Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Characterization of splicing and isoform dysregulation in ASD at cellular resolution

Award Number: R01MH140323
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/18/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

Group Awards By:

View Award Description

Characterization of splicing and isoform dysregulation in ASD at cellular resolution - SUMMARY Alternative splicing generates isoform diversity and plays an important role in disease. We previously profiled postmortem prefrontal cortices of individuals with major psychiatric disorders and found substantial dysregulation of isoform expression at the bulk tissue level in ASD compared to neurotypical controls. Moreover, changes in isoform expression, rather than overall changes in gene expression, showed the largest effect sizes and genetic enrichments. Our understanding of the contribution of isoform dysregulation to psychiatric disorders remains incomplete because they cannot be fully resolved at the cell type-level by commonly used short-read RNAseq technologies. To address this deficit, we will profile the postnatal development dynamics and cellular context of isoform dysregulation by generating genome-wide high- resolution maps at cellular resolution across the lifespan. We will further integrate these data with existing genotypes for the same subjects to conduct allelic-isoform analyses to map regulatory genetic effects on isoform expression. In Aim 1 we will profile splicing changes in high-quality postmortem prefrontal cortex (PFC) brain tissues of 74 ASD and 74 neurotypical controls at single-nucleus (sn) resolution from childhood to adulthood, using long-read multiplexed arrays isoform sequencing (MAS-Seq) and our IsoPropeller analysis framework to resolve their complete isoform structure and quantitate cell-type specific isoform expression. We will then use these data to identify significant changes in isoform abundance and usage between ASD and controls, and fully delineate cell type and age-dependent expression patterns. In Aim 2 we will leverage our existing cell-type isoform abundance datasets, and further cto deconvolute cell-type specific expression patterns and with the newly generated data in our aim 1 combine analyze dysregulated isoforms across RNA-Seq datasets from >1k ASD and control PFC samples, and to further construct isoform-level co-expression networks. Available genotyping data for the same set of ASD and neurotypical controls will be used to examine cis-regulatory genetic effects on expression by splicing and allelic isoform analyses of expression patterns and to perform functional characterization. Finally, in Aim 3, we will validate selected isoform changes by RNA fluorescent in situ hybridization (FISH) and quantitative isoform-specific PCR in FANS-sorted neuronal and non-neuronal cