Part 1. Overview Information

Key Dates

All applications are due 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.

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the NOFO) 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.

IMPORTANT: Per NOT-OD-24-086 updated application forms (FORMS-I) will be used for this opportunity. The updated forms are not yet available and will be posted 30 calendar days or more prior to the first application due date. Once posted, you will be able to access the forms using one of the following submission options:

1. NIH ASSIST
2. An institutional system-to-system (S2S) solution
3. Grants.gov Workspace

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Introduction

The National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health (NIH), is transforming the translational science process so that new treatments and cures for disease can be delivered to patients faster, delivering more treatments for all people more quickly. NCATS strives to develop innovations to reduce, remove or bypass costly and time-consuming bottlenecks in the translational research pipeline in an effort to speed the delivery of new drugs, diagnostics and medical devices to patients.

This notice of funding opportunity (NOFO) aims to promote innovative research to increase knowledge of understudied proteins associated with rare diseases. The submission of small research grant (R03) applications is encouraged from organizations proposing projects leading to a better understanding of eligible proteins listed below within the context of rare disease.

Small research (R03) grants provide flexibility for initiating discrete, well-defined projects that realistically can be completed in one year and require only limited levels of funding. This program supports different types of projects including, but not limited to, the following:

• Pilot or feasibility studies;
• Small, self-contained research projects;
• Development of research methodology; 
• Development of assays to support compound screening projects; and/or
• Development of human cell or animal based models.

These awards will support generation of preliminary data and tools around eligible understudied protein(s) with the intent of elucidating the function of these proteins in the context of rare disease and obtaining sufficient preliminary data and/or research resources for subsequent grant applications and/or drug discovery projects. These grants are non-renewable.

Background
The human genome has revealed a great deal about the human proteome, though significant portions of the genome remain understudied. Only a subset of expressed proteins demonstrates the requisite properties to serve as targets for the development of therapeutics. Many bona fide drug targets likely remain to be studied in the Druggable Proteome (DP), which can be defined as the fraction of proteins which have the ability to bind drug-like molecules. The term "drug-like" refers to the physical, biochemical, and pharmacological attributes of small molecule compounds that are generally recognized to be required for efficacious clinical drugs in humans. While the number of proteins in the DP is upwards of 4,500, the existing clinical pharmacopeia is represented by only a few hundred targets, leaving a huge swath of druggable biology unexploited.

The expanded exploration of the relationship between the protein and the rare disease phenotype, or the development of a useful tool or reagent can accelerate research into a previously understudied protein. Many interesting and critical biological processes and potential therapeutic avenues remain unexplored because an initial catalyzing event (e.g., association with a biologic process or phenotype, creation of tools or reagents for the protein, etc.) has not yet occurred. The purpose of this NOFO is to spark such catalyzing events through the support of small R03 awards to identify novel drug targets for the treatment of human disease, specifically rare disease.

Objectives and Scope

The goal of this specific solicitation is to provide a needed opportunity for the collection of preliminary data around the role of understudied proteins associated with rare diseases. This NOFO will provide funding to support research that will characterize new targets for treatment of human disease among the understudied proteins of the Druggable Proteome. These projects should be carried out in a short period of time with limited resources as defined by the funding mechanism.

It has been recognized through workshops and publications that understudied proteins become illuminated when (1) there are tools to study the protein (e.g., tools that modulate protein activity) and/or (2) there is biochemical, cellular, or animal model evidence of disease/physiological relevance. This NOFO was developed to address the need for expanded research and validation experiments on eligible understudied protein(s), with the intent of producing preliminary data to address the lack of biochemical, cellular, or animal model data associated with many understudied proteins. It is expected that the award will be used to obtain preliminary data and/or research resources for subsequent grant applications and/or drug discovery projects.

