We have posted an Implementation of New Initiatives and Policies page on the NIH Grants & Funding Website to pull together the latest information on recent and upcoming changes that impact applications and grants administration.

Page Highlights

• NIH Grants and Funding Information Status. Keep up to date on how NIH grants and funding information is evolving as we align with new agency priorities (e.g., status of communications, funding opportunities, application guidance, and more).
• Upcoming Changes. Get the latest status on in-progress initiatives like our adoption of Biographical Sketch and Current and Pending (Other) Support.
• Recent Changes. Learn about key initiatives implemented in 2024 that culminated in numerous changes to grant application content and review for due dates on or after January 25, 2025 and any adjustments made to those initiatives.

Bookmark the link, share it widely, and visit regularly for updated information.

NIH has been hard at work over the last two years developing guidance and training to help prepare the community for the implementation of the simplified review framework. That framework went into effect on January 25, 2025 and applies to applications for most research project grants.

We are often asked how the new framework will affect the preparation of applications. The simplified review framework is a new way of reviewing the same research strategies you’ve always developed, which means neither the components nor the structure of your application are expected to change.

As always, applicants should be responsive to the Notice of Funding Opportunity (NOFO) that they are applying to, especially Sections IV. Application and Submission Information and V.  Application Review Information.

Other Information

• Applicant Guidance for Simplifying the Review Framework

• How to Apply – Application Guide

• Recent Changes Implemented for Due Dates on or after January 25, 2025

• NIH All About Grants Podcast: Simplified Review Framework

Nucleic Acids Res. 2025 Mar 20;53(6):gkaf207. doi: 10.1093/nar/gkaf207.

ABSTRACT

Human health depends on perplexing defensive cellular responses against microbial pathogens like Viruses. Despite the major effort undertaken, the (epi)genomic mechanisms that human cells utilize to tailor defensive gene expression programs against microbial attacks have remained inadequately understood, mainly due to a significant lack of recording of the in vivo functional cis-regulatory modules (CRMs) of the human genome. Here, we introduce the virus-responsive fate of the human (epi)genome as characterized in naïve and infected cells by functional genomics, computational biology, DNA evolution, and DNA Grammar and Syntax investigations. We discovered that multitudes of novel functional virus-responsive CRMs (vrCRMs) compose typical enhancers (tEs), super-enhancers (SEs), repetitive-DNA enhancers (rDEs), and stand-alone functional genomic stretches that grant human cells regulatory underpinnings for layering basal immunity and eliminating illogical/harmful defensive responses under homeostasis, yet stimulating virus-responsive genes and transposable elements (TEs) upon infection. Moreover, extensive epigenomic reprogramming of previously unknown SE landscapes marks the transition from naïve to antiviral human cell states and involves the functions of the antimicrobial transcription factors (TFs), including interferon response factor 3 (IRF3) and nuclear factor-κB (NF-κB), as well as coactivators and transcriptional apparatus, along with intensive modifications/alterations in histone marks and chromatin accessibility. Considering the polyphyletic evolutionary fingerprints of the composite DNA sequences of the vrCRMs assessed by TFs-STARR-seq, ranging from the animal to microbial kingdoms, the conserved features of antimicrobial TFs and chromatin complexes, and their pluripotent stimulus-induced activation, these findings shed light on how mammalian (epi)genomes evolved their functions to interpret the exogenous stress inflicted and program defensive transcriptional responses against microbial agents. Crucially, many known human short variants, e.g. single-nucleotide polymorphisms (SNPs), insertions, deletions etc., and quantitative trait loci (QTLs) linked to autoimmune diseases, such as multiple sclerosis (MS), systemic lupus erythematosus (SLE), Crohn's disease (CD) etc., were mapped within or vastly proximal (±2.5 kb) to the novel in vivo functional SEs and vrCRMs discovered, thus underscoring the impact of their (mal)functions on human physiology and disease development. Hence, we delved into the virus-responsive fate of the human (epi)genome and illuminated its architecture, function, evolutionary origins, and its significance for cellular homeostasis. These results allow us to chart the "Human hyper-Atlas of virus-infection", an integrated "molecular in silico" encyclopedia situated in the UCSC Genome Browser that benefits our mechanistic understanding of human infectious/(auto)immune diseases development and can facilitate the generation of in vivo preclinical animal models, drug design, and evolution of therapeutic applications.

PMID:40131776 | DOI:10.1093/nar/gkaf207

NIH recently launched several enhancements to allow the public to more easily and quickly find funding information for various NIH research areas. The new look and feel of the NIH Research, Condition, and Disease Categorization (RCDC) Categorical Spending webpage adds to NIH’s long-standing efforts to enhance transparency and accountability into NIH funding decisions and the research areas NIH supports.

RCDC launched in 2008 as a tool within NIH’s Research Portfolio Online Reporting Tools (RePORT) suite. It provides estimates of annual support level for more than 300 research, condition, and disease categories based on grants, contracts, and other funding mechanisms used across the NIH, as well as disease burden data published by the CDC National Center for Health Statistics. More on the RCDC process is available on this post from 2018.

The new visual and contextual changes aim to improved usability and understanding of the RCDC categorization process. In particular, the categorical spending page was reorganized so data are more prominent and easier to navigate.

Navigation improvements simplify finding information on FAQs, the Categorization Process, and the biomedical thesaurus. The information in the data tables are more visible due to collapsed textual information  and frozen table headers (Figure 1).

When selecting a particular category, the line graph on the top left of the page will  automatically adjust to reflect funding amounts over time for that topic area (Figure 2, left image). Selecting support data for a given fiscal year will also reveal information about specific projects (Figure 2, right image).

Results can be narrowed further if interested in a particular NIH Institute or Center (Figure 3). To sort in this way, a user would need to click on the dollar amount for a given disease/research area and a given fiscal year in the main table.

Application identification numbers can now be exported for funded awards for any fiscal year in any given category. Previously RCDC only reported the project number for an award. Because application IDs are unique to an individual fiscal year, it is easier to now connect results from RCDC with those obtained in other RePORT tools.

Do you want to learn more about how applications will be reviewed under the simplified review framework for most research project grants? Whether you’re a peer reviewer awaiting training or a researcher preparing an application, we invite you to review our reviewer guidance page for the simplified review framework. There, you can learn more about how reviewers will be instructed to evaluate applications under the new framework.  

Just remember, the simplified review framework is a new way of reviewing the same research strategy and is not expected to change how applicants prepare applications. See our applicant guide for more information on navigating the transition to the simplified review framework. 

Other Information 

• Simplifying Review of Research Project Grant Applications 

• Simplified Review Framework FAQs 

• NIH All About Grants Podcast – Simplified Review Framework 

Front Cell Dev Biol. 2025 Feb 20;13:1552716. doi: 10.3389/fcell.2025.1552716. eCollection 2025.

ABSTRACT

INTRODUCTION: In vertebrate limb morphogenesis, wingless-related integration site (Wnt) proteins and fibroblast growth factors (Fgfs) secreted from the apical ectodermal ridge (AER) coordinate proximodistal outgrowth. Fgfs also sustain sonic hedgehog (Shh) in the zone of polarizing activity (ZPA). Shh directs anteroposterior patterning and expansion and regulates AER-Fgfs, establishing a positive regulatory feedback loop that is vital in sustaining limb outgrowth. The transcription factor LIM homeodomain 2 (Lhx2) is expressed in the distal mesoderm and coordinates AER and ZPA signals that control cellular proliferation, differentiation, and shaping of the developing limb. Yet how Lhx2 is transcriptionally regulated to support such functions has only been partially characterized.

METHODS/RESULTS: We have identified two limb-specific cis-regulatory modules (CRMs) active within the Lhx2 expression domain in the limb. Chromatin conformation analysis of the Lhx2 locus in mouse embryonic limb bud cells predicted CRMs-Lhx2 promoter interactions. Single-cell RNA-sequencing analysis of limb bud cells revealed co-expression of several Fgf-related Ets and Wnt-related Tcf/Lef transcripts in Lhx2-expressing cells. Additionally, disruption of Ets and Tcf/Lef binding sites resulted in loss of reporter-driven CRM activity. Finally, binding of β-catenin to both Lhx2-associated CRMs supports the associated binding of Tcf/Lef transcription factors.

DISCUSSION: These results suggest a role for Ets and Tcf/Lef transcription factors in the regulation of Lhx2 expression through these limb-specific Lhx2-associated CRMs. Moreover, these CRMs provide a mechanism for Fgf and Wnt signaling to localize and maintain distal Lhx2 expression during vertebrate limb development.

PMID:40052149 | PMC:PMC11882541 | DOI:10.3389/fcell.2025.1552716

The first step to NIH funding is closely reading your funding opportunity, which contains important information about eligibility, application submission, and review. Let’s take a guided video tour of the structure of a typical NIH Notice of Funding Opportunity, or NOFO. 

Here are the highlights:  

• Structure of a Funding Opportunity
• Instruction Hierarchy
• Eligibility Information
• Submission Reminders
• Application Review Information
• Key Takeaways

Are you a signing official or principal investigator planning to be away from the office?  Do not let award management tasks pile up in your absence. Simply use the delegation feature in eRA Commons to allow others to act on your behalf. To accommodate scheduled absences and the need for assistance with award management tasks, delegation of specific duties and privileges are baked into the design of eRA Commons. 

Open the Admin (Account Management) module and click the Delegations menu option to work with delegations. Delegation capabilities vary based on your role and the authority being delegated. Scientific roles, such as a principal investigator (PI) can do direct delegations of their authorities (progress report, Status, Personal Profile, xTrain) to another PI or assistant.  

Signing officials (SOs) and business officials have an additional ability to delegate privileges on behalf of another user. This might be done if a PI is unexpectedly unavailable and someone else needs to work on their progress report.  SOs can also delegate institutional authority, which is the authority to act on behalf of an institution or organization. For instance, usually only SOs can submit reports for an award, but institutional authority granted by an SO to a PI enables the PI to submit these reports.  

Any user can delegate Personal Profile authority, so that others can update their Personal Profile.  

See instructions and a complete list of who can delegate which authorities in the Delegations online help topic. Also learn more about delegations on the Manage Delegation webpage.  

bioRxiv [Preprint]. 2025 Jan 9:2025.01.09.632114. doi: 10.1101/2025.01.09.632114.

ABSTRACT

In vertebrates, germ layer specification represents a critical transition where pluripotent cells acquire lineage-specific identities. We identify the maternal transcription factors Foxi2 and Sox3 to be pivotal master regulators of ectodermal germ layer specification in Xenopus . Ectopic co-expression of Foxi2 and Sox3 in prospective endodermal tissue induces the expression of ectodermal markers while suppressing mesendodermal markers. Transcriptomics analyses reveal that Foxi2 and Sox3 jointly and independently regulate hundreds of ectodermal target genes. During early cleavage stages, Foxi2 and Sox3 pre-bind to key cis-regulatory modules (CRMs), marking sites that later recruit Ep300 and facilitate H3K27ac deposition, thereby shaping the epigenetic landscape of the ectodermal genome. These CRMs are highly enriched within ectoderm-specific super-enhancers (SEs). Our findings highlight the pivotal role of ectodermal SE-associated CRMs in precise and robust ectodermal gene activation, establishing Foxi2 and Sox3 as central architects of ectodermal lineage specification.

HIGHLIGHTS: Foxi2 and Sox3 are master regulators for the ectodermal germ layer and sub-lineagesFive ectodermal cell states of early gastrulae are regulated by Foxi2 and Sox3Foxi2 and Sox3 binding sites in the genome are enriched in ectoderm super-enhancersSE-associated genes show high expression levels, low noise, stabilizing ectodermal regulation.

PMID:39829826 | PMC:PMC11741269 | DOI:10.1101/2025.01.09.632114

NIH (including help desks) will be closed on Monday, February 17, 2025 for the federal holiday (Washington’s Birthday). If a grant application due date falls on a federal holiday, the application deadline is automatically extended to the next business day.

We invite you to join us for two webinars that spotlight our NIH Research Enhancement Award (R15) and Fellowship programs.

NIH Research Enhancement Award (R15): What You Need to Know and Recent Changes
January 30, 2025, 2:30-4:00 PM ET
Register now!

In this virtual event, you will learn about the two NIH R15 programs:

• Academic Research Enhancement Award for Undergraduate-Focused Institutions (AREA)
• Research Enhancement Award Program for Health Professional and Graduate Schools (REAP).

R15 research project grants are designed to provide support for meritorious research at institutions that have not been major recipients of NIH support, to strengthen the research environment at these institutions, and to give students an opportunity to gain significant biomedical research experience.

An Introduction to the NIH Fellowship Program for Prospective Candidates

February 11, 2025, 10:00 – 11:30 AM ET

Register Now!

You may already know that there’s a lot that goes into an NIH fellowship application, and you may be wondering where to start. At this live, virtual event NIH experts will:

• Discuss NIH’s fellowship programs
• Break down the fellowship application and peer review process
• Share Practical tips for preparing a competitive application
• Answer your questions at live Q&A sessions

The NIH fellowship program provides individual training opportunities to support fellows at various career stages, including at graduate, and postdoctoral levels. This webinar is valuable for fellowship candidates, sponsors, and research program administrators new to the NIH and the fellowship application process.

Don’t miss out on the opportunities to explore these exciting programs.

The Personal Profile module in eRA Commons is where you — as a principal investigator, award recipient, trainee, reviewer or other Commons user — tell NIH and other awarding agencies about yourself. Awarding agencies need to know about you to grant awards, process those awards and more. Here are a few reasons that it is extremely important to keep your Personal Profile updated.

• All communications between awarding agencies and you are sent to contact methods that you enter into your Personal Profile.
• Reports, such as the Research Performance Progress Report (RPPR), cannot be submitted if award recipients have incomplete Personal Profiles.
• Trainees cannot be appointed without complete Personal Profiles.
• Early Stage Investigator (ESI) status is calculated from Personal Profile data entered by principal investigators in the Education section.
• Personal Profile data is used to help agency review staff identify reviewers’ conflict of interest with applications they are reviewing; and is the place reviewers enter information to get their review meeting honorariums.

Personal Profile is the central repository of information about all Commons registered users. It lets you own and maintain the accuracy for your own personal information. This profile information is integrated throughout eRA systems. It is used to determine reviewer conflicts, link publications, populate application data, track trainee effort, and to ensure that Early Stage Investigator status is accurately calculated. In addition, you have the option to provide demographic information to help NIH better understand its research workforce. Read more about how to manage your Personal Profile.

Linking your ORCID iD (Open Researcher and Contributor ID) to your eRA Commons account enables automatic importation of publications into biosketches, reducing burden and saving you time. You can use Personal Profile to connect your eRA Commons account to your ORCID iD (Open Researcher and Contributor ID), which is a unique 16-digit identifier that enables connections between researchers and their research and scholarship. A linked ORCID iD is required for all senior/ key personnel listed on  an application for a  due date on or after May 25, 2025. See the video titled Link Your ORCID iD to Your eRA Commons Account.

So, if you have not recently updated your Personal Profile, please do so soon. It will benefit both the awarding agency and you.

Also see:

• Manage Personal Profile webpage
• Personal Profile Module online help
• Update on Linking ORCID To Implement Persistent Identifier Requirements While Reducing Burden and Improving Transparency blog post
• NIH All About Grants Podcast: Growing ORCIDs podcast episode

NIH has issued agency-specific information regarding its implementation of the U.S. Government Policy for Oversight of Dual Use Research of Concern and Pathogens with Enhanced Pandemic Potential (DURC/PEPP Policy). The policy, which goes into effect May 6, 2025, is a unified federal oversight framework for conducting and managing certain types of federally funded life sciences research on biological agents and toxins.

The DURC/PEPP Policy requirements apply to all NIH-funded research, including grants and cooperative agreements, Research and Development (R&D) contracts, NIH intramural research projects, and other funding agreements (e.g., Other Transactions). For more details, see the full Guide Notice.

Int J Mol Sci. 2024 Dec 20;25(24):13631. doi: 10.3390/ijms252413631.

