Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	This Funding Opportunity Announcement (FOA) is developed as a Common Fund initiative (http://commonfund.nih.gov/) through the NIH Office of the Director, Office of Strategic Coordination (http://dpcpsi.nih.gov/osc/). The FOA will be administered by a trans-NIH team led by the National Heart Lung and Blood Institute (NHLBI).
Funding Opportunity Title	Defining A Comprehensive Reference Profile of Circulating Human Extracellular RNA (U01)
Activity Code	U01 Research Project Cooperative Agreements
Announcement Type	Reissue of RFA-RM-12-011
Related Notices	None
Funding Opportunity Announcement (FOA) Number	RFA-RM-13-014
Companion Funding Opportunity	None
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.310
Funding Opportunity Purpose	The purpose of this funding opportunity announcement (FOA) is to support projects that will generate reference profiles of both short and long non-coding regulatory extracellular RNAs (exRNA), including any environmentally-derived exRNA (e.g. from diet, microbiome), from a diversity of healthy human body fluids including blood, saliva, urine, breast milk, semen, amniotic fluid, cerebrospinal fluid, ascites and pleural effusions. Studies using existing human biospecimen collections are strongly encouraged. This FOA is only for studies related to human samples; animal or other non-human disease model studies are not responsive to this FOA.

Posted Date	September 19, 2013
Open Date (Earliest Submission Date)	October 22, 2013
Letter of Intent Due Date(s)	October 22, 2013
Application Due Date(s)	November 22, 2013, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	January - March, 2014
Advisory Council Review	May, 2014
Earliest Start Date	July, 2014
Expiration Date	November 23, 2013
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) 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. 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 the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

The concept that RNA molecules are secreted extracellularly and act as endocrine signals to alter the phenotypes of target cells, both locally and at distant sites, represents a novel paradigm in intercellular signaling. Recent advances in RNA sequencing technologies have identified a large and diverse population of extracellular RNA (exRNA) including microRNAs and long non-coding RNA (lncRNAs). Emerging observations suggest that RNA regulation is much more complex than previously believed. For example, approximately 60% - 80% of all protein encoding genes are regulated by microRNAs and the recently discovered circular RNAs can interact with microRNA regulators of gene expression. Meanwhile, certain lncRNAs appear to have roles in processes such as (1) regulation of cellular differentiation, (2) physical association in protein complexes or with chromatin, and/or (3) epigenomic regulation. Thus extracellular delivery of these RNAs could have profound implications for a wide range of physiologic and pathologic processes. In humans, exRNAs are found in various body fluids, including blood, saliva, urine, breast milk, cerebral spinal fluid (CSF), amniotic fluid, ascites, and pleural effusions highlighting the importance of exRNAs in health and disease. Recent reports in the literature suggest that exRNA have both protective and pathogenic roles in a variety of human diseases. Further, functional plant- and microbe-derived exRNAs have been identified in human serum and cells suggesting that trans-kingdom exRNA communication could explain associations between environmental exposures and health or disease. Taken together, the above findings highlight the transformative opportunities the NIH Common Fund Extracellular RNA Communication Working Group has identified in this emergent field. While exRNA were originally thought to be encapsulated in extracellular vesicles (EVs), recent studies have also demonstrated their presence in serum, nuclease-resistant complexes with RNA-binding carrier proteins, such as HDL and Argonaute. However, the foundational principles of exRNA packaging, distribution, and uptake need to be better defined. A better understanding of exRNA sorting (to EVs or RNA-binding proteins), secretion, targeting, and effector function in target cells would generate opportunities to identify novel strategies for prognosis, diagnosis, and intervention of many diseases.