The NIH supports research on a broad range of diseases that are defined as rare; that is diseases affecting fewer than 200,000 individuals in the United States (per the Rare Disease Act of 2002). Collectively, there are an estimated 10,000 rare diseases, which cumulatively affect millions of people in the United States. Most are serious or life-threatening, with a disproportionate number of rare diseases affecting children. At this time, effective treatments are available for fewer than 5%. Pharos has linked over 6,000 proteins to rare diseases, with over 80% of these proteins considered extremely understudied. For the purposes of this NOFO, eligible proteins are those that have an association with rare disease through data mining of the NCATS Genetic and Rare Diseases Information Center (GARD), are considered understudied (those proteins that lack small molecule binders and/or have limited biological characterization, and have low numbers of associated publications) and are within a protein family that is traditionally considered druggable.

Proteins open for study under this NOFO:

Enzymes

AADACL2, ABHD1, ABHD12B, ABHD14A, ABHD14B, ABHD15, ABHD16B, ABHD17B, ABHD17C, ABHD3, ABHD8, ACOXL, AKAP14, ALKBH6, ANAPC4, ANKRD44, ARHGAP23, ARHGAP28, ARHGAP40, ARL10, ARL16, ARL6, ARL9, ASNSD1, ASPHD1, ASPHD2, ATP5EP2, ATP6AP1L, ATP6V0E2, B3GNT4, C11orf54, C2orf88, CA5BP1, CARNMT1, CASP12, CBLC, CDADC1, CERCAM, CES1P1, CHSY3, CMAHP, CNEP1R1, COA1, CYB5RL, DCAKD, DDX31, DDX3Y, DDX51, DDX55, DDX60L, DHRS1, DHRS13, DHRS7B, DHRS7C, DHRSX, DHX57, DMAC2, DPY19L2P1, DPY19L2P2, DPY19L3, DPY19L4, ECHDC2, ECHDC3, EEF1AKMT3, ELFN2, ENDOD1, EPS8L2, ETFBKMT, FAHD2A, FASTKD1, FASTKD3, FAXDC2, FBLL1, FOLH1B, FOXRED2, GAL3ST3, GAL3ST4, GALNT16, GARNL3, GATC, GBA3, GFOD1, GFOD2, GGACT, GGTA1P, GKAP1, GLB1L2, GLB1L3, GLT1D1, GLT8D2, GSTT1, GUCA1C, GUSBP1, GVINP1, GXYLT1, GXYLT2, HACD4, HDHD2, HDHD3, HECTD2, HECTD3, HS3ST6, IRGQ, ISG20L2, JAKMIP2, JAKMIP3, KAZALD1, KIAA1191, L3HYPDH, LONRF1, LONRF2, LONRF3, MANEAL, MBLAC1, MBLAC2, MDH1B, METTL17, METTL21A, METTL22, METTL25, MOB3A, MOB3B, MOB3C, MPPED1, MTHFSD, MYRFL, NAA16, NAA38, NAT16, NAT8B, NKAIN1, NKAIN4, NLGN4Y, NT5DC1, NYAP1, NYAP2, OAZ2, OGFOD3, OVCH1, OVCH2, OXLD1, PCED1A, PCED1B, PCMTD2, PCYOX1L, PGGHG, PHACTR2, PHYHIP, PHYHIPL, PINLYP, PIP4P2, PLA2G4F, PLBD1, PLPP7, PLPPR1, PLPPR2, PM20D2, PMS2P3, POP1, PPIL4, PPIL6, PPP1R16A, PPP1R21, PPP1R35, PPP1R36, PPP1R37, PPP1R3D, PPP1R3E, PPP4R4, PPP5D1, PRORSD1P, PRSS33, PRXL2B, PTAR1, PTPDC1, PTPN20, PUS7L, PUSL1, RAB9B, RALGAPB, RASL10B, RERGL, RFNG, RIMKLA, RNF130, RNF149, RNF182, RPUSD2, RPUSD3, RPUSD4, SAP130, SCRN2, SDR42E1, SPATA5L1, SPHKAP, SPINT3, SRGAP2B, SYDE2, TAF1D, TATDN3, TCAF1, TDH, THNSL1, TIMM10B, TMEM129, TMPRSS11B, TPGS2, TPTE2P1, TREX1, TRIML2, TRMT2B, TRMT44, TRUB2, TSTD1, TSTD2, TTLL11, UGGT2, UGT3A1, UGT3A2, UNKL, USP31, USP54, USP9Y, VAT1L, VCPKMT, VMA21, ZDHHC18, ZDHHC22

