Expired PA-13-197: The Role of Extracellular RNA in Mediating the Health Effects of Alcohol (R21)

Part 1. Overview Information

Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Funding Opportunity Title	The Role of Extracellular RNA in Mediating the Health Effects of Alcohol (R21)
Activity Code	R21 Exploratory/Developmental Research Grant Award, Development, Programs
Announcement Type	New
Related Notices	NOT-OD-16-004 - NIH & AHRQ Announce Upcoming Changes to Policies, Instructions and Forms for 2016 Grant Applications (November 18, 2015) NOT-OD-16-006 - Simplification of the Vertebrate Animals Section of NIH Grant Applications and Contract Proposals (November 18, 2015) NOT-OD-16-011 - Implementing Rigor and Transparency in NIH & AHRQ Research Grant Applications (November 18, 2015) June 3, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same. August 21, 2013: Removed reference to ASSIST in section IV.3, since ASSIST is currently only available for multi-project applications. May 30, 2013 (NOT-OD-13-074) - NIH to Require Use of Updated Electronic Application Forms for Due Dates on or after September 25, 2013. Forms-C applications are required for due dates on or after September 25, 2013.
Funding Opportunity Announcement (FOA) Number	PA-13-197
Companion Funding Opportunity	None
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.273
Funding Opportunity Purpose	The purpose of this FOA is to provide support for innovative research into the role of extracellular RNA (exRNA) in the development of alcohol-related diseases and end-organ injuries. As used here, the term exRNA refers to RNA molecules circulating outside of cells, either within vesicles or associated with carrier molecules. It is anticipated that this FOA will generate data that may lead to breakthroughs in our understanding of the role of exRNA communication in the initiation, progression and maintenance of the diverse medical disorders caused by excessive, long-term alcohol consumption. In the future this knowledge may be critical in the diagnosis, treatment and management of vulnerable patient populations debilitated by the vast array of alcohol-induced pathologies and enable clinicians to improve disease outcomes and, consequently, public health. In addition, research supported by this FOA may also provide information on the mechanistic basis of the health benefits of moderate alcohol consumption.

Key Dates

Posted Date	April 15, 2013
Open Date (Earliest Submission Date)	May 16, 2013
Letter of Intent Due Date(s)	Not Applicable
Application Due Date(s)	Standard dates apply, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
AIDS Application Due Date(s)	Standard AIDS dates apply, by 5:00 PM local time of applicant organization.
Scientific Merit Review	Standard dates apply
Advisory Council Review	Standard dates apply
Earliest Start Date	Standard dates apply
Expiration Date	May 8, 2016
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Table of Contents

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

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

The purpose of this FOA is to provide support for innovative research into the role of extracellular RNA (exRNA) in the development of alcohol-related diseases and end-organ injuries. As used here, the term exRNA refers to RNA molecules circulating outside of cells, either within vesicles or associated with carrier molecules. It is anticipated that this FOA will generate data that may lead to breakthroughs in our understanding of the role of exRNA communication in the initiation, progression and maintenance of the diverse medical disorders caused by excessive, long-term alcohol consumption. In addition, research supported by this FOA may also provide information on the mechanistic basis of the health benefits of moderate alcohol consumption.

The R21 mechanism is intended to encourage new exploratory and developmental research projects. For example, such projects could assess the feasibility of a novel area of investigation or a new experimental system that has the potential to enhance health-related research. Another example could include the unique and innovative use of an existing methodology to explore a new scientific area. These studies may involve considerable risk but may lead to a breakthrough in a particular area, or to the development of novel techniques, agents, methodologies, models, or applications that could have a major impact on a field of biomedical, behavioral, or clinical research.

Applications for R21 awards should describe projects distinct from those supported through the traditional R01 mechanism. For example, long-term projects, or projects designed to increase knowledge in a well-established area, will not be considered for R21 awards. Applications submitted under this mechanism should be exploratory and novel. These studies should break new ground or extend previous discoveries toward new directions or applications.

Background

Excessive and chronic alcohol consumption damages virtually all tissues of the body, increases the risk of certain cancers, and can cause birth defects, resulting in major public health concerns. Moreover, excessive alcohol consumption also imposes a substantial economic burden in terms of health care costs and lost productivity. Despite impressive progress in the field, the mechanisms driving the onset and progression of alcohol-related diseases are still not fully understood. This is due to the complex actions of alcohol exerting its effects on multiple systems in living tissue. In contrast to other drugs and toxins, alcohol simultaneously induces disturbances in homeostasis at multiple sites, which together determine the course of the disease.

