It is critical that applicants follow the Research (R) 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 purpose of this funding opportunity announcement (FOA) is to encourage applications that propose systems biology approaches using clinical samples from HIV-infected patients to elucidate the mechanisms underlying HIV-related heart, lung, blood, and sleep (HLBS) comorbidities. The ultimate goal is to better understand disease progression, which may help identify new therapeutic targets that pre-empt the onset of HLBS comorbidities in the HIV population.

The pathogenesis of HIV-related HLBS comorbidities is likely multifactorial due to a complex interplay of HIV, inflammation, antiretroviral therapies (ARTs), co-infections, and traditional risk factors. Many of the HLBS comorbidities in ART-treated, HIV-infected patients could be related to the same or similar pathophysiological processes found in the general population, such as inflammation. Because of their heightened state of inflammation that begins at the time of infection, HIV-infected individuals may present a natural, accelerated model to better understand the role of inflammation in the progression of HLB diseases and sleep disorders.

Despite advancements in animal models currently in use for HIV research (e.g., humanized rodent models and non-human primates infected with simian immunodeficiency virus), the field remains constrained by the absence of animal models that fully recapitulate all aspects of infection and pathogenesis of HIV in patients. Thus, in order to accurately define the progression of HIV-related HLBS conditions with clinical outcomes, it is critical to utilize patient biospecimens.

A 2015 NHLBI Working Group on "Refining Current Scientific Priorities and Identifying New Scientific Gaps in HIV-Related HLBS Research" indicated a need for patient biospecimens to identify biomarkers to assess the risk of HIV-related HLBS comorbidities and elucidate underlying pathophysiological mechanisms. The Working Group members identified the importance of considering an individual's variability in genes, environment, lifestyle, and drug regimen in the treatment of HIV-related HLBS conditions. The participants recommended that a reverse translational systems biology approach (i.e., experimental and computational methods) from clinical phenotype to biological mechanisms was needed to characterize HIV-related HLBS comorbidities.

Synergistic approaches that combine experimental omics, computational methods, and clinical endpoints have the potential to open new avenues for research in HIV-related HLBS comorbidities. These strategies can be exploited to identify new molecules/biomarkers and biological pathways involved in normal physiology and diseased states. These methods may help to answer questions such as: 1) do chronic diseases in the blood and heart share similar pathophysiologic mechanisms?; and 2) is the same chronic inflammation found in the lung important for the development of cardiovascular or blood diseases in HIV infection? Cooperation between scientists and clinical cohort studies examining similar pathophysiologic mechanisms in and across different organ systems will provide key information about common pathological features in the context of HIV infection.

This FOA is designed to address the recommendations from the Working Group by stimulating the use of integrated approaches to answer questions of significance to HIV-related HLBS conditions.

This FOA invites investigators to conduct research on the fundamental mechanisms of HIV-related HLBS comorbidities. Projects would be expected to analyze clinical samples using omics approaches and computational modeling to elucidate the perturbations in genes, proteins, metabolites, and signaling pathways associated with the development of HIV-related HLBS conditions.

Study Design. The primary goal is to advance understanding of the molecular underpinnings of HIV-related HLBS comorbidities. Applications should propose statistically valid, hypothesis-driven, or hypothesis-generating, evidence-based projects aimed at elucidating cellular processes and molecular events that are altered by HIV and lead to the accelerated progression of HIV-related HLBS comorbidities. All project aims should align with the NIH Office of AIDS Research high priority scientific areas (NOT-OD-15-137).

Responsive applications must utilize patient samples along with any available clinical data from HIV-infected subjects by either leveraging existing resources with stored biospecimens or proposing to collect new biospecimens (e.g., plasma, serum, cells, and tissue) over multiple timepoints to the extent possible to characterize disease progression. It is suggested that applicants follow guidelines for labeling and storage recommended by biorepositories, such as the NHLBI Biologic Specimen and Data Repository (BioLINCC). In alignment with the NIH policy on the consideration of sex as a biological variable (NOT-OD-15-102), use of clinical samples from both sexes would be highly encouraged.

It is strongly encouraged that proposed projects utilize multiple omics technologies to examine available human subject samples. The omics approaches could include, but not be limited to: 1) genomics to define the genetic mapping and DNA sequencing of gene sets or the complete genome; 2) transcriptomics to identify the complete set of RNA transcripts produced by the genome; 3) proteomics to assess protein level changes and post-translational modifications; 4) epigenomics to study changes in the regulation of gene activity and expression independent of gene sequence; and 5) metabolomics to generate metabolite profiles of the functional state of the patient.