Epigenetic Proteins

ASXL2, BRD8, BRWD1, BRWD3, CHD2, CHD5, CHD6, CHD9, DIDO1, DPF1, DPF3, FXR2, G2E3, GLYR1, GTF3C4, HAT1, HDGFL1, HDGFL3, ING5, INTS12, JADE1, JADE2, JADE3, JMJD1C, KDM3B, KIAA2026, L3MBTL2, MBD5, MBTD1, MLLT6, MPHOSPH8, MSL3, MUM1, PHF10, PHF11, PHF14, PHF2, PHF20L1, PHF21A, PHF21B, PHF23, PHF3, PHF7, PHRF1, PRDM11, PRMT2, PWWP2B, PYGO1, RIOX1, RIOX2, SCML2, SETD5, SETD6, SFMBT2, SHPRH, SMYD4, SMYD5, TAF3, TCF19, TDRD10, TDRD15, TDRD3, TDRD6, TDRD7, TDRD9, TDRKH, TRIM66, UBR7, UTY, ZGPAT, ZMYND8

GPCRs

ADGRA1, ADGRA3, ADGRB2, ADGRB3, ADGRD1, ADGRD2, ADGRE1, ADGRE3, ADGRF1, ADGRF4, ADGRF5, CELSR2, F2RL2, GPR101, GPR107, GPR12, GPR135, GPR137, GPR146, GPR150, GPR153, GPR157, GPR158, GPR160, GPR162, GPR171, GPR173, GPR176, GPR19, GPR22, GPR26, GPR27, GPR31, GPR37L1, GPR62, GPR78, GPR82, GPR85, GPRC5B, GPRC5C, GPRC5D, MAS1L, MRGPRF, NPBWR2, NPY6R, OPN1MW, P2RY8, RGR

Ion Channels

ASIC4, BEST2, BEST3, CACNA2D3, CACNA2D4, CACNB1, CACNB3, CACNG3, CACNG4, CACNG6, CACNG8, CALHM2, CALHM5, CALHM6, CLCA2, CLCA4, CLCC1, CLCN4, CLCN6, CLIC2, CLIC3, CLIC5, CLIC6, FXYD6, FXYD7, GLRA4, GPR89A, GPR89B, GRID1, KCNE4, KCNJ15, KCNJ18, KCNJ9, KCNK12, KCNK16, KCNK7, KCNMB2, KCNMB4, LRRC55, PKD1L1, PKD1L2, PKD2L2, PLLP, SCN2B, SCN3B, SCN4B, SLC26A1, TMC2, TMC3, TMC4, TMC5, TMEM38A, TMEM38B, TMEM63A, TMEM63B, TMEM63C, TTYH1, TTYH2, TTYH3

Kinases

ADCK2, ADPGK, AK3, AK6, AK9, ALPK1, ALPK2, BCKDK, CAMKV, EPHA10, ETNK1, ETNK2, FGGY, FN3KRP, GALK2, GK5, GLYCTK, GUCY2F, IDNK, IP6K2, IP6K3, ITPK1, KSR2, LRRK1, MAP3K21, MAP3K4, MAST2, MAST4, MOS, MYO3A, NADK, NADK2, NEK11, NEK3, NIM1K, NME3, NME4, NME5, NME6, NMRK1, NRBP1, NRK, OXSR1, PAN3, PANK4, PDIK1L, PFKFB1, PHKA1, PI4K2A, PIP5K1B, PKDCC, POMK, PRKY, PRPS2, PSKH1, PSKH2, PSTK, RPS6KC1, RPS6KL1, RSKR, SCYL1, SCYL2, SCYL3, STK31, STK32C, STK36, STKLD1, TBCK, TEX14, TP53RK, TTBK1, TTBK2, UCKL1, ULK4, VRK2, VRK3, WNK2