The Common Fund Extracellular RNA Communication Program has been developed to address critical issues in this nascent field. Both fundamental scientific discovery and innovative tools and technologies will be required to advance the field. This FOA is focused on one of the key issues that need attention: the generation reference profiles of exRNAs in normal healthy individuals that may subsequently facilitate disease diagnosis and therapeutic outcomes. The other areas that are being addressed through associated FOAs, already awarded, include: (a) defining the fundamental principles of exRNA function including the development of the molecular tools, technologies, and imaging modalities to enable a mechanistic understanding of exRNA biogenesis, sorting, release, and uptake (RFA-RM-12-012); (b) developing a community resource that will provide a centralized source for data, standardized protocols for exRNA isolation and characterization, and coordination toward consortium-wide goals supported by centralized databases to nucleate the research community (RFA-RM-12-010); and (c) demonstrating the clinical utility of exRNAs as therapeutic agents and/or biomarkers and support the development of the scalable technologies required for these studies (RFA-RM-12-013 and RFA-RM-12-014). Awards funded under these FOAs are anticipated to involve activities conducted by multidisciplinary teams of investigators. Awardees from all 5 initiatives will form a consortium, with the overarching goal of determining fundamental principles associated with exRNAs. Comparisons across studies will be essential to establish these cross-cutting principles so investigators must be willing to act as part of the consortium and work collaboratively.

Recent observations demonstrate that exRNAs play an important role(s) in inter-cellular signaling and can have a profound impact on organismal physiology. Studies have shown, for example, that tumor-derived exRNAs can promote tumor growth and that endothelial cell-derived exRNAs can regulate gene expression in smooth muscle cells. In addition, there are new reports suggesting dietary derived exRNAs, found in human sera may play a role in modulating LDL levels. Microbes also secrete RNAs via extracellular vesicles and this may be a mechanism by which the microbiome influences host cell function from a distance. These observations suggest a mechanism of inter-kingdom information exchange through exRNAs. Hence an opportunity exists to investigate an entirely new paradigm of intercellular and inter-organismal communication by identifying fundamental principles of exRNA secretion, delivery, and the impact of RNAs secreted into the circulation or into other body fluids. In addition to foundational biology, an opportunity exists to test the clinical utility of exRNAs as therapeutic molecules and/or diagnostic and prognostic indicators. Fundamental to this premise is the development of reference profiles of exRNAs in body fluids of the healthy population that will be supported through this research opportunity. A systematic analysis of circulating exRNA in body fluids of healthy individuals and environmentally derived exRNA, as applicable, would form the basis to facilitate novel strategies for diagnosis, intervention, and therapy for many diseases.

This initiative is funded through the NIH Common Fund, which supports cross-cutting programs that are expected to have exceptionally high impact. All Common Fund initiatives invite investigators to develop bold, innovative, and often risky approaches to address problems that may seem intractable or to seize new opportunities that offer the potential for rapid progress.

The concept of RNA as an endocrine signal has emerged over the past few years as RNAs have been discovered in extracellular vesicles or bound to lipids or proteins circulating in serum or other body fluids. The impact of extracellular RNAs (exRNAs) is largely unknown, but in cellular contexts where they have been analyzed, they have been demonstrated to function as modulators and regulators of a wide range of target cell function. Despite the recognition of the paracrine regulatory effects of these RNAs, a major scientific gap is our knowledge concerning the type and quantity of exRNAs in human body fluids. There is great need to generate standard reference human exRNAs profiles which will enable the scientific community to further elucidate the role(s) of exRNAs in human physiology.

Objectives of this research program:

The purpose of this this FOA is to support projects that will generate reference profiles of both short and long non-coding regulatory exRNAs, including any environmentally-derived exRNA (e.g. from diet, microbiome), from a diversity of healthy human body fluids including blood, saliva, urine, breast milk, semen, amniotic fluid, cerebrospinal fluid, ascites and pleural effusions. These body fluids should be derived from healthy human subjects to serve as reference data for future analyses of the role of exRNAs in normal biological processes and in disease conditions. The profiles should include exRNAs in vesicles and exRNAs bound to carrier proteins such as lipoproteins and Argonaute and also include environmentally derived exRNA species such as from the diet.