Applications would also be expected to integrate, visualize, and analyze the omics data using computational strategies to identify perturbations in the networks and pathways underlying HIV-related HLBS comorbidities. A key goal of applications submitted to this initiative will be to generate novel hypotheses in the HIV HLBS research space. Thus, applicants only need to provide preliminary data and/or other supporting evidence indicating that the research team has the ability to complete the proposed work. Applicants should propose to validate one or more of the hypotheses generated through their investigation. Investigators are expected to have data sharing plans to ensure that the large volumes of omics datasets generated are available to the scientific community and deposit data in publically accessible databases.

Leveraging Existing Research Infrastructure. A key objective of this initiative is to encourage investigators to leverage available research resources, such as existing clinical cohorts, biological specimens, or imaging banks whenever possible. Existing research infrastructure may include NHLBI-supported studies and repositories, as well as programs supported by other NIH Institutes, which have accompanying clinical data. Investigators proposing to leverage resources from existing programs should follow the standard procedures for concept submission and review by the scientific committees of those programs.

Specific examples of existing research infrastructure include, but are not limited to:

• Ongoing and/or completed NIH observational cohorts and clinical trials (ClinicalTrials.gov)
• Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE)
• The National Myelodysplastic Syndromes (MDS) Study
• Multicenter AIDS Cohort Study (MACS)
• Women’s Interagency HIV Study (WIHS)
• AIDS Clinical Trials Group (ACTG)
• Centers for AIDS Research (CFAR) Network of Integrated Clinical Systems (CNICS)
• International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)
• Pediatric HIV/AIDS Cohort Study (PHACS)
• Veterans Aging Cohort Study (VACS)
• NHLBI Biologic Specimen and Data Repository (BioLINCC)
• NCI Repositories

Investigator Expertise. Applicants are strongly encouraged, but not required to use the multiple program director/principal investigator (PD/PI) mechanism to facilitate collaborations between HLBS and HIV investigators. Areas of expertise that may be represented include infectious diseases, immunology, cell biology, omics (including genomics, transcriptomics, proteomics, epigenomics, metabolomics, and the handling of large data sets), molecular biology, and computational modeling. Early career investigators are strongly encouraged to apply to gain exposure to HIV-related HLBS research.

Grantee Meetings.

Grantee Meetings. Upon initiation of the program, the NHLBI will arrange annual meetings to encourage the exchange of information among the investigators who participate in this program. At these meetings, investigators will present their results, help evaluate the progress of this FOA, and have the opportunity to form collaborations. Attendance at these meetings will be required.

Examples of research topics include, but are not limited to those listed below:

• Define the omics signatures/biomarkers (e.g., protein post-translational modifications) of whole organ/subcellular compartments (e.g., mitochondria) and biochemical pathways that are elevated and/or unique to the phenotype of HIV-related cardiovascular diseases (e.g., myocardial infarct, heart failure with preserved ejection fraction, and coronary artery disease) and lung diseases (e.g., chronic obstructive pulmonary diseases, pulmonary hypertension, and pulmonary fibrosis)
• Investigate how pathways of inflammation, aberrant fibrosis, and left ventricular remodeling contribute to HIV-related cardiac injury
• Establish whether thrombosis and vessel remodeling play a role in HIV-related vascular injury and if these processes are accelerated in HIV
• Study whether exosomes from HIV-infected cells lead to metabolic changes and cellular dysfunction and whether they may be utilized as potential biomarkers to predict HIV-related CVD and venous thromboembolism (VTE)
• Investigate the mechanisms that result in the HIV hypercoaguable state and the impact of HIV infection, as well as the adverse effects of HIV medications
• Assess the interplay of inflammation, immune dysregulation, or endothelial, platelet, and coagulation activation in the etiology of HIV vascular events
• Define the relationship between clonal hematopoiesis of indeterminate potential (CHIP) and inflammation in age-related acquisition of somatic mutations and its association with HIV infection
• Explore approaches to address coagulation and endothelial activation to reduce HIV CVD and VTE risk
• Discriminate the effect of HIV infection from that of natural aging and from the mutagenesis observed in myelodysplastic syndromes (MDS) to address senescence of human bone marrow cells
• Elucidate the differences in gene mutations and growth factors that are involved in the abnormal proliferation of small vessel smooth muscle and endothelial cells during HIV-related pulmonary arterial hypertension and embolism
• Characterize how chronic HIV infection leads to lung remodeling and dysfunctional repair mechanisms utilizing metabolomics and transcriptomics approaches to detect alterations in gene regulation and downstream metabolic pathways
• Define early biomarkers triggered by HIV infection that influence circadian rhythms and lead to sleep disorders

• Applications that do not propose to utilize samples from human subjects.
• Applications that do not have a primary focus on HIV-related heart, lung, blood, and sleep comorbidities.
• Applications that focus on topics identified as low priority scientific areas by the NIH Office of AIDS Research (NOT-OD-15-137).
• Applications that propose clinical trials as defined by the NIH in NOT-OD-15-015. Clinical trial applications must be submitted through a FOA specifically designed for clinical trials (NOT-OD-16-147), such as PAR-16-300, PAR-16-301, PAR-16-405, or their reissuances if applicable.