Transcription Factors

ELK3, FIZ1, GMEB2, HMGXB3, HMGXB4, IKZF5, KDM5D, MIER3, NKX1-1, RCOR3, RFX8, SP140L, SP5, SRY, ST18, TFAP2D, THAP10, THAP12, THAP6, THAP7, TSC22D2, USF3, ZBED2, ZBED4, ZBTB26, ZBTB34, ZBTB37, ZBTB41, ZBTB42, ZBTB43, ZBTB44, ZBTB45, ZBTB47, ZFHX2, ZFP14, ZFP3, ZFP30, ZFP41, ZFP69, ZFY, ZGLP1, ZKSCAN2, ZKSCAN4, ZNF101, ZNF112, ZNF114, ZNF117, ZNF121, ZNF134, ZNF136, ZNF138, ZNF14, ZNF140, ZNF180, ZNF181, ZNF189, ZNF19, ZNF195, ZNF197, ZNF200, ZNF205, ZNF211, ZNF221, ZNF226, ZNF227, ZNF230, ZNF232, ZNF234, ZNF236, ZNF248, ZNF25, ZNF250, ZNF251, ZNF253, ZNF254, ZNF257, ZNF26, ZNF260, ZNF264, ZNF273, ZNF275, ZNF276, ZNF280D, ZNF282, ZNF285, ZNF287, ZNF30, ZNF302, ZNF317, ZNF319, ZNF32, ZNF320, ZNF329, ZNF333, ZNF334, ZNF34, ZNF345, ZNF37A, ZNF383, ZNF394, ZNF396, ZNF397, ZNF404, ZNF415, ZNF416, ZNF419, ZNF429, ZNF43, ZNF430, ZNF431, ZNF432, ZNF440, ZNF441, ZNF442, ZNF444, ZNF445, ZNF446, ZNF449, ZNF45, ZNF468, ZNF480, ZNF486, ZNF487, ZNF491, ZNF492, ZNF493, ZNF497, ZNF500, ZNF502, ZNF507, ZNF510, ZNF512, ZNF513, ZNF514, ZNF519, ZNF526, ZNF527, ZNF528, ZNF529, ZNF532, ZNF540, ZNF548, ZNF550, ZNF551, ZNF552, ZNF554, ZNF555, ZNF556, ZNF557, ZNF558, ZNF559, ZNF560, ZNF561, ZNF562, ZNF566, ZNF567, ZNF57, ZNF570, ZNF571, ZNF572, ZNF573, ZNF577, ZNF581, ZNF585A, ZNF585B, ZNF586, ZNF596, ZNF599, ZNF600, ZNF605, ZNF606, ZNF610, ZNF611, ZNF614, ZNF615, ZNF616, ZNF619, ZNF620, ZNF621, ZNF623, ZNF624, ZNF626, ZNF627, ZNF641, ZNF653, ZNF660, ZNF662, ZNF665, ZNF669, ZNF670, ZNF672, ZNF676, ZNF678, ZNF680, ZNF681, ZNF682, ZNF688, ZNF689, ZNF696, ZNF697, ZNF70, ZNF708, ZNF709, ZNF721, ZNF724, ZNF726, ZNF730, ZNF736, ZNF75A, ZNF75D, ZNF763, ZNF764, ZNF765, ZNF766, ZNF768, ZNF770, ZNF771, ZNF775, ZNF776, ZNF777, ZNF778, ZNF780A, ZNF780B, ZNF781, ZNF782, ZNF785, ZNF786, ZNF789, ZNF791, ZNF793, ZNF8, ZNF808, ZNF814, ZNF816, ZNF821, ZNF823, ZNF829, ZNF83, ZNF835, ZNF836, ZNF837, ZNF844, ZNF846, ZNF879, ZNF880, ZNF891, ZSCAN12, ZSCAN18, ZSCAN2, ZSCAN22, ZSCAN25, ZSCAN29, ZSCAN5A, ZSCAN9, ZXDB, ZXDC