Please consider the following when developing your application:

• Given the poorly understood human exRNA landscape, proposed human exRNA reference profiles MUST include a set of assays that will enable detection of the full spectrum of potential non-coding regulatory exRNA species (e.g. short, long, and circular RNAs). The goal is to generate a comprehensive catalog that is inclusive of exRNAs secreted in extracellular vesicles or bound to carrier proteins such as lipoproteins and Argonaute.
• Applicants should describe their previous experience and current capability regarding production level RNA-seq or related relevant assays.
• One of the goals for the exRNA Reference Profiling FOA as a whole is to generate exRNA reference profiles from a wide array of body fluids from healthy human subjects. These body fluids could include blood, saliva, urine, breast milk, semen, amniotic fluid, cerebrospinal fluid, ascites and pleural effusions. Applicants may wish to propose the profiling of multiple body fluid types and/or indicate how they could incorporate additional types of body fluids from other sources.
• pplicants MUST propose to perform reference profiling on human samples. Applications that propose to perform profiling of non-human samples will not be responsive to this FOA. Other already funded components of the exRNA Communication Program are investigating biogenesis of exRNA using a variety of non-human model systems.
• In order to be responsive to this FOA, applicants MUST propose to use existing human samples that have been appropriately archived, annotated, linked to appropriate metadata, and are amenable to profiling. While prospective sample collection will not be allowed for discovery purposes, a limited prospective collection would be permissible for validation of exRNA profiles discovered in archived samples sets. The cohorts from which samples will be derived should be associated with high-quality phenotypic and other relevant data.
• The sample sets should be reflective of the general U.S. population and include statistical justification for the number of samples proposed. Plans for confirmatory or cross validation studies should be included in the application.
• Applicants are encouraged to assemble a multidisciplinary team including experts in exRNA biology, high-throughput sequencing, biostatistics and bioinformatics. The team should also include investigators familiar with all aspects of the parent studies from which samples are to be derived. A collaborative effort rather than a fee for service type arrangement would be deemed responsive.

Milestones and Timeline:

A timeline (Gantt chart) including milestones is required for all studies. Milestones are goals that create go/no-go decision points in the project and must include clear and quantitative criteria for success. Yearly quantitative milestones are required in order to provide clear indicators of a project's continued success or emergent difficulties and will be used to evaluate the application not only in peer review but also in consideration of the awarded project for funding of non-competing award years. Milestones and the timeline must be provided in a separate heading at the end of the Approach section.

ExRNA Consortium Agreement

A key component of this program is the formation of consortium partnerships amongst all awardees. A Memorandum of Understanding (MOU) developed by the NIH Common Fund should serve as a guidance document to provide a framework under which consortium relationships are established. Templates for Confidential Disclosure Agreements (CDAs) and Collaborative Research Agreements (CRAs) have been developed by the NIH Office of Technology Transfer.

Communication Plan

• convene regular (monthly) conference calls with all consortium members
• coordinate efforts with other awardees, in particular with the DMRR
• participate and present findings at annual workshops convened by the DMRR
• jointly publish findings in a timely manner

Performance Requirements

• meet yearly milestones as defined by investigators and NIH program at the time of award
• willing to work with, cooperatively interact with and actively seek input from NIH

Sharing Plan

• Broad sharing of data and biological specimens with academic, industry and government researchers is a critical feature of this program that is consistent with applicable laws, regulations, and policies. All subjects must be properly consented to allow appropriate sample and data distribution to researchers in academics and industry

The DMRR and designated NIH databases will be utilized for the banking and distribution of biological and clinical data. Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) will be expected to harmonize all data and resource generation with the Data Management and Resource Repository (DMRR). A high level of collaboration, coordination and interaction between the Project PIs of this FOA and the DMRR is expected. The DMRR is expected to establish repositories of critical reagents, resources, and information as well as promote and facilitate cross-project collaborations (see RFA-RM-12-010).

Funding Instrument	Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.
Application Types Allowed	New The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The total amount of funds available is $3.8 million per year. It is anticipated that 3-5 projects will be supported.
Award Budget	The budget can be up to $700,000 in Total Costs and needs to reflect the actual needs of the proposed project.
Award Project Period	The scope of the proposed project should determine the project period. The maximum project period is 5 years.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

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
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government including the NIH intramural research program
• U.S. Territory or Possession

Other

• 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
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) 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 NIH support.

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 SF424 (R&R) Application Guide.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the instructions in the SF424 (R&R) 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.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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 plan the review.