Non-responsive applications will not be reviewed.

See Section VIII. Other Information for award authorities and regulations.

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:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o 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
• 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) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not 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. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. 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.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions 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:

Director, Office of Scientific Review
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7214
Bethesda, MD 20892-7924 (Express Mail Zip: 20817)
Telephone: 301-435-0279
Email: nhlbichiefreviewbranch@nhlbi.nih.gov

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

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. Additional instructions are below:

• Applicants are strongly encouraged, but not required to use the multiple program director/principal investigator (PD/PI) mechanism to facilitate collaborations between HLBS and HIV investigators.
• Areas of expertise that may be represented include infectious diseases, immunology, cell biology, omics (including genomics, transcriptomics, proteomics, epigenomics, metabolomics, and the handling of large data sets), molecular biology, and computational modeling.
• Early career investigators are strongly encouraged to apply to gain exposure to HIV-related HLBS research.

All instructions in the SF424 (R&R) Application Guide must be followed. Additional instructions are below:

Grantee Meetings. Investigators should allocate support for 1-2 representatives from each research team to travel to four grantee meetings in or near Bethesda, MD each project year.

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, with the following additional instructions:

Research Strategy: Use this section to describe how th project will utilize patient samples along with clinical data from HIV-infected subjects by either leveraging existing resources with stored biospecimens or proposing to collect new biospecimens in a manner appropriate for rigorous omics analyses. For example, the MACS, WIHS, and Veterans Aging Cohort Study (VACS) cohorts have available plasma, serum, or cell samples with accompanying clinical endpoints from HIV patients for investigator use. The projects would also be expected to apply omics approaches and computational modeling to elucidate the perturbations in genes, proteins, metabolites, and signaling pathways associated with the development of HIV-related HLBS comorbidities.

In the research strategy, include the following:

• Clear justification of why the proposed basic science research specifically addresses an important area in HIV-related HLBS comorbidities.
• Plans to facilitate communication and collaboration among multi-disciplinary investigator teams (e.g., team meetings, teleconferences, and websites).
• A timeline highlighting plans for initiation and completion of the research based on the required internal reviews of the leveraged programs
• A statement indicating willingness to participate in Grantee Meetings arranged by the NHLBI.

Letters of Support:

Applicants proposing to seek support from existing cohorts, resources, biorepositories, industry, or other third parties must include a letter of agreement from the leadership of the relevant leveraged program/entities confirming permission to use the infrastructure. The letter must include a clear description of access to any new or archived specimens and data and to animal models (if applicable), as required for the proposed studies. Such agreements must be in compliance with NHLBI policies on third party involvement (http://www.nhlbi.nih.gov/funding/policies/thirdparty.htm).

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans 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 PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

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

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. 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. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to 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 and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

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. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

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 and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in the policy.

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.

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? 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?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those 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? Does the application include plans for multi-disciplinary collaboration from HIV and HLBS investigators? Is there a clear description of how the investigators will facilitate collaboration and communication among multi-disciplinary teams and integrate HIV and relevant HLBS expertise?

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 overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? 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? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects? Does the application leverage existing resources and/or programs to enhance HIV-related HLBS comorbidities research? Has the investigator provided Letters of Support from the leadership of the leveraged program confirming permission to use the infrastructure of the program? Have the investigators provided a reasonable timeline of when they will be able to initiate and complete research, based on the required internal reviews of the leveraged programs?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

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.

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.

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

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.

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

For Renewals, the committee will consider the progress made in the last funding period.

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.

Not Applicable

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).

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) Genomic Data Sharing Plan (GDS).

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

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 NHLBI, 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 NHLBI Advisory Council. 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. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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 terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this 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.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually 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.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)

Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726

Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)

Telephone: 301-710-0267

Renee Wong, Ph.D.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-451-6808
Email: wongr2@nhlbi.nih.gov

Director, Office of Scientific Review
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0279
Email: nhlbichiefreviewbranch@nhlbi.nih.gov

Erin Davis
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-402-3839
Email: erin.davis@nih.gov

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 Part 75.