Transporters

ABCA10, ABCA13, ABCA5, ABCA6, ABCA8, ABCA9, ABCB8, ABCC12, ABCD4, ABCF1, ABCF2, ATP10A, ATP10B, ATP10D, ATP11A, ATP11B, ATP11C, ATP13A1, ATP13A3, ATP13A4, ATP13A5, ATP1B4, ATP8A2, ATP8B2, ATP8B4, ATP9A, ATP9B, SLC10A4, SLC10A5, SLC10A7, SLC12A7, SLC12A8, SLC13A3, SLC16A10, SLC16A11, SLC16A12, SLC16A13, SLC16A14, SLC16A5, SLC16A6, SLC16A8, SLC16A9, SLC17A3, SLC17A4, SLC18B1, SLC22A15, SLC22A16, SLC22A17, SLC22A18AS, SLC22A23, SLC23A3, SLC24A2, SLC24A3, SLC24A4, SLC25A14, SLC25A2, SLC25A22, SLC25A23, SLC25A24, SLC25A25, SLC25A26, SLC25A28, SLC25A30, SLC25A32, SLC25A33, SLC25A34, SLC25A35, SLC25A36, SLC25A38, SLC25A39, SLC25A41, SLC25A42, SLC25A43, SLC25A44, SLC25A45, SLC25A46, SLC25A48, SLC25A53, SLC26A11, SLC26A7, SLC26A8, SLC26A9, SLC27A3, SLC2A10, SLC2A11, SLC2A13, SLC2A4RG, SLC2A6, SLC30A4, SLC30A5, SLC30A6, SLC30A7, SLC30A9, SLC35A5, SLC35B1, SLC35B3, SLC35B4, SLC35C1, SLC35C2, SLC35D1, SLC35D2, SLC35D3, SLC35E1, SLC35E2A, SLC35E2B, SLC35E4, SLC35F1, SLC35F2, SLC35F3, SLC35F4, SLC35F5, SLC35G2, SLC35G3, SLC35G6, SLC36A1, SLC37A1, SLC37A2, SLC38A10, SLC38A11, SLC38A6, SLC38A7, SLC38A9, SLC39A10, SLC39A11, SLC39A12, SLC39A13, SLC39A3, SLC39A5, SLC39A9, SLC41A2, SLC41A3, SLC43A1, SLC43A2, SLC43A3, SLC44A3, SLC44A5, SLC45A1, SLC45A4, SLC46A2, SLC46A3, SLC48A1, SLC4A1AP, SLC4A2, SLC4A3, SLC50A1, SLC51B, SLC52A1, SLC5A12, SLC5A9, SLC6A14, SLC6A15, SLC6A16, SLC6A17, SLC6A18, SLC7A10, SLC7A14, SLC7A6, SLC7A8, SLC9A7, SLC9A9, SLC9B2, SLCO3A1, SLCO5A1

This NOFO accepts different types of projects with the intent of generating preliminary and/or validation data including, but not limited to, the following:

• Isolation and purification of understudied proteins and initial in vitro characterization;
• Characterization of cell- and tissue-specific protein expression, localization, and function of understudied protein(s) in native environments;
• Verification or placement of understudied protein(s) in signaling cascades, including upstream signals and downstream activities;
• Pre-clinical animal studies of understudied proteins that help to illuminate the role of an understudied protein in the context of human disease;
• Use of novel tools to validate preliminary disease or physiological associations with understudied proteins in animal models, biomimetic systems, or ex vivo human samples;
• Development of accessory reagents (e.g., antibodies, peptide fragments, labeled versions of the protein, etc.) for use in downstream studies to generate preliminary data;
• Assay development, optimization, and validation with the intent of using these assays for further study of selected understudied protein(s);
• Use of data mining and experimental validation to analyze public data resources to identify and study protein-protein interaction networks or generate hypotheses about the function of understudied protein(s);
• Studies to identify endogenous ligands for understudied proteins that could lead to study of preliminary structure-activity-relationships (SAR);
• Structure determination or preparation of understudied proteins for structure determination and characterization by x-ray crystallography, cryo-electron microscopy, or similar approaches.