ABSTRACT

The notochord is an axial structure required for the development of all chordate embryos, from sea squirts to humans. Over the course of more than half a billion years of chordate evolution, in addition to its structural function, the notochord has acquired increasingly relevant patterning roles for its surrounding tissues. This process has involved the co-option of signaling pathways and the acquisition of novel molecular mechanisms responsible for the precise timing and modalities of their deployment. To reconstruct this evolutionary route, we surveyed the expression of signaling molecules in the notochord of the tunicate Ciona, an experimentally amenable and informative chordate. We found that several genes encoding for candidate components of diverse signaling pathways are expressed during notochord development, and in some instances, display distinctive regionalized and/or lineage-specific patterns. We identified and deconstructed notochord enhancers associated with TGF-β and Ctgf, two evolutionarily conserved signaling genes that are expressed dishomogeneously in the Ciona notochord, and shed light on the cis-regulatory origins of their peculiar expression patterns.

PMID:39769393 | DOI:10.3390/ijms252413631

Methods Mol Biol. 2025;2889:11-24. doi: 10.1007/978-1-0716-4322-8_2.

ABSTRACT

FLP-FRT, a well-established technique for genome manipulation, and the revolutionary CRISPR/Cas9, known for its targeted indels, are combined in a novel approach. This unique method is applied to the Hox genes in the Drosophila melanogaster bithorax complex, which are closely located to the cis-regulatory modules that define their spatial-temporal regulation. The number and position of these genes are directly correlated to their expression pattern. This chapter unveils the exciting potential of this combinatorial use of FLP-FRT and CRISPR-Cas9 to rearrange the cis-regulatory modules of the Hox complex in Drosophila melanogaster.

PMID:39745602 | DOI:10.1007/978-1-0716-4322-8_2

Front Immunol. 2024 Dec 6;15:1415317. doi: 10.3389/fimmu.2024.1415317. eCollection 2024.

ABSTRACT

COVID-19 is characterized by systemic pro-inflammatory shifts with the development of serious alterations in the functioning of the immune system. Investigations of the gene expression changes accompanying the infection state provide insight into the molecular and cellular processes depending on the sickness severity and virus variants. Severe Delta COVID-19 has been characterized by the appearance of a monocyte subset enriched for proinflammatory gene expression signatures and a shift in ligand-receptor interactions. We profiled the chromatin accessibility landscape of 140,000 nuclei in PBMC samples from healthy individuals or individuals with COVID-19. We investigated cis-regulatory elements and identified the core transcription factors governing gene expression in immune cells during COVID-19 infection. In severe cases, we discovered that regulome and chromatin co-accessibility modules were significantly altered across many cell types. Moreover, cases with the Delta variant were accompanied by a specific monocyte subtype discovered using scATAC-seq data. Our analysis showed that immune cells of individuals with severe Delta COVID-19 underwent significant remodeling of the chromatin accessibility landscape and development of the proinflammatory expression pattern. Using a gene regulatory network modeling approach, we investigated the core transcription factors governing the cell state and identified the most pronounced chromatin changes in CD14+ monocytes from individuals with severe Delta COVID-19. Together, our results provide novel insights into cis-regulatory module organization and its impact on gene activity in immune cells during SARS-CoV-2 infection.

PMID:39712003 | PMC:PMC11662282 | DOI:10.3389/fimmu.2024.1415317

PLoS One. 2024 Dec 5;19(12):e0311752. doi: 10.1371/journal.pone.0311752. eCollection 2024.

ABSTRACT

As the number of sequenced insect genomes continues to grow, there is a pressing need for rapid and accurate annotation of their regulatory component. SCRMshaw is a computational tool designed to predict cis-regulatory modules ("enhancers") in the genomes of various insect species. A key advantage of SCRMshaw is its accessibility. It requires minimal resources-just a genome sequence and training data from known Drosophila regulatory sequences, which are readily available for download. Even users with modest computational skills can run SCRMshaw on a desktop computer for basic applications, although a high-performance computing cluster is recommended for optimal results. SCRMshaw can be tailored to specific needs: users can employ a single set of training data to predict enhancers associated with a particular gene expression pattern, or utilize multiple sets to provide a first-pass regulatory annotation for a newly-sequenced genome. This protocol provides an extensive update to the previously published SCRMshaw protocol and aligns with the methods used in a recent annotation of over 30 insect regulatory genomes. It includes the most recent modifications to the SCRMshaw protocol and details an end-to-end pipeline that begins with a sequenced genome and ends with a fully-annotated regulatory genome. Relevant scripts are available via GitHub, and a living protocol that will be updated as necessary is linked to this article at protocols.io.

