrumental in initiating the adaptive immune response by T and B cells.

In contrast to the innate immune response, the adaptive immune system provides long-lived pathogen-specific protective immunity, which may persist for the life of the host. Both T and B cells have receptors that recognize unique components of the pathogen, such as a peptide or protein.

Activation of the adaptive immune response leads to the production of antibodies by B cells, the generation of cytotoxic T cells, or cytokine release that helps to clear the pathogen. Robust adaptive immune responses are critical for recovery from infection, as well as vaccine efficacy.

In addition, long-lived T and B cell responses, a phenomenon known as immunological memory, are the basis for the use of vaccines to induce pre-exposure protection to specific pathogens. A systems biology approach will support the study of complex regulatory mechanisms that are crucial for effective immune responses.

Immunology is well suited to using a systems biology approach because a number of cellular subsets can be studied and findings can be pursued in well developed model organisms and applied to human immunology and disease. The NIAID has supported dedicated systems biology programs directed at host-pathogen interactions since 2002.

These programs have elucidated a number of new pathways, novel genes and their functions, and novel functions of known genes/proteins; including the demonstration of the role of newly discovered genes in human disease.

It is anticipated that applying a systems biology approach to the study of immune responses will provide important and novel insights into the basic principles guiding how immune networks are designed and operate in normal and pathologic settings.

The overarching goal of this FOA is to generate and assemble the information required to define common and unique features across immune response pathways, and to integrate the pathways and networks that initiate, sustain, moderate, and resolve immune responses.

This systems biology initiative will be a large scale collaborative program that requires multi-disciplinary teams of investigators with expertise in immunology, mouse genetics, genomics, proteomics, infectious disease, bioinformatics, and computational science to better understand the innate and adaptive immune responses to pathogens, as well as the regulatory mechanisms that orchestrate host innate and adaptive immune responses to infection.

The research program will be centered on genome wide screens of mutant mice to define key regulatory immune response genes. Investigators will choose a subset of the newly discovered immune regulatory genes from the mouse studies to validate in human correlation studies. Although clinical trials are excluded from this FOA, it is expected that the validation will be performed with primary human cells or tissues.

All scientific findings, new techniques, research tools, and project-associated databases will be made available to the wider scientific community to allow for rapid follow-on discoveries that would benefit public health. An educational component will provide workshops or on-line learning environments for researchers to make use of the tools and data generated by the program.

It is anticipated that this initiative will lead to a better understanding of the immune response during infection and/or vaccination and will provide detailed information for translational approaches in the discovery and development of vaccines and immunotherapeutics.

At the end of the project period it is expected that each program should have identified and quantified several of the following aspects of host immune responses as they relate to the team’s primary research focus area: functions of novel genes/proteins; new functions of known genes/proteins; interacting cell types and spatial/temporal relationships during signal transduction or gene transcription pathways; and new potential candidates for biomarkers, diagnostics, or include both animal and human studies and the development and maintenance of a public website to facilitate the dissemination of novel animal models, reagents, and data, as outlined below: Incomplete and/or non-responsive applications will not be reviewed.

Screens of Mouse Models for the Identification of Key Immune Response Genes.

The systems biology analysis must be based on high-throughput screens of existing or newly developed mouse models for identification of key regulatory immune response genes, supported by detailed genomics, proteomics, computational biology, and bioinformatics approaches to determine the gene products functions in innate and/or adaptive immunity to infection with and/or vaccination against NIAID Emerging/Re-emerging and Biodefense Pathogens (as listed at http://www.

niaid. nih. gov/topics/emerging/pages/list.

aspx ). Studies may also use additional pathogens that pose serious threats to human health, but at least one of the projects proposed in the U19 must be predominately centered on an NIAID Emerging/Re-emerging Pathogen. HIV studies are excluded from this FOA.

Mutagenesis approaches are preferred for development of appropriate mouse models, since these methods do not rely on knowledge of the genetic regulation of an observed phenotype. For example, random mutagenesis with ethylnitrosourea (ENU) has been used successfully by several groups to identify unique innate and adaptive immune response genes involved in immunity to pathogens.

These methods were supported by novel screening assays to detect phenotypic changes in immunity, followed by rapid gene identification approaches. Another, relatively untapped resource for large-scale analysis is the wealth of recombinant inbred mouse strains, congenic mouse strains, the Collaborative Cross strains, or the Diversity Outbred strains that exhibit differences in their susceptibility or resistance to infection.