This NOFO encourages the development and/or use of non-animal methodologies (NAMs) for exploring understudied proteins in rare diseases.  Proposed NAMs can include combinations of new and established technologies and methods that are used to replace traditional animal testing, such as tissue chips.

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 their organization to develop an application for support. Early-stage investigators are encouraged to apply. Individuals from diverse backgrounds, including individuals from underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

This NOFO is intended to jump start research on understudied proteins that are associated with rare diseases and provide applicants with funding to perform basic biochemical and/or biological work to further the characterization of understudied proteins associated with rare disease. The proposed project must focus on one or more of the eligible proteins listed above. Preliminary data are not required, and appropriate justification for the proposed approach can be provided through literature citations, data from other sources, or from investigator-generated data if any are available. The project should address critical barriers to understanding the role of understudied proteins in fundamental physiology, in disease processes, and/or as novel therapeutic agents.

Rare Disease Identification - The proposed project must also be focused within the primary context of a rare disease. A list of rare diseases can be found in the NCATS GARD database (https://rarediseases.info.nih.gov/) or the NORD database, among others. If the disease is not listed in either of these databases, a rare disease may be identified by one or more references confirming that the prevalence of the disease/condition is 200,000 or fewer patients in the U.S.

The following will be considered non-responsive and will not be reviewed:

• Projects that meet the NIH definition of a clinical trial;
• Projects where the majority of the proposed work focuses on proteins outside of those featured on the above lists;
• Applications that propose clinical drug development studies for understudied protein(s);
• Applications not studying a rare disease (200,000 or fewer patients in the U.S.).

See Section VIII. Other Information for award authorities and regulations.

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

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)

Local 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).

Federal Governments

• 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 Organizations) 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 allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply- 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. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information.

• System for Award Management (SAM) – 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.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registrations; all registrations must be in place by time of submission. 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 SAM registration in order to complete the Grants.gov registration.

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

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

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 How to Apply-Application Guide.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility

Number of Applications

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity 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.

Page Limitations

All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

SF424(R&R) Cover

All instructions in the How to Apply - Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations

All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Other Project Information

All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Senior/Key Person Profile

All instructions in the How to Apply- Application Guide must be followed.

R&R or Modular Budget

All instructions in the How to Apply- Application Guide must be followed.

R&R Subaward Budget

All instructions in the How to Apply-Application Guide must be followed.

PHS 398 Cover Page Supplement

All instructions in the How to Apply- Application Guide must be followed.

PHS 398 Research Plan

All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions:

This NOFO is intended to jump start research on understudied proteins that are associated with rare diseases and provide applicants with funding to perform basic biochemical and/or biological work to further the characterization of understudied proteins in the context of rare disease. The proposed project must focus on one or more of the eligible proteins listed above. Preliminary data are not required, and appropriate justification for the proposed approach can be provided through literature citations, data from other sources, or from investigator-generated data if any are available. The project should address critical barriers to understanding the role of understudied proteins in fundamental physiology, in disease processes, and/or as novel therapeutic agents.

Proteins not listed above as eligible for study under this NOFO may only be used in projects proposed for this NOFO as controls for experiments involving eligible proteins from the approved list and shall not be the focus of experimental work.