Alcohol-induced diseases have been traditionally studied as organ-specific diseases. During the past four decades, important scientific advances have provided insight into how alcohol and its metabolism affects individual systems in brain, liver, immune, cardiovascular, and endocrine systems. However, there is an increasing realization of the importance of understanding interactions between different organs and systems in the presence of alcohol. Emerging data indicate that these interactions could provide important insights into the mechanisms by which alcohol-induced pathology in one organ influences the functioning of other organs, leading to the multiple organ dysfunction often observed in alcohol abuse. As such, a comprehensive understanding of how alcohol influences the communication between different cells and tissues is clearly important, not only for understanding the toxic effects of alcohol abuse on the human body, but also for understanding how moderate alcohol consumption can have health benefits.

Until recently, RNA was thought to function exclusively within cells, as the product of transcription of genomic DNA. However, it is increasingly clear that a substantial fraction of RNA can be found outside of cells, circulating within the extracellular space and in body fluids. Much of this extracellular RNA (exRNA) is found within membrane-bound vesicles that are secreted by many, if not all, cell types. ExRNA containing vesicles can be detected in many bodily fluids, including blood, urine, cerebrospinal fluid, saliva, breast milk, and amniotic fluid. RNA within exosomes produced by one cell type can modulate the biology of recipient cells, indicating that secretion of exosomal RNA represents a novel mode of intercellular communication. In addition to RNA exosomes contain common and cell-type specific proteins, as well as a variety of RNA molecules. ExRNA can also be found outside of exosomes, associated with carriers such as Argonaute or high-density lipoprotein. Less information is available about the biosynthesis and function of this non-exosomal exRNA, but recent evidence indicates the potential of this material as a biomarker of disease.

To date, the rapid advances in exosome biology and studies of extracellular RNA have had a limited impact on alcohol research. Therefore, we encourage applicants to apply current approaches and methods of exosome science and extracellular RNA biology to important questions in alcohol research.

Some examples of research findings from studies of exRNA biology that are of potential relevance to alcohol research are:

Liver and Kidney Disease: ExRNA in the urine primarily reflects secretion from kidney cells. As such, urinary exosomes are under active investigation as biomarkers of kidney disease. However, changes in urinary exosomes can be observed in animal models of liver injury. There is also evidence that the profile of RNAs associated with HDL is altered in patients with familial hypercholesterolemia.
Neurologic Disease: Exosomes can be obtained from the cerebrospinal fluid, and changes in CSF exosomal markers have been documented in brain diseases including Alzheimer’s disease.
Pregnancy: During pregnancy, the trophoblast and placenta secrete exosomes that can be detected and characterized in serum. The composition of these exosomes changes during pregnancy, and alterations in exosomal contents has also been documented during pregnancy associated disease states such as pre-eclampsia.
Cardiovascular Disease: Alterations in exRNAs in serum have been documented in multiple cardiovascular diseases, including animal models of ischemic heart disease, heart failure, and coronary artery disease.
Cancer: Different tumor types secrete exosomes that may function in immunosuppression, but may also be valuable as prognostic or diagnostic biomarkers.
Gastrointestinal: Exosomes derived from intestinal epithelial cells contain MHC related peptides, and can interact with the immune system.
Infectious disease: Exosomes released from cells infected with bacterial pathogens can interfere with cytokine-mediated activation of immune macrophages.

Specific Areas of Research Interest

Areas of alcohol research to which exRNA biology could be applied include but are not limited to:

Investigation of exRNAs in urine or serum as biomarkers of reversible alcohol-related tissue injury, in either human clinically relevant samples or animal models.
Investigation of exRNAs from exosomes in urine or serum as biomarkers of the beneficial effects of moderate alcohol consumption, in either human clinically relevant samples or animal models.
ExRNA signaling in relation to fetal alcohol exposure.
Alterations in HDL-associated exRNAs under conditions of alcohol abuse and/or obesity
The role of exRNA signaling in gut-brain-liver-adipose tissue communication under conditions of damaging or beneficial alcohol consumption.
The role of exRNA signaling from peripheral organs in the addictive properties of alcohol
Studies of exRNA released from gut microbiota in relation to alcohol consumption
Transcriptomic investigation of exRNA composition in different animal models of alcohol exposure.
Changes in hepatic exRNA production during the initiation and progression of alcohol-related liver diseases including alcoholic hepatitis.
The role of exRNA in mediating or modulating the effects of alcohol on immune signaling and inflammation.

Section II. Award Information

Funding Instrument	Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
Application Types Allowed	New Resubmission Revision The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
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.
Award Budget	Direct costs may not exceed $200,000 in any year or $275,000 over the 2 year project period.
Award Project Period	The scope of the proposed project should determine the project period. The maximum period is 2 years.

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

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

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

Foreign Institutions

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

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

Required Registrations

Applicant Organizations

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

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

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

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

Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(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.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

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.

2. Content and Form of Application Submission

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.

Page Limitations

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

Required and Optional Components

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

SF424(R&R) Cover