National Institutes of Health (NIH)
Funding Opportunity Title
Lymphatics in Health and Disease in the Digestive, Cardiovascular and Pulmonary Systems (R21)
R21 Exploratory/Developmental Research Grant Award
Funding Opportunity Announcement (FOA) Number
Companion Funding Opportunity
Catalog of Federal Domestic Assistance (CFDA) Number(s)
93.847, 93.837, 93.838, 93.839
Funding Opportunity Purpose
This FOA is to encourage Exploratory/Developmental Grant (R21) applications for research into aspects of lymphatic vessel physiology and pathophysiology related to health and disease of digestive, cardiovascular and pulmonary system organs and resolution of thromboembolic events, and inflammation and immune responses as they relate to these diseases. However, studies with the major focus on immune mechanisms will not be considered responsive. Studies to understand the factors that control local lymphatic vessel functional anatomy and physiology during health or disease in these organs and systems, and the mechanisms by which alterations of lymphatic vessel function affect organ function, are of interest.
August 8, 2012
Open Date (Earliest Submission Date)
September 16, 2012
Letter of Intent Due Date
Application Due Date(s)
Standard dates apply, by 5:00 PM local time of applicant organization.
AIDS Application Due Date(s)
Standard dates apply.
Scientific Merit Review
Standard dates apply.
Advisory Council Review
Standard dates apply.
Earliest Start Date(s)
Standard dates apply.
September 8, 2013
Due Dates for E.O. 12372
Required Application Instructions
It is critical that applicants follow the instructions in the SF 424 (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
Lymphatic vessels, a major component of most organs in the body, perform critical roles in organ functions. Their role in disease is poorly understood and rarely studied. This announcement encourages applications for research on lymphatic vessel physiology and pathophysiology related to health and disease of the digestive, cardiovascular and pulmonary systems, resolution of thromboembolic events, and inflammation and immune responses as they relate to these diseases. However, studies with the major focus on immune mechanisms are not applicable. Studies to understand the factors that control lymphatic vessel functional anatomy and physiology during health or disease, and the mechanisms by which alterations of normal lymphatic vessel structure and function affect the systems and processes enumerated above are of interest.
The lymphatic system is a crucial component of nutrient and hormone absorption, fluid homeostasis and immunity. In the digestive system, lymphatic vessel function is interwoven with organ function, both anatomically and physiologically and these vessels lie at the nexus of critical hormonal, digestive and immune functions. For example, each villus in the small intestine has a lymphatic vessel, the lacteal, associated with it, that is instrumental in absorption of digested fats. Lymphatic vessels selectively transport certain hormones from enteroendocrine cells, provide a major absorption pathway for some drugs, and are the route of uptake of some nutrients, in addition to fats. Lymphatic endothelium mediates passage of immune cells through an array of adhesion molecules and chemokines. Thus, lymphatic vessels potentially play active roles in the relationship of gut health to the microbiome and in inflammatory disease, however the factors that affect these roles, and the resultant effects on the local tissue, are underexplored. Even less is understood about lymphatics in other organs of the digestive system, such as liver. Research in some organs demonstrates that lymphatic vessels have altered numbers and morphologies under conditions of inflammation. Yet, we know very little about the normal micro-anatomy, regulation, and interactions of lymphatics in the digestive system in the context of health and even less in the context of digestive diseases and inflammation. Similarly, little is understood regarding lymphangiogenesis in digestive system organs. Altered function of the lymphatic vessels has the potential for far-reaching consequences to digestive system function and overall health. For example, loss of lymphatic fluid and plasma protein into the gastrointestinal lumen is associated with inflammatory bowel disease and leads to edema and hypoproteinemia. Edema associated with insufficient lymphatic drainage has been associated with fat deposition in localized areas of the body, yet mechanisms for this effect are unclear.
Whether and how lymphatic drainage affects transplant of digestive organs is also unclear. Furthermore, as a transportation system that intersects with the blood circulatory system, the lymphatic vessels and lymph from the gut have the potential to affect distant organs (e.g., cardiopulmonary function). Research on lymphatic vessels of digestive organs holds the potential for greater understanding of not only lymphatic system function, and local organ function, but whole body health, as well.
On November 3-4, 2009, the NIDDK sponsored an exploratory workshop on Lymphatics and the Digestive System: Physiology, Health and Disease. In addition to reviewing current relevant research, major questions for future research were also identified through participant discussions. This announcement for R21 applications is to stimulate research in response to these needed, important questions in the digestive system. It is recognized that research on lymphatics in the digestive system may require novel scientific ideas or new model systems, tools or technologies for which there is little preliminary information but which will have a significant impact on future research. This announcement for R21 applications is intended to support such novel research. Studies on the role of lymphatic vessels in the function of organs of interest to the NIDDK are encouraged.
Specific areas of interests for the National Heart, Lung, and Blood Institute (NHLBI) include approaches that will identify the genetic, molecular, and cellular defects that contribute to congenital malformation of the lymphatic system; congenital-lymphatic-malformation-induced pulmonary dysfunction; whether and how lymphangiogenesis affects cardiovascular and pulmonary diseases; whether and how lymphatic drainage affects transplant of heart or lungs; whether and how lymphatic vessel hyperplasia in the dermal interstitium is involved in salt-sensitive hypertension; and whether and how the manipulation of platelet-lymphatic endothelial cell interaction may provide clinical benefit during thromboembolic events.
