Expired PA-14-068: Neurobiology of Migraine (R01)

Part 1. Overview Information

Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute of Neurological Disorders and Stroke (NINDS) National Institute on Alcohol Abuse and Alcoholism (NIAAA) National Institute on Deafness and Other Communication Disorders (NIDCD) National Institute of Dental and Craniofacial Research (NIDCR) National Center for Complementary and Integrative Health (NCCIH formerly NCCAM) Office of Research on Women’s Health (ORWH)
Funding Opportunity Title	Neurobiology of Migraine (R01)
Activity Code	R01 Research Project Grant
Announcement Type	Reissue of PA-10-258
Related Notices	May 10, 2017 - New NIH "FORMS-E" Grant Application Forms and Instructions Coming for Due Dates On or After January 25, 2018. See NOT-OD-17-062. April 27, 2017 - Notice to Extend the Expiration Date for PA-14-068. See Notice NOT-NS-17-027. 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 4, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same.
Funding Opportunity Announcement (FOA) Number	PA-14-068
Companion Funding Opportunity	PA-14-069, R21 Exploratory/Developmental Research Grant
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.853, 93.273, 93.173, 93.121, 93.213, 93.313
Funding Opportunity Purpose	This Funding Opportunity Announcement (FOA) is issued by the National Institute of Neurological Disorders and Stroke (NINDS) in conjunction with the NIH Pain Consortium. It solicits R01 grant applications from institutions/organizations to perform innovative research that will elucidate the mechanisms underlying migraine, expand our current knowledge of the role of genetic, physiological, biopsychosocial, and environmental influences in migraine susceptibility and progression, and explore new therapeutic targets and therapies for acute migraine management and longer term prevention.

Key Dates

Posted Date	January 13, 2014
Open Date (Earliest Submission Date)	May 5, 2014
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)	Not Applicable
Scientific Merit Review	Standard dates apply
Advisory Council Review	Standard dates apply
Earliest Start Date	Standard dates apply
Expiration Date	New Date September 8, 2017 per issuance of NOT-NS-17-027. (Original Expiration Date: May 8, 2017)
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

This Funding Opportunity Announcement (FOA) is issued by the National Institute of Neurological Disorders and Stroke in conjunction with the NIH Pain Consortium. It solicits R01 grant applications from institutions/organizations to perform innovative research that will elucidate the mechanisms underlying migraine, expand our current knowledge of the role of genetic, physiological, biopsychosocial, and environmental influences on migraine susceptibility and progression, and explore new therapeutic targets and therapies for migraine management and prevention. Episodic migraine headaches affect a large percentage of the population (17% of women and 6% of men), account for most pain-related emergency room visits, and may persist as a chronic and disabling condition that extends throughout the lifespan. Chronic migraine (15 or more headache days per month) affects 2% of the adults.

Despite the prevalence of migraine and a long history of research, many questions remain regarding the pathophysiology, progression, and the multitude of endogenous and exogenous factors that influence this complex disorder. Over the past decades the effectiveness of certain headache medications and theories of the mechanisms underlying the throbbing or pulsating pain associated with migraine drove research towards exploration of the vascular events associated with this disorder. Subsequent scientific advances led to the recognition that neural and inflammatory processes play an important role in migraine pain and associated neurological symptoms and that genetic variations, environmental effects, and psychosocial states influence susceptibility to migraines and migraine progression.

Our improved understanding of the mechanisms underlying the multiple phases of migraine and its modulators opened new and promising avenues for discovery of its causes and persistence, as well as potential therapeutic targets. The phases of migraine, including prodrome, aura, pain, and interictal periods, involve complex neurovascular mechanisms which are driven by different neurological events and influenced by numerous physiologic, genetic, and environmental factors. Exogenous factors, such as food additives, perfumes, bright lights, physical exertion, and alcohol may act to trigger this cascade of migraine phases. Sex hormone fluctuations clearly play a role in the initiation and frequency of headache attacks, but the mechanisms through which their effects are exerted and the associations between hormone levels and headache phases are unclear. Steroid hormones likely interact with other contributing factors such as stress, but here again the associations are poorly understood. Therapeutic strategies to ameliorate hormonal exacerbation of headaches are lacking. Gene mutations for rare forms and candidate genes for more common forms of migraine have been identified recently and are ready for or are undergoing functional analysis to better understand their roles in migraine and their potential as therapeutic targets. Further advances will be facilitated through development of genetic models to assay function, to screen effective headache drugs and to test new therapeutic strategies.

