Background
It is well established that the gut microbiome is essential for human health, since maturation and homeostasis of the immune system depends on intestinal flora. In respiratory medicine, the lung microbiome has also emerged as unique and potentially having a pivotal role in determining disease course and response to treatment. Since the seminal work of the NIH Common Fund-sponsored Human Microbiome Project (HMP) and Integrative HMP (iHMP), as well as NHLBI initiatives such as the Lung HIV Microbiome Project, we have gained vast knowledge about the microbiome composition and the dynamic associative relationships that exist with the host in the gut, skin, oral cavity, lung, and urogenital tract. Changes in microbial composition and relative abundance of the human microbiome, known as dysbiosis, have been described for a variety of autoimmune and metabolic diseases and conditions within the interest of NHLBI mission such as asthma, COPD, cystic fibrosis, diabetes and obesity, hypertension, graft versus host disease (GVHD), coronary disease, sleep disorders, and pulmonary fibrosis. Although a few areas have made progress toward showing the functional role of the microbiome, most host-microbiome studies performed to date have been largely associative, and the detailed processes by which the microbiota can influence the host remain elusive. As we are starting to understand the extent of these complex and dynamic microbe-host exchanges, research opportunities emerge to identify and characterize such microbial-host interactions, which are critical to designing microbiome-based interventions for prognostic, diagnostic and treatment purposes in a variety of diseases and conditions in which the microbiome plays a critical role.

Research Scope
With the vast evidence associating microbiome disturbance with disease, we can address a substantial gap in our understanding of how changes in the bacterial, viral, and fungal microbiota in the gut, lung and/or oral cavity may affect distal organ/mucosal sites directly through microbial translocation, through signaling mechanisms and/or bioactive molecules, or via crucial immune stimulation/activation of key regulatory pathways early in life . Bi-directional host signaling and environmental factors such as the timing and availability of nutrients shape microbiota composition, function, and metabolites. Recent advances indicate that irregularities in circadian-dependent host functions such as mucosal barriers, defensins, and immune cells are associated with markers of dysbiosis and the risk of disease.

The regulatory and metabolic capacity of the human microbiome may also play a fundamental role in the conversion of drugs and priming the immune system. Understanding drug transformation through microbial metabolism is increasingly necessary, and it may lead to the discovery of biomarkers that could correlate with therapeutic success or treatment outcome. Conversely, drug treatments have the potential of altering the host microbiome, which can act as a surrogate biomarker during a course of therapy leading to implementation of necessary adjustments at the individual level.

Objectives
The objective of this FOA is to attract investigator-initiated multidisciplinary R01 research projects to define mechanistic interactions between the microbiome (gut/lung/oral or combinations) that influence normal physiology and pathophysiology of diseases within NHLBI's mission (see NHLBI Strategic Vision and mission). This FOA aims to address this gap in causation, leveraging the use of available biospecimens from existing cohorts and biobanks, using state of the art technologies (including high throughput sequencing, transcriptomics, proteomics, metabolomics, single cell profiles) and animal models, if applicable, with the goal to further our understanding of the complex microbiome-host interactions and functions. This FOA also encourages multidisciplinary collaborations among scientists in a wide range of disciplines including those with HLBS expertise (pulmonologists, cardiologists, hematologists, sleep and circadian experts ), immunology, microbiome and microbial ecology, metabolism, genomics, other '-omics' sciences, and bioinformatics.

Specific Areas of Research Interest
Potential examples of the scientific questions that could be addressed in response to this FOA include, but are not limited, to the following :

• What specific microbial metabolites or microbial activated pathways contribute to poor outcomes such as immune dysfunction and disease relapse following hematopoietic stem cell transplantation?
• What specific microbial metabolites or microbial-activated pathways contribute to blood pressure regulation?
• What is the influence of the gut and/or lung microbiome on processes associated with the progression of pulmonary fibrosis (e.g., alveolar epithelial injury, fibroblast differentiation, extracellular matrix remodeling, immune cell activation)?
• What is the role of microbiota in the pathogenesis of sickle cell disease, such as patients presenting with vaso-occlusive crisis ?
• What circadian abnormalities in host and microbiota functions impair hormonal, metabolic, and immunological inter-relationships associated with HLBS pathobiology and disease?
• What host mechanisms are affected by sleep deficiency and lead to pathobiological changes in microbiota composition associated with increased risk of disease?
• What is the impact of the donor and/or recipient gut microbiome on graft survival following lung transplantation (e.g., what are the mechanistic associations between the gut microbiome and the development of lung allograft rejection)?
• What are the interactions between host and microbiome (activation pathways and molecules) that contribute to differences in clinical phenotypes and disease courses between patients?
• How does the microbiota or microbial metabolites impact hematopoiesis, the hematopoietic niche, and blood stem cell homing?
• Elucidate the networks between innate and adaptive immunity in HLBS diseases and the effect of dysbiosis in such networks.
• What role does the microbiome play in the formation of Factor VIII ( FVIII) inhibitors in patients with Hemophilia A?

This FOA is not intended to support the following types of projects:

• Applications that propose patient-oriented research such as clinical trials or epidemiological research.
• Applications focused solely on characterization of the microbiome (e.g., 16S analysis only).

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

• 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

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.

Letter of Intent

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
Telephone: 301-435-0270
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. 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: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide. When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information
All instructions in the SF424 (R&R) Application Guide must be followed with the following additional instructions: All instructions in the SF424 (R&R) Application Guide must be followed. Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

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 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?

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.

Not Applicable

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.

Not Applicable

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

Division of Lung Diseases
Emmanuel Mongodin, PhD
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-827-5968
Email: emmanuel.mongodin@nih.gov

Division of Blood Diseases
Ronald Warren, Ph.D.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-827-8288
Email: ronald.warren@nih.gov

Division of Cardiovascular Sciences
Youngsuk Oh, Ph.D..
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0560
Email: yoh@nhlbi.nih.gov

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

John Bucheimer
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-827-8018
Email: JohnBucheimer@mail.nih.gov

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.