Expired PAR-14-202: Environmental Contributors to Autism Spectrum Disorders (R21)

Part 1. Overview Information

Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute of Environmental Health Sciences (NIEHS) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) National Institute of Mental Health (NIMH)
Funding Opportunity Title	Environmental Contributors to Autism Spectrum Disorders (R21)
Activity Code	R21 Exploratory/Developmental Research Grant
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 4, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same. May 8, 2014 - See Notice NOT-ES-14-007. Notice for Correction to Eligibility of Foreign Components.
Funding Opportunity Announcement (FOA) Number	PAR-14-202
Companion Funding Opportunity	PAR-14-203, R01 Research Project Grant
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.242; 93.865; 93.113
Funding Opportunity Purpose	The purpose of this FOA is to stimulate and foster research to (1) identify environmental contributors to risk and expression of autism spectrum disorders (ASD) and (2) understand how environmental factors impact the underlying biologic processes implicated in ASD. The R21 grant mechanism is intended to encourage exploratory and developmental research projects by providing support for the early and conceptual stages of these projects. 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 biomedical, behavioral, or clinical research. A range of approaches are being encouraged by this FOA, from basic mechanistic studies using in vitro and in vivo model systems to studies that add new data collection activities and/or make use of extant data or biospecimens in existing human studies. Studies that address hypotheses related to the joint contribution of genes and environment are of particular interest. It is anticipated that knowledge gained from the research supported by this FOA will be used to inform public health prevention and intervention strategies.

Key Dates

Posted Date	May 2, 2014
Open Date (Earliest Submission Date)	July 26, 2014
Letter of Intent Due Date(s)	July 26, 2014
Application Due Date(s)	August 26, 2014; August 26, 2015; August 26, 2016, 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	January 2015; January 2016; January 2017
Advisory Council Review	May 2015; May 2016; May 2017
Earliest Start Date	July 1, 2015; July 1, 2016; July 1, 2017
Expiration Date	August 27, 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

Background

Autistic disorder and related conditions, known collectively as autism spectrum disorders (ASD), are characterized by significant impairments in reciprocal social communication and the presence of repetitive and/or restricted behaviors and interests. The symptoms of ASD emerge in the first three years of life. Some individuals are mildly impaired by their symptoms, while others are severely disabled. In addition to the core behavioral features of autism, many individuals are affected by other medical conditions, including epilepsy and intellectual disability. In most cases, ASD is a life-long condition and represents an enormous collective burden for affected individuals and families. Once thought to be rare, the most recent surveillance data show that ASD affects as many as 1 in 68 children within the United States. The prevalence of ASD has risen dramatically over the past twenty years, and recent data indicate that the upward trend continues. Part of this increase reflects changes in diagnostic criteria, improved identification linked to increased awareness by families, educators and clinicians and the wider availability of services for affected individuals. These factors alone are unlikely to fully explain the dramatic increase in prevalence, however, and a portion may reflect changes in the patterns and/or intensity of environmental exposures, acting in concert with genetic susceptibility.

Recent progress in understanding autism etiology

Increased attention and funding for ASD research in the past decade have spurred considerable progress in identifying etiologic risk factors and the underlying pathobiology. The phenotypic heterogeneity of ASD is consistent with the idea that the autism spectrum encompasses a range of disorders, with many different causes. The pattern of brain abnormalities observed in individuals with ASD, together with promising results of biomarker research in infants, suggest that disruption of the biologic process(es) that ultimately give rise to ASD symptoms begins very early in life.

Multiple lines of evidence support a strong genomic basis for ASD, including results from twin and family studies and the known association with single gene disorders and chromosomal abnormalities. Recent findings point to an unexpected role for rare structural genomic variations, ranging from de novo insertions and deletions to single nucleotide variation. To date, a very large number of rare structural variants have been linked to ASD, with different genes, or sets of genes affected in different individuals with ASD. Many ASD genes appear to converge on a few common biologic pathways, including those focused on synaptic maturation and maintenance. A role for epigenomics is suggested by the presence of ASD in individuals with disorders associated with epigenetic mutations (Fragile X syndrome) or that involve key epigenetic regulatory factors (Rett syndrome), parent of origin effects and/or linkage with imprinted chromosomal regions.