Migraines often co-occur with other chronic pain and/or affective disorders, suggesting that shared susceptibility and common underlying mechanisms increase the risk for developing multiple co-morbid chronic conditions. Biopsychosocial, genetic, socioeconomic, ethnic and racial differences all need to be explored as potential contributing factors to help determine those at risk and to develop appropriate treatment strategies. The complexity of the disorder and the magnitude of its impact on public health highlight the need for further research. This FOA is intended to attract innovative and cross-disciplinary applications to expand our current knowledge and management of migraine. Research of interest includes the study of predictive and susceptibility factors, the mechanisms underlying the phases of migraine, modulatory influences that induce and sustain headache, and both pharmacological and non-pharmacological therapy development. The research community is encouraged to expand on the emerging scientific discoveries related to neural and inflammatory mechanisms, maladaptive plastic changes in the nervous system associated with chronic headache, and genetic contributions to migraine. This Announcement also highlights the need to explore endogenous, genetic, environmental, and lifestyle triggers and influences on migraine.

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

Identification of genes and gene variants involved in the complex processes of migraine and gene polymorphisms and gene-environment interactions that underlie or modulate migraine
Assessment of the target sites, mechanisms, and effects of neuromodulators, including hormones on neuronal events associated with migraine
Evaluation of the influence of sex/gender in symptomatic presentation of migraine and nervous system hypersensitivity as it relates to pain
Exploration of mechanisms of nervous system hypersensitivity including hyperalgesia, photophobia, phonophobia, and allodynia associated with migraine
Exploration of inflammatory processes related to migraine
Development and validation of animal models of migraine phases and genetic models, including the evaluation of sex differences in those animal models
Identification of molecules and processes that target cellular mechanisms involved in migraine, and development of high throughput screening tools to identify drug candidates for acute and preventive therapies
Exploration of mechanisms of onset and progression of headache in pediatric population
Determination of shared mechanisms underlying migraine and other chronic pain and/or affective disorders and development of appropriate treatment strategies
Evaluation of endogenous and environmental factors, such as stress, foods, perfumes, alcohol, and light which may trigger migraines or alter their characteristics
Determine risk factors for migraine and its progression such as biopsychosocial, genetic, socioeconomic, ethnic and racial differences that contribute to susceptibility to migraine
Development of interventions, novel therapeutics, and integrated strategies for acute and preventive treatment of migraines
Development of clinical studies to evaluate non-pharmacological and pharmacological interventions
Identify and evaluate the influence of sex/gender on targeted cellular mechanisms that may affect novel pharmacologic therapeutic or other treatment development and efficacy
Basic and clinical research on the mechanisms and treatments of medication overuse headache

NCCAM is interested in research that would elucidate the mechanisms by which a given complementary/integrative health approach beneficially affects migraine, either as an acute intervention and/or prophylactically. For this FOA, complementary/integrative health approaches could include those within the Mind and Body domain, but not in the Natural Products domain, and would include, but are not limited to, the following: meditation, mindfulness, yoga, tai chi, qi-gong, acupuncture, massage, spinal manipulation. The primary outcomes for these studies should be directly focused on the mechanism(s), though it may be appropriate to have secondary outcomes that assess clinical outcomes. There should be sufficient prior data to indicate either efficacy or effectiveness of the proposed complementary/integrative health approach.

NIDCR is interested in the neurobiological mechanisms underlying migraine headache as they pertain to overlap with pathophysiological mechanisms of chronic temporomandibular and other orofacial pain disorders. Research examining common genetic, environmental, neurobiological, and biobehavioral factors underlying the co-occurrence of these disorders is encouraged. NIDCR is interested in funding meritorious research that focuses on studies addressing the comorbidity of temporomandibular and other orofacial disorders and migraine headache.

NIDCD is interested in the development of diagnostic, intervention and novel therapeutic tools for headache pain associated with a variety of communication disorders such as tinnitus, Meniere’s disease, odynophagia and burning mouth syndrome.

Applications to NINDS to perform clinical trials are not supported by this FOA. Exploratory (phase 1, 2) and multisite efficacy (phase 3) clinical trials should be submitted to NINDS through PAR-13-278 and PAR-13-281. NINDS places a high priority on the development and evaluation of such clinical interventions and has established specific mechanisms for supporting these types of applications (for more details see http://www.ninds.nih.gov/funding/funding_announcements/Funding-Bins-Clinical-Research.htm). Applicants are encouraged to contact staff prior to application submission.

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 Renewal 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	Application budgets are not limited but need to reflect the actual needs of the proposed project.
Award Project Period	The maximum project period is five 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.

Instructions for Application Submission

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.

SF424(R&R) Cover