Studies that focus on mechanisms of immunity are not appropriate to this announcement. Clinical research and clinical trials are not intended to be supported under this Funding Opportunity Announcement.
Examples of research areas of interest under this program announcement include, but are not limited to the following:
1. What are the mechanisms whereby altered lymphatic vessel structure and function affect organ health and function? Do lymphatic vessels have a role in disease initiation and propagation?
2. Is lymphatic vessel structure and function altered in the presence of inflammation in organs of the digestive system, heart or lungs, and what are the mechanisms involved?
3. Is lymphangiogenesis affected in disease conditions affecting the digestive system, cardiovascular system or pulmonary system, and what mechanisms are involved?
4. Is lymph composition from digestive organs actively modulated and how?
5. Does lymph composition originating from diseased digestive tract impact cardiopulmonary health?
6. What are the roles of lymph vessel anatomy and cell junctions in sampling of the environment of the mucosa? How does this relate to the microbiome and maintenance of mucosal homeostasis?
7. Is there a relationship between regional drainage of lymph and local accumulation of fat in organs? What are the mechanisms involved and how does this relate to organ function?
8. What are the mechanisms by which impaired lymph pumping or transport affect nutrient transport, hormonal transport and water transport from digestive organs?
9. Are there organ-specific characteristics of vessels of the lymphatic system?
10. What is the interplay of gut microbiome and dietary constituents on the structure and function of lymphatic vessels?
11. How do environmental factors such as diet and dietary constituents change the structure and function of local lymphatic vessels as they relate to the health and disease of digestive system organs?
12. Normal lymphatic vascular development is regulated through the interactions of platelets and lymphatic endothelial cells. Can platelet/endothelial cell interaction be manipulated to regulate lymphangiogenesis, reduce localized swelling, and prevent thromboembolic events?
13. What are lymphatic remodeling pathways in airway inflammatory diseases?
14. Does lymphangiogenesis have a role in atherosclerosis and, if so, through what mechanism(s)?
15. What is the role of the lymphatic system in reverse cholesterol transport?
16. What is the role of lymphatic vessels in the dermal interstitium in salt balance and in salt-sensitive hypertension?
17. What is the role of lymphatic drainage in normal cardiac function and recovery after cardiac injury, such as myocardial infarction?
Application Types Allowed
Funds Available and Anticipated Number of Awards
The number of awards is contingent upon NIH appropriations, and the submission of a sufficient number of meritorious applications.
Application budgets are limited to $125,000 in direct costs per year for R21 applications.
Award Project Period
The scope of the proposed project should determine the project period. The maximum period is 2 years for an R21 project.
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
The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
Nonprofits Other Than Institutions of Higher Education
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.
Applicant organizations must complete the following registrations
as described in the SF 424 (R&R) Application Guide to be eligible to apply
for or receive an award. Applicants must have a valid Dun and Bradstreet
Universal Numbering System (DUNS) number in order to begin each of the following
All Program Director(s)/Principal Investigator(s) (PD(s)/PI(s))
must also work with their institutional officials to register with the eRA
Commons or ensure their existing eRA Commons account is affiliated with the eRA
Commons account of the applicant organization.
All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least 4-6 weeks prior to the application due date.
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 PD(s)/PI(s), visit the Multiple Program Director(s)/Principal Investigator(s) Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF 424 (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 in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed. Resubmission applications may be submitted, according to the NIH Policy on Resubmission Applications from the SF 424 (R&R) Application Guide.
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.
The forms package associated with this FOA includes all applicable components, mandatory 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.
All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:
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.
Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
Foreign (non-US) 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 in advance of the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.
Organizations must submit applications via 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.
Applicants are responsible for viewing their application 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 SF 424 (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.
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF 424(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.
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 Central Contractor Registration (CCR). 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, NIH. Applications that are incomplete will not be reviewed.
In order to assist investigators in the course of their research, the NIDDK and NHLBI will host up to one meeting of the Program Director(s)/Principal Investigator(s) supported under this announcement to join investigators supported under the companion announcements for exchange of research advances, techniques and tools. The meeting will be held in the Bethesda, MD area. Investigators are advised that they may include costs to attend one such investigator meeting in their requested budget.
Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115
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.
For this particular announcement, note the following:
The R21 exploratory/developmental grant supports investigation of novel scientific ideas or new model systems, tools, or technologies that have the potential for significant impact on biomedical or biobehavioral research. An R21 grant application need not have extensive background material or preliminary information. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications; however, they may be included if available.
Reviewers will provide an overall impact/priority 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? 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 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(s)/PI(s), 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?
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?
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?
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/priority 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 Human Subjects Protection and Inclusion Guidelines.
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 Human Subjects Protection and Inclusion Guidelines.
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.
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.
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/priority 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. Review assignments will be shown in the eRA Commons.
As part of the scientific peer review, all applications:
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. 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:
After the peer review of the application is completed, the PD(s)/PI(s) 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
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, CCR 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
When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) 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.
We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.
GrantsInfo (Questions regarding application instructions and
process, finding NIH grant resources)
eRA Commons Help Desk (Questions regarding eRA Commons
registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
Jill L. Carrington, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
H. Eser Tolunay, Ph.D.
Division of Cardiovascular Sciences
National Heart, Lung, and Blood Institute
Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).
Grants Management Specialist
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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.
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