PMID:39637210 | DOI:10.1371/journal.pone.0311752

Virus Res. 2024 Oct 26:199487. doi: 10.1016/j.virusres.2024.199487. Online ahead of print.

ABSTRACT

Glucocorticoid receptor (GR) activation enhances Human alpha-herpes virus 1 (HSV-1) replication and explant-induced reactivation from latency. Furthermore, GR and Krüppel-like factor 15 (KLF15) cooperatively transactivate cis-regulatory modules (CRMs) that drive expression of infected cell protein 0 (ICP0), ICP4, and ICP27. KLF and specificity protein (Sp) family members bind GC-rich or C-rich sequences and belong to the same super-family of transcription factors. Based on these observations, we hypothesized CRMs spanning the ICP0 promoter are transactivated by GR and Sp1 or Sp3. CRM-A (-800 to -635), CRM-B (-485 to -635), and CRM-D (-232 to -24), but not CRM-C, were significantly transactivated by GR, DEX, and Sp1 or Sp3 in mouse neuroblastoma cells (Neuro-2A). Mutagenesis of Sp1/Sp3 binding sites were important for transactivation of CRM-A and CRM-B. Chromatin immunoprecipitation studies revealed significantly higher levels of GR occupied ICP0 promoter sequences when Sp1 or Sp3 was over-expressed suggesting these transcriptions factors recruit GR to ICP0 CRM sequences. Mithramycin A, an antibiotic that preferentially binds GC-rich DNA and impairs Sp1/Sp3 dependent transactivation also reduced virus shedding reactivation from latency in mice latently infected with HSV-1. These studies indicate GR and certain stress-induced cellular transcription factors preferentially bind GC rich DNA, which stimulates HSV-1 gene expression and reactivation from latency in trigeminal ganglia of latently infected mice.

PMID:39490590 | DOI:10.1016/j.virusres.2024.199487

Plant Cell Physiol. 2024 Oct 16:pcae121. doi: 10.1093/pcp/pcae121. Online ahead of print.

ABSTRACT

Understanding plant responses to developmental and environmental cues is crucial for studying morphological divergence and local adaptation. Gene expression changes, governed by cis-regulatory modules (CRMs) including enhancers, are a major source of plant phenotypic variation. However, while genome-wide approaches have revealed thousands of putative enhancers in mammals, far fewer have been identified and functionally characterized in plants. This review provides an overview of how enhancers function to control gene regulation, methods to predict DNA sequences that may have enhancer activity, methods utilized to functionally validate enhancers, and the current knowledge of enhancers in plants, including how they impact plant development, response to environment, and evolutionary adaptation.

PMID:39412125 | DOI:10.1093/pcp/pcae121

Elife. 2024 Oct 11;13:RP96738. doi: 10.7554/eLife.96738.

ABSTRACT

Annotation of newly sequenced genomes frequently includes genes, but rarely covers important non-coding genomic features such as the cis-regulatory modules-e.g., enhancers and silencers-that regulate gene expression. Here, we begin to remedy this situation by developing a workflow for rapid initial annotation of insect regulatory sequences, and provide a searchable database resource with enhancer predictions for 33 genomes. Using our previously developed SCRMshaw computational enhancer prediction method, we predict over 2.8 million regulatory sequences along with the tissues where they are expected to be active, in a set of insect species ranging over 360 million years of evolution. Extensive analysis and validation of the data provides several lines of evidence suggesting that we achieve a high true-positive rate for enhancer prediction. One, we show that our predictions target specific loci, rather than random genomic locations. Two, we predict enhancers in orthologous loci across a diverged set of species to a significantly higher degree than random expectation would allow. Three, we demonstrate that our predictions are highly enriched for regions of accessible chromatin. Four, we achieve a validation rate in excess of 70% using in vivo reporter gene assays. As we continue to annotate both new tissues and new species, our regulatory annotation resource will provide a rich source of data for the research community and will have utility for both small-scale (single gene, single species) and large-scale (many genes, many species) studies of gene regulation. In particular, the ability to search for functionally related regulatory elements in orthologous loci should greatly facilitate studies of enhancer evolution even among distantly related species.

PMID:39392676 | PMC:PMC11469670 | DOI:10.7554/eLife.96738