More targeted high-throughput genomics methods for the generation of novel mouse models (e.g., targeted mutagenesis of candidate genes, high throughput knock-outs, knock-ins, or deletion mutants) may be utilized, with adequate justification of the benefits these approaches bring to large-scale identification of novel It is expected that the majority of the animal work will use mouse models.

In some instances, other animal models have proven to be better models of human infectious disease.

If a second, additional animal model is proposed in these studies, it must be well justified by a compelling rationale for choosing the additional animal model, a discussion of the feasibility of high-throughput screens in the additional animal model, and an explanation of how the reagents, the availability of the animal model, and the genomic information from this animal model will lead to the identification of key regulatory genes that cannot be determined in the mouse models.

All animals and associated reagents generated through the program should be distributed to the research community through appropriate existing repositories, such as the NIAID Taconic Exchange program ( http://www. taconic. com/emerging/listing.

htm ), the NCRR Mutant Mouse Regional Resource Centers ( http://www. mmrrc. org ), NIAID Biodefense and Emerging Infections Research Resources Repository ( http://www.

niaid. nih. gov/labsandresources/resources/dmid/midbrr/pages/default.

aspx ), Correlation Studies for the Analysis of a Subset of the Immune Regulatory Genes Identified in the Animal Model(s). Each Program must provide for appropriate translation of research findings into a context that is relevant and potentially applicable to human disease.

The research activities to be performed include correlation studies to analyze, in human cell or tissue samples, a subset of the immune regulatory genes identified in the high-throughput screens of mouse models. While human cell lines may be used in initial screens, results must be validated in primary human cells or tissues.

The analyses shall be designed to determine the function of immune response genes in human cells that were initially defined in the mouse. These human correlation studies can be proposed as a Specific Aim within a project or as a separate stand alone project. If human samples are to be obtained from independently-funded ongoing or planned clinical trials, documented approval from the clinical trial director should be provided.

While NIAID will support clinical research in this FOA, clinical trials will not be supported ( http://grants. nih. gov/grants/policy/hs/index.

htm ). Website, Models, Reagents and Data As part of a required Bioinformatics Core (see below), a description and the availability of animal models, novel reagents, computational tools, and data generated by the funded investigators will be made available to the broader scientific community.

Therefore, each funded research team will be required to develop and maintain a public website that includes information on mouse models and their availability, reagents generated through the program, experimental protocols, both raw and processed data, and any newly developed analysis tools for usage by the broader research community.

An educational component must be included within the Administrative and Educational Core (see below) of each U19, to provide training through such means as online tutorials or workshops/symposia hosted at relevant meetings or as stand-alone training.

The educational component is intended to provide the research community with enhanced knowledge of systems biology approaches and their applications in the study of the immune system, particularly the utilization of computational analysis tools in the systems biology domain. For example, these could be short training sessions, workshops or symposia (not more than a few days).

Topics could include understanding how to use network analysis tools to evaluate immunological data or phosphoflow data analysis and interpretation. The scope of this work requires that interdisciplinary teams be formed that are capable of pursuing coordinated activities that bridge disparate scientific disciplines and expertise.

By promoting a systematic and quantitative analysis of immune responses on many levels, this initiative offers a unique opportunity to build on current programs and to coordinate these activities toward a common goal. Bringing multidisciplinary groups together creates opportunities for synergy that would rarely happen otherwise.

To accomplish a task of this magnitude, it will be necessary for the team to recruit expertise from a multitude of experimental scientific areas, including immunology, molecular and cellular biology, mouse genetics, biochemistry, genomics, and proteomics.

Enlistment of strong computational biology expertise will also be key to ensure project success, including bioinformatics and mathematical support that may be necessary to manage the large datasets and network analyses that will be pursued. The research teams may be located at one institution or may be formed through a consortium of different institutions.

Frequent interactions and communication within the research team are key elements to the program’s success. Because of the nature of this Program some projects may be descriptive or discovery; not all are required to be hypothesis driven.

Examples of research areas in the context of infection and/or vaccination that are responsive to this FOA include, but are not limited to, the following (not listed in priority order): Regulation of innate immune cell function in response to infections or vaccines (e.g., macrophages, dendritic cells, NK cells, and NK T Control of expression of and signaling through immune receptors, such as Toll-like Receptors and NK regulatory receptors, or antigen and Dissection of the molecules and pathways involved in the regulation of the innate/adaptive interface.

Mechanisms that regulate antibody production to pathogens, such as heavy chain class switching, affinity maturation/somatic hypermutation, plasma cell generation and maintenance, and parameters required for generation of protective antibody responses. Mechanisms for the generation and maintenance of immune memory in Regulation of mucosal immunity in infection or vaccination. MicroRNA regulation of the immune system.

Control and roles of apoptosis in immune response. Undertanding the mechanisms that regulate inflammatory responses only in the context of a pathogen infection or vaccination. Understanding mechanisms of adjuvants and potential new targets for adjuvant development.

Examples of research areas that are NOT responsive to this FOA include the following areas. NOTE that applications proposing such studies will be considered non-responsive and Analysis of genes, pathways, or regulatory mechanisms of immunity using only in vitro systems (e.g., absence of in vivo mouse studies). Studies using only animal models.

Studies using only human cells or tissues. Bacterial or viral pathogenesis studies in the absence of a detailed analysis of innate or adaptive immunity to the pathogens. Systems analysis of innate and adaptive immune mechanisms focusing on immune-mediated diseases (e.g., autoimmunity, allergy, asthma).

Clinical trials of experimental therapeutic or prevention strategies/products. However, please note that clinical research involving the use of human samples is required by this FOA ( http://funding. niaid.

nih. gov/researchfunding/sci/human/pages/hshandbook. aspx ).

Information for Multi-Project Applications This initiative will use the U19 Cooperative Agreement grant mechanism. Essential elements of the U19 include: (1) a minimum of two interrelated Research Projects organized around a central theme; (2) collaborative efforts and interactions among these independent projects and their investigators to achieve a common goal; (3) an Administrative and Educational Core; and (4) a Bioinformatics Core.

In addition, one or more optional Scientific Cores are allowed. Lack of synergy and interaction among the Research Projects and Scientific Cores will adversely affect the impact score of a multi-project application, even if the merit of individual projects is high.

For detailed instructions for the preparation of the U19 application, please see PHS 398 Application Guide and Supplemental Instruction for the Preparation of Multi-Project Applications under Part 2. Section IV. Application and Submission Information.

Each U19 Program Project application must include at least two inter-related Research Projects. Each Research Project should be prepared according to the standard PHS 398 instructions as modified in the NIAID guidelines for preparing multi-project applications ( http://funding. niaid.

nih. gov/ncn/grants/multi/index. htm ).

In addition to the standard scientific description, the interactions among projects and core facilities should be described within each Project. The Projects may be descriptive in nature, discovery, or hypothesis driven, but should provide synergy within the program. and Educational Core (required) An Administrative and Educational Core is required and will support the coordination of efforts across the components of the U19.

The Administrative and Educational Core will be responsible for activities not directly supported by the individual projects or scientific cores; including organizing quarterly teleconferences with the NIAID Program Staff, assisting the NIAID Staff with site visits, preparing the annual progress reports or publications from multiple projects within the U19, and coordinating the sharing of resources generated by the program (and budget accordingly).

The educational component is intended to provide the research community with enhanced knowledge of systems biology approaches and their applications in the study of the immune system, particularly the utilization of computational analysis tools in the systems biology domain. The PD(s)/PI(s) of the application (or one of the PD/PIs if it is a multi-PD/PI application) must serve as the Leader of the Administrative and Educational Core.

The budget for this Core must request funds for the PD(s)/PI(s) to attend an initial kick-off meeting and then semi-annual meetings to review progress that will be held in The budget of the educational component of the program will be included in the Administrative and Educational Core.

A Bioinformatics Core is required to support at least 2 projects and be responsible for ensuring the availability of the data generated by the funded investigators to the broad scientific community.

As part of this Core each funded research program will be expected to develop and maintain a public website and a resource sharing plan that includes information on mouse models and their availability, reagents generated through the program, experimental protocols, and raw and processed data, consistent with achieving the goals of this program.

In addition, any analysis tools that are generated through the program should be available at the website. Publically available data analyses tools can be hosted at the website or have links to them at the website. It is expected that a bioinformatics core will also coordinate with the scientific projects within the program to analyze the data generated by the experimental groups.

The budget for the development and maintenance of the website should be included in the Bioinformatics Core. Applications that do not contain the required components will not be reviewed. One or more Scientific Cores may be proposed in a U19 application.

Each Scientific Core must be used by at least two research projects. Scientific Cores should be limited to providing standard assays, reagents, technologies, or other available services to investigators. Scientific Cores may include technical services (e.g., flow cytometry, multiplex cytokine analysis, sample collection), animal cores, or other non-administrative activities that directly support the research program.

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, scientific or program staff will assist, guide, coordinate, or participate in project activities.

Application Types Allowed Glossary and the PHS398 Application Guide provide details on these application Funds Available and Anticipated Number of Awards NIAID intends to commit an estimated total of $7 million in FY 2011 to fund 1-3 awards.. Application budgets are not limited, but need to reflect actual needs of the proposed project. Scope of the proposed project should determine the project period.

The maximum award period is 5 years. described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA. Section III.

Eligibility Information Higher Education Institutions: Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education: Hispanic-serving Institutions Historically Black Colleges and Universities (HBCUs) Tribally Controlled Colleges and Universities (TCCUs) Alaska Native and Native Hawaiian Serving Institutions Nonprofits Other Than Institutions of Higher Education Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Nonprofits without 501(c)(3) IRS Status (Other than Institutions For-Profit Organizations (Other than Small Businesses) City or Township Governments Special District Governments Indian/Native American Tribal Governments (Federally Recognized) Indian/Native American Tribal Governments (Other than Federally Eligible Agencies of the Federal Government U.S. Territory or Possession Independent School Districts Public Housing Authorities/Indian Housing Authorities Native American tribal organizations (other than Federally recognized tribal governments) Faith-based or Community-based Organizations Non-domestic (non-U.S.) Entities (Foreign Organizations) Non-domestic (non-U.S.) Entities (Foreign Organizations) are eligible to apply.

Foreign (non-U.S.) components of U.S. Organizations are allowed. Applicant organizations must complete the following registrations as described in the PHS398 Application Guide to be eligible to apply for or receive an award.

Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following Contractor Registration (CCR) must maintain an active registration, to be renewed at least annually All Program Directors/Principal Investigators (PD/PIs) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least four (4) weeks prior to the application due date.

Eligible Individuals (Program Director/Principal Investigator) Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director/Principal Investigator (PD/PI) is invited to work with his/her organization 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 institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the PHS398 This FOA does not require cost sharing as defined in the NIH Grants Additional Information on Eligibility Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed. IV.

Application and Submission Information 1. Address to Request Application Package Applicants are required to prepare applications according to the current PHS 398 application forms in accordance with the PHS 398 Form of Application Submission It is critical that applicants follow the instructions in the Application Guide , except where instructed in this funding opportunity announcement to do otherwise.

Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and By the date listed in Part 1.

Overview Information , prospective applicants are asked to submit a letter of intent that includes the following information: Descriptive title of proposed research Name, address, and telephone number of the PD(s)/PI(s) Names of other key personnel Participating institutions Number and title of this funding opportunity The letter of intent should be sent to: Division of Extramural Activities National Institute of Allergy and Infectious Diseases Bethesda, MD 20817-7616 (for express/courier service; non-USPS service) Telephone: (301) 451-2666 Applications must be prepared using the PHS 398 research grant application forms and instructions for preparing a research grant application.

Submit a signed, typewritten original of the application, including the checklist, and three 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 (U.S. Postal Service Express or regular mail) Bethesda, MD 20817 (for express/courier service; non-USPS service) At the time of submission, two additional paper copies of the application and all copies of the appendix files must be sent to: Division of Extramural Activities National Institute of Allergy and Infectious Diseases Bethesda, MD 20817-7616 (for express/courier service; non-USPS service) Telephone: (301) 451-2666 All page limitations described in the PHS398 Application Guide must be followed, with the following exceptions or additional Research Projects are each limited to 12 pages and all cores are limited to 6 pages.

Supplemental Instruction for the Preparation of Multi-Project Applications The following section supplements the instructions found in Form PHS 398 for preparing a multi-project grant application.

Additional instructions are required because the Form PHS 398 is designed primarily for individual, free-standing research project grant applications, and has no specific instructions for multi-project applications consisting of research projects interrelated by a common theme. The supplemental instructions for multi-project applications below are divided as follows: A.

General Instructions addresses collaborative efforts among research projects, the administrative and organizational structure as well as the overall facilities and environment, and B. Specific Instructions for Individual Research Projects describes modifications to PHS Form 398 instructions on selected items to address the collaborative or interactive role of the C.

Specific Instructions for Cores Describes modifications to PHS Form 398 instructions on selected items to address the collaborative or interactive role of the Core. All applications must be submitted on Form PHS 398. The multi-project grant application should be assembled and paginated as one complete document.

Items 1 - 14: complete these items as instructed. This should be the first page of the entire application and all succeeding pages should be numbered consecutively. Using Page 2 of Form 398; provide a succinct but accurate description (abstract) of the OVERALL multi-project application addressing the major, common theme of the program.

Do not exceed the space provided. Project/Performance Sites List the performance sites where the research will be conducted. Under "Key Personnel", list the PD/PD/PIof the multi-project application, followed by the Project and Core Leaders of the component research projects and cores, and other key personnel and then other significant contributors.

Do not use Form Page 3 of the PHS 398; a more comprehensive table of contents is needed for a multi-project application. Bearing in mind that the application will be scientifically reviewed project by project and core by core, prepare a detailed Table of Contents that will enable reviewers to readily locate specific information pertinent to the overall application as well as to each component research project and core.

A page reference should be included for the budget for each project and each core. Further, each research project should be identified by number (e.g. Project 1), title, and responsible Project Leader, and each Core should be identified by letter (e.g. Core A), title, and responsible Core Leader. The page location of a COMPOSITE BUDGET should be indicated in the "Table of Contents."

Do not use Form Page 4 of PHS Form 398. Instead, using the suggested format presented below, prepare a Composite Budget For All Proposed Years of Support. (Justification for budget elements should not be presented here but in the individual budgets of the projects and cores.)

Consolidated Direct Cost Budget for All Proposed Years of Support 5. Total Direct Costs for the Entire Budget Period Complete the Total Direct Cost line entries for all requested budget periods (years) and the Total Direct Cost for Entire Period of Support entry. Detailed budgets are required within the descriptions of each project and core (see below).

If the FOA allows for budget requests beyond 5 years, use a second Form Page 5 to reflect the additional budget years Biographical sketches of all professional personnel for all components should be placed at the end of the application with the PI/PD first, followed by those of other key personnel in alphabetical order. Do not complete.

Essential information is to be presented in the individual research project and core sections of the application. Aims (Limited to 1 page.) List in priority order, the broad, long-range objectives and goals of the proposed Program.

Concisely and realistically describe the hypothesis or hypotheses to be tested. Research Strategy (Limited This narrative section summarizes the overall research plan for the multi-project application and is limited to 12 pages. The multi-project application should be viewed as a confederation of interrelated research projects, each capable of standing on its own scientific merit, but complementary to one another.

This is an important section for it provides the group of investigators an opportunity to give conceptual wholeness to the overall Program by giving a statement of the general problem area and by laying out a broad strategy for attacking the problems. As the strategy develops, each individual research project and core should be cited briefly as to its place in the overall scheme.

Summarize the special features in the environment and/or resources that make this application strong or unique. In addition, provide detailed annual milestones for the major goals and objectives for the Program. If the application is a renewal, the Program past performance and the major accomplishments from the prior funding period as described in the PHS 398 Instructions.

Preliminary studies and/or progress reports must be contained within the page limits of the Research One Checklist, placed at the end of the application, is to be submitted for the entire application. Refer to Section IV. 6.

Appendix Materials below, for instructions on submitting appendix materials. For each project or core in the multi-project application, 3 publications plus other approved material are allowed. B.

Specific Instructions for Individual Research Projects Except for the requirements below, follow the PHS 398 Specific Instructions found at http://grants1. nih. gov/grants/funding/phs398/phs398.

doc#_Toc130797900 in preparing each research project. For each individual Research Project, include: Face page (see special instructions, below) Description & Key personnel (PHS 398 Form Page 2) Table of Contents (PHS 398 Form Page 3) Budget Pages (PHS 398 Form Pages 4 and 5); with budget The Face Page of