Recent efforts to identify environmental contributors to ASD and their interaction with genetic/genomic susceptibility have also begun to make progress. For example, results of several studies report an increased risk of ASD associated with exposure to traffic-related air pollution during gestation and early postnatal life. Other environmental factors with suggestive evidence for an association with ASD include maternal exposure to pesticides, infections, dietary folate and specific pharmaceuticals. An enhanced susceptibility to environmental exposures is suggested by the presence of abnormal immune responses, as well as metabolic and mitochondrial abnormalities observed in some individuals with ASD. Both maternal and paternal age at conception increase risk for ASD in the offspring, and this may reflect, in part, the accumulation of exposure-related genetic abnormalities in germ cells. Finally, there has been speculation that exposures affecting ASD risk act through epigenomic mechanisms. This is a plausible hypothesis given the demonstrated role of epigenomics in ASD-related conditions and the increasing data available to support the impact of environmental chemicals on epigenomic regulation of gene transcription.

Despite the progress cited above, additional attention is needed to accelerate the pace of research aimed at identifying environmental contributors to ASD. The published epidemiologic findings are intriguing, but most need independent replication and the neurobiology underlying reported associations is unclear. Very few mechanistic studies using in vitro approaches or model systems have been initiated. While many environmental exposures have known neurodevelopmental effects, and merit investigation as ASD risk factors, few have been studied in sufficient detail. Investigators have not exploited fully existing epidemiologic and clinical data and samples that could be used for the study of environmental contributors to ASD. For the most part, genetic and genomic studies are occurring in parallel with those on the environment, with little attention to a consideration of joint genetic and environmental contributors.

Purpose

The purpose of this FOA is to stimulate interest in pursuing hypotheses related to identification and mechanistic understanding of environmental contributors to risk and expression of autism spectrum disorders. The near-term expected outcomes are an increase in the number of investigators exploring environmental etiologies of ASD, expanded use of existing population and clinical ASD resources and application of new tools and approaches for mechanistic studies in model systems. The expected longer term outcome is an improved understanding of environmental causation of ASD leading to public health prevention and intervention strategies to reduce the disabilities associated with ASD.

The R21 grant mechanism used under this FOA is intended to encourage exploratory and developmental research projects by providing support for the early and conceptual stages of these projects. 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 biomedical, behavioral, or clinical research.

Specific Areas of Research Interest

New collaborations between autism researchers and toxicologists are encouraged in pursuit of interdisciplinary research approaches. Human studies proposed under this FOA should capitalize on existing study infrastructure and samples rather than propose development of new cohorts.

Research questions and approaches meriting additional attention include but are not limited to those listed below.

Human studies in clinical and population samples are needed to:

add data collection/integration of exposure measures to existing studies to enable testing of new hypotheses regarding environment and ASD risk
add ASD or related phenotypic outcomes to existing large clinical or epidemiology studies that have well-characterized exposure measures and can be used for analyses of environment-ASD relationships
use novel computational tools and in silico modeling to integrate knowledge about chemicals, genes, proteins and pathways and guide exploration of exposure-disease relationships in ASD epidemiology/clinical studies.
conduct analyses to identify potential differences in the association of exposures and autism risk in population subgroups defined by sex, race and ethnicity, socioeconomic status, geography, clinical features and/or other relevant characteristics
identify biomarkers of susceptibility to exposures (e.g., changes in gene expression, metabolic profiles, mitochondrial response) and explore their interrelationships and their relevance to ASD risk and related phenotypes
use postmortem materials or other extant biospecimens to determine levels of specific environmental chemicals and their relation to ASD risk and/or expression
explore the relationship between environmental exposures, inherited and de novo rare structural variation (e.g., copy number variation, single nucleotide variation) and ASD risk
identify specific patterns of epigenetic and epigenomic alterations (e.g., DNA methylation and hydroxymethylation, histone modifications, higher order chromatin remodeling and non coding RNA regulation), in ASD and explore their potential association with and/or regulation by environmental exposures.

Studies using in vitro, cellular and whole organism models are needed to:

develop and apply screening approaches to identify candidate exposures that interact with biologic pathways/genes implicated in ASD
capitalize on genetically engineered models that recapitulate features of ASD or ASD-related endophenotypes to determine how exposures alter expression of those phenotypes
make use of new mouse population resources (e.g., Collaborative Cross, Diversity Outbred Cross) to explore gene environment interaction in ASD phenotypes or endophenotypes.
enrich ongoing human studies by incorporating in vitro or in vivo assays to prioritize targets for analysis of gene-environment hypotheses and/or to pursue functional analysis of results of association analyses
elucidate the mechanism/underlying biology related to exposures that have been reported as ASD risk factors in human studies (e.g., role of inflammation and oxidative stress response in traffic-related air pollution effects on ASD-related pathways)
explore use of induced pluripotent stem cells (iPSc) from genetically and clinically characterized individuals with ASD to explore patterns of sensitivity/resistance to candidate environmental exposures

Applications submitted in response to this FOA should have a primary focus on an environmental agent within the missions and priority areas of one of the participating NIH institutes, as detailed below. Applicants proposing to focus on environmental exposures that are not identified explicitly in the sections below are encouraged to contact Scientific/Research staff at the participating institutes to discuss whether specific exposures are within the mission interests and priorities.