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 activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Pothur R Srinivas, Ph.D., MPH
NIH Common Fund Extracellular RNA Working Group
Telephone: 301-402.3712
Fax: 301-480-1455
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed. Applicants should include in their budgets sufficient travel-related funds to attend bi-annual workshops to be held in conjunction with investigators funded under this Common Fund initiative on Extracellular RNA. The yearly budget for the bi-annual workshops to be held in the greater Washington, D.C. metro area is not to exceed $6,000.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Research Strategy:

• Given the poorly understood human exRNA landscape, proposed human exRNA reference profiles MUST include a set of assays that will enable detection of the full spectrum of potential non-coding regulatory exRNA species (e.g. short, long, and circular RNAs). The goal is to generate a comprehensive catalog that is inclusive of exRNAs secreted in extracellular vesicles or bound to carrier proteins such as lipoproteins and Argonaute.
• Applicants MUST describe how their proposed assays and/or data analysis methods will facilitate identification of both endogenous exRNA species and exogenous (environmentally derived) exRNA species. Identification of the types and quantities of trans-kingdom exRNAs (e.g. those derived from diet, microbiome, parasites, etc) could further understanding of the association between environmental exposures and health or disease.
• Applicants should describe the extent to which the consent forms associated with the proposed samples to be assayed enable broad sharing of samples within the consortium and broad sharing of data with the scientific community. All reference profiling data generated through this project must be deposited in the ExRNA Data Management Resource/Repository (DMRR) and will ultimately be deposited into publically accessible databases such as GEO or controlled access databases such as dbGAP.
• Applicants should describe their previous experience in analyzing RNA-seq related datasets and describe their plans for analyzing the data they propose to collect.
• Applicants MUST propose to perform reference profiling on human samples. Applications that propose to perform profiling of non-human samples will not be responsive to this FOA. Other already funded components of the exRNA Communication Program are investigating biogenesis of exRNA using a variety of non-human model systems.

Applicants should also provide (a) a detailed quantitative criteria by which milestone achievement will be assessed, (b) a detailed timeline for the anticipated attainment of each milestone and the overall goal and (c) identify any impediments that could require an addendum to the research plan, milestones, or timeline with a discussion of alternative approaches.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications to Grants.gov Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.

Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.

An informational webinar is scheduled for October 9, 2013 between 1:00 PM and 3:00 PM Eastern time and the link can be found at http://commonfund.nih.gov/exrna/index.aspx

Responsiveness Criteria:

In order to be responsive to this FOA, applicants MUST propose to use existing human samples that have been appropriately archived, annotated, linked to appropriate metadata, and are amenable to profiling. While prospective sample collection will not be allowed for discovery purposes, a limited prospective collection would be permissible for validation of exRNA profiles discovered in archived samples sets. Applications that propose to perform profiling on non-human samples will not be responsive to this FOA. The cohorts from which samples will be derived should be associated with high-quality phenotypic and other relevant data.

Applications Involving the NIH Intramural Research Program

The requests by NIH intramural scientists will be limited to the incremental costs required for participation. As such, these requests will not include any salary and related fringe benefits for career, career conditional or other Federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative or F&A costs). These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses. Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits.

If selected, appropriate funding will be provided by the NIH Intramural Program. NIH intramural scientists will participate in this program as PD/PIs in accord with the Terms and Conditions provided in this FOA. Intellectual property will be managed in accord with established policy of the NIH in compliance with Executive Order 10096, as amended, 45 CFR Part 7; patent rights for inventions developed in NIH facilities are NIH property unless NIH waives its rights.

Should an extramural application include the collaboration with an intramural scientist, no funds for the support of the intramural scientist may be requested in the application. The intramural scientist may submit a separate request for intramural funding as described above.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? How useful will the generation of reference exRNA profiles using the proposed assay methods, body fluid types, and archived samples be for the scientific community?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Do project team members and/or associated collaborators have prior experience and/or necessary qualifications to successfully execute and implement the proposed research including, where appropriate, the ability to partner and collaborate with other scientists or organizations? Are the relationships of the key personnel to the applicant organization and, if applicable, to other partnering organizations (e.g., academic laboratories, clinical sites and/or strategic partners) appropriate for the work? Does the project team have strong previous experience and/or current capability regarding RNA-seq or other relevant assays? Does the team also include sufficient expertise in exRNA biology?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed? Are the new approaches/methodologies comprehensive and/or have a competitive advantage over existing/alternate methodologies?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Is there a plan to incorporate additional types of body fluids from other sources? Does the application take into account the decreasing cost of sequencing? Are the technologies or experimental approaches state of the art and are the proposed exRNA profiling methods reasonable? Are the proposed approaches, tools and technologies scientifically justified? Does the application identify major technical risks, and are the proposed efforts to mitigate or address the risks clearly defined and feasible? How well do proposed approaches enable the detection of the full spectrum of exRNA species? How well do the proposed assays/methods facilitate identification of endogenously and exogenously derived exRNA species? How well will the proposed archived samples serve as sources for generating exRNA profiles and do they have associated phenotypic and metadata in place? Do the samples reflect the general U.S. population? Will the proposed samples enable broad sample sharing across the consortium and broad data sharing with the scientific community? Are data submission, management and support procedures described sufficiently to allow efficient and timely upload of data to the DMRR? Are appropriate, quantitative milestones provided and clearly defined? Are the milestones feasible, well developed and quantifiable with regard to the specific aims of each stage? Are the critical decision points (i.e. go/no go decision points) and timelines appropriate and feasible for the project? Are adequate criteria provided to assess milestone completion in order to make a decision to advance studies during the non-competing years of the project.

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed? Is there assurance provided that appropriate informed consents are in place for the use samples?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Children

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Applications from Foreign Organizations

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the Center for Scientific Review, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• Determining experimental approaches, designing protocols, setting project milestones and conducting experiments;
• Adhere to the NIH policies regarding intellectual property, data release and other policies that might be established during the course of this activity;
• Accept and implement any other common guidelines and procedures developed for the NIH Common Fund Extracellular RNA Program and approved by the NIH Common Fund Extracellular RNA Steering Committee;
• Accept and participate in the cooperative nature of the NIH Common Fund Extracellular RNA Consortium;
• Attend bi-annual workshops organized by the NIH and the DMRR.

Intellectual Property

The generation of exRNA reference profiles may involve collaborations with other organizations such as academic, other government agencies, and/or non-profit research institutions not directly involved in the NIH-funded Extracellular RNA Program. NIH recognizes that intellectual property rights are likely to play an important role in achieving the goals of this program. To this end, all awardees shall understand and acknowledge the following:

• The awardee is solely responsible for the timely acquisition of all appropriate proprietary rights, including intellectual property rights, and all materials needed for the applicant to perform the project.
• Before, during, and subsequent to the award, the U.S. Government is not required to obtain for the awardee any proprietary rights, including intellectual property rights, or any materials needed by the awardee to perform the project.
• The awardee is required to report to the U.S. Government all inventions made in the performance of the project, as specified by 35 U.S.C. Sect. 202 (Bayh-Dole Act).

Awardees are expected to make new information and materials known to the research community in a timely manner through publications, web announcements, reports to the NIH Common Fund Extracellular RNA Steering Committee, and other mechanisms.

Data

Awardees will retain custody of and have primary rights to the data and resources developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

Publications

The Principal Investigator will be responsible for the timely submission of all abstracts, manuscripts and reviews (co)authored by project investigators and supported in whole or in part under this Cooperative Agreement. The Principal Investigator and Project Leaders are requested to submit manuscripts to the NIH Project Scientist within two weeks of acceptance for publication so that an up-to-date summary of program accomplishments can be maintained. Publications and oral presentations of work conducted under this Cooperative Agreement are the responsibility of the Principal Investigator and appropriate Project Leaders and will require appropriate acknowledgement of NIH support. Timely publication of major findings is encouraged.

Awardees will retain custody of and have primary rights to the data and resources developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

NIH Common Fund Extracellular RNA Project Scientists will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination. However, the role of NIH Common Fund Extracellular RNA Project Scientists will be to facilitate and not to direct the activities.

Each NIH Common Fund Extracellular RNA Project Scientist shall participate as a member of the NIH Common Fund Extracellular RNA Steering Committee.