Evidence Supporting Rare Disease Classification – The Significance section of the Research Strategy must include a section providing evidence supporting rare disease classification.  A list of rare diseases can be found in the NCATS GARD database (https://rarediseases.info.nih.gov/) or the NORD database, among others. If the disease is not listed in either of these databases, a rare disease may be identified by one or more references confirming that the prevalence of the disease/condition that is the primary focus of the research application is 200,000 or fewer patients in the U.S. If the disease/condition has been granted orphan status by the FDA, provide this information in this paragraph. If the application does not include this information, then it will be considered non-responsive and will not be reviewed.

Biological Rationale - The Research Strategy section should include a background section that clearly outlines the biological rationale for the application, including: 1) a description of the biological rationale linking the understudied target and the rare disease of interest and 2) a description of how this work might move research on rare disease forward.

Future Directions – The Future Directions section should include a short summary of plans after the completion of this project and how this work will lead to future studies around the protein(s) of interest in the context of rare disease.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply- Application Guide.

Other Plan(s): 

All instructions in the How to Apply-Application Guide must be followed, with the following additional instructions:

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply- Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply- Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the How to Apply- Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the How to Apply- Application Guide must be followed.

PHS Assignment Request Form

All instructions in the How to Apply- Application Guide must be followed.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 2. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to 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. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

Applicants are responsible for viewing their application before the due date 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 How to Apply-Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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 Section 7.9.1 Selected Items of Cost.

Applications must be submitted electronically following the instructions described in the How to Apply 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 How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. 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. See Section III of this NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at [email protected].

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

For this particular NOFO, note the following: 

The R03 small grant supports discrete, well-defined projects that realistically can be completed in one year and that require limited levels of funding. Because the research project usually is limited, an R03 grant application may not contain extensive detail or discussion. Accordingly, reviewers should evaluate the conceptual framework and general approach to the problem. This NOFO is intended to jump start research on understudied proteins that are associated with rare diseases and provide applicants with funding to perform basic biochemical and/or biological work to further the characterization of understudied proteins associated with a rare disease. Preliminary data are not required, particularly in applications proposing pilot or feasibility studies and appropriate justification for the proposed work can be provided through literature citations, data from other sources, or from investigator-generated data.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following scored review criteria and additional review criteria (as applicable for the project proposed). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

Reviewers will evaluate Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate criterion score. 

As applicable for the project proposed, reviewers will consider the following additional items while determining scientific and technical merit, but will not give criterion scores for these items, and should consider them in providing an overall impact score.

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

2. Review and Selection Process

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. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications will receive a written critique.

Applications may undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.

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:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov. NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

In accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk.  For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

2. Administrative and National Policy Requirements

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. 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, Recipients, and Activities.
• If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website.
  • HHS recognizes that NIH research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations.  NIH may terminate awards under certain circumstances.  See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support. 

Not Applicable

Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement Section 8.4.1 Reporting. To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

A final RPPR, 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 Section 8.6 Closeout. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Karlie Sharma, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-451-4965
Email: [email protected]

Enrique Michelotti, PhD
National Institute of Mental Health (NIMH)
Telephone: 301-443-5415
Email: [email protected]

Maggie Morris Fears, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-761-5444
Email: [email protected]

Janet Cyr
NIDCD - NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
Phone: 301-402-3458
E-mail: [email protected]

Severn Borden Churn, Ph.D.
NINDS - NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
Phone: 301-827-5828
E-mail: [email protected]

Alicia Chou, M.S.
National Institute of Dental and Craniofacial Research (NIDCR)
Phone: 301-594-487
Email: [email protected]

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

Yuping Burr
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-480-7622
Email: [email protected]

Heather Weiss
National Institute of Mental Health (NIMH)
Telephone: 301-443-4415
Email: [email protected]

Tamia Carter
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-2982
Email: [email protected]

Samantha J Tempchin
NIDCD - NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
Phone: (301) 435-1404
E-mail: [email protected]

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Email: [email protected]

Gabriel Hidalgo, MBA
National Institute of Dental and Craniofacial Research (NIDCR)
Phone: 301-827-4630
Email: [email protected]

Section VIII. Other Information

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 2 CFR Part 200.