NIEHS interests

NIEHS is interested in applications that have a focus on environmental exposures within its mission, especially when considered in the context of genetic susceptibility and gene-environment interaction, including exposure-related epigenetic modification of gene expression resulting in DNA methylation, histone modifications, or changes in ncRNA. Studies linking prenatal exposures within the NIEHS mission to autistic phenotypes with consideration to vulnerable windows during development are of particular interest.

Environmental agents which are considered of primary interest for NIEHS include: industrial chemicals or manufacturing byproducts, metals, pesticides, herbicides, air pollutants and other inhaled toxicants, particulates or fibers, fungal, and bacterial or biologically derived toxins. Investigators who propose studies with a primary focus on NIEHS mission relevant exposures are encouraged to consider inclusion of other relevant environmental exposures (e.g., nutrition) in order to assess their role(s) as cofactors/modifiers of the risk or protection associated with the primary exposure(s). Applications that propose laboratory-based studies using only model compounds (i.e., those without potential for human exposure) must provide a clear, reasonable and specific description as to how research on the model compound will lead to a better understanding of the mechanisms involved in responses to specific environmental agents which are included in the mission responsibility of the NIEHS. Applicants are strongly encouraged to contact NIEHS Scientific/Research staff prior to submission to determine if their project meets the interests of the NIEHS.

NICHD interests

NICHD is interested in applications that focus on environmental exposures that occurred prenatally during critical windows of fetal development and that impact early child development. Examples of exposures include medications used during pregnancy, prenatal infections, maternal immune or inflammatory conditions, other medical conditions of the mother, specific nutrient or dietary exposures, and psychosocial factors. Specifically, NICHD is interested in studies focusing on prenatal exposures that alter the genetic or epigenetic profile and predispose to autism susceptibility; factors that alter the maternal or offspring microbiome and affect infant development; prenatal exposures to maternal disease, condition(s), or medication(s); and the presence of significant inflammation in utero and how it might be quantitatively related to altered cellular function and development in the offspring. NICHD is also interested in specific gene-environment interactions influenced by prenatal exposures. Applicants are strongly encouraged to contact NICHD Scientific/Research staff prior to submission to determine if their project meets the interests of the NICHD.

NIMH interests

NIMH is interested in research projects that seek to elucidate the role of genetic and epigenetic mechanisms modulated by environmental exposure(s) on gut microbiome in patients with ASD and control populations with the goal of identifying genetic pathways associated with ASD. Investigators are strongly encouraged to leverage existing longitudinal exposure data and detailed phenotypic assessments available on patients with ASD to evaluate the effect of environment on host gut microbiome and its role in autism.

NIMH is also interested in studies elucidating the relationship of environmental factors to genetic or epigenetic signatures that have been implicated in ASD, and in the identification and analysis of gene-environment interactions in the context of Genome wide Association Studies (GWAS) or other large scale genetic studies. Such analyses should leverage existing genetic and epigenomic data for characterization of phenotypes. Also of interest are projects that would utilize the National Database for Autism Research (NDAR) to develop methods to provide data on environmental exposures to the research community, without revealing the exact geospatial location of a research subject.

NIMH encourages the use of cutting edge approaches to understand how environmental exposures impact genomic, cell signaling, systems and circuit mechanisms regulating cognitive, affective, and social domains of function relevant to ASD, as well as the critical developmental processes underlying these mechanisms. Also encouraged are studies that seek to understand how environment perturbs normative neurobiological development of systems and circuits relevant to cognitive, affective, and social behavior using innovative approaches such as simultaneous high density electrophysiological recordings of multiple brain areas and optogenetic approaches. Computational modeling approaches to investigate how exposures alter complex rhythmic patterns of neuronal activity that underlie dynamic gating of information and how they are linked to relevant- functional alterations are also encouraged.

Applicants are strongly encouraged to contact NIMH Scientific/Research staff prior to submission to determine if their project meets the interests of NIMH.

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 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	The combined budget for direct costs for the 2-year project period may not exceed $275,000. No more than 200,000 may be requested in any single year.
Award Project Period	The scope of the proposed project should determine the project period. The maximum project 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)
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

Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are not 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. 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.

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.

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:

Patricia Greenwel, Ph.D.
Telephone: (301) 435-1169
Email: [email protected]

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