The Project Scientists will:

• Participate (with the other Steering Committee members) in the group process of setting research priorities, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols, project milestones or approaches as warranted;
• Serve as a liaison between the awardees, the Advisory Councils for those Institutes that plan to administer elements of the NIH Common Fund Extracellular RNA Project and the larger scientific community;
• Coordinate the efforts of the awardee with others engaged in exRNA research, including other awardees under this FOA and those awardees involved in related NIH programs;
• Attend all Steering Committee meetings and assist in developing operating guidelines, quality control procedures, and consistent policies for dealing with recurrent situations that require coordinated action;
• Periodically report progress to the Directors, NIH institutes involved in the NIH Common Fund Extracellular RNA initiative and the Directors of the Division of Program Coordination, Planning, and Strategic Initiatives and Office of Strategic Coordination;
• Lend relevant expertise and overall knowledge of NIH-sponsored research to facilitate the selection of scientists not affiliated with the awardee institutions who are to serve as External Scientific Consultants;
• Serve as liaison between the Steering Committee and the External Scientific Consultants;
• Serve on subcommittees of the Steering Committee as appropriate;
• Provide advice in the management and technical performance of the investigation;
• Assist in promoting the availability of data and resources developed in the course of this project to the scientific community at large;
• Participate in data analyses, interpretations, and where warranted, co-authorship of the publication of results of studies conducted through this initiative;
• Assist awardees in the development, if needed, of policies for dealing with situations that require coordinated action;
• Retain the option to recommend the withholding or reduction of support from any cooperative agreement that either substantially fails to achieve its goals according to the milestones agreed to at the time of award, fails to maintain state-of-the-art capabilities, or fails to comply with the Terms and Conditions of the award.
• Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

A Steering Committee will serve as the main governing board of the Extracellular RNA Communications Consortium. The Steering Committee membership will include NIH Project Scientists and the PI of each awarded cooperative agreement. The PI of each award (or designee) will have one vote on the Steering Committee. The Project Scientists may vote, but the total votes will count as a maximum of one-third of the total number of votes. The Steering Committee Chair will not be an NIH staff member. Additional members may be added by action of the Steering Committee. Other government staff may attend the Steering Committee meetings, if their expertise is required for specific discussions. The Steering Committee will:

• Discuss progress in meeting the goals of various exRNA projects;
• Develop recommendations for uniform procedures and policies necessary to meet the goals of the Research Network, for example for data quality measures and assessment, conventions for data deposition, or measuring costs and throughput. Adoption of procedures and policies developed by the Steering Committee will require concurrence by External Scientific Consultants.
• The Steering Committee will also serve as a venue for coordination on the improvement of exRNA scientific methods, for example by disseminating best practices and collectively evaluating new procedures, resources, and technologies.
• The Steering Committee will consider collective goals for the Consortium, will determine how joint publication of results will contribute toward the goals of the exRNA Program, and will coordinate joint publication as needed to demonstrate overarching principles of exRNAs. It will schedule the time for, and prepare concise (3 to 4 pages) summaries of, the Steering Committee meetings, which will be delivered to members of the group within 30 days after each meeting.
• Each full member will have one vote. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

External Scientific Consultants:

• The External Scientific Consultants (ESC) will be responsible for reviewing and evaluating the progress of the exRNA Communications Consortium toward meeting their individual and collective goals. The ESC will be appointed by and provide recommendations to the NIH about continued support of the components of the Consortium. The Consultant Panel is composed of four to six senior scientists with relevant expertise who are not PIs of a cooperative agreement involved in the Consortium. The membership of the ESC may be enlarged permanently, or on an ad hoc basis, as needed.
• The ESC will meet at least once a year. During part of this meeting, there will be a joint meeting with the Steering Committee to allow the ESC to interact directly with the awardees. Annually, the ESC will make recommendations regarding progress of the Consortium and present advice about changes, if any, which may be necessary to the NIH.

When multiple years are involved, awardees will be required to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

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Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: [email protected]

Pothur R. Srinivas, Ph.D., MPH
National Heart Lung and Blood Institute (NHLBI)
Telephone: 301-402-3712
Email: [email protected]

Richard Panniers, Ph.D.
Center for Scientific Review (CSR)
Telephone: 301-435-1741
Email: [email protected]

Tracee S. Foster
National Heart Lung and Blood Institute (NHLBI)
Telephone: 301-402-3843
Email: [email protected]

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

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 Part 52 and 45 CFR Parts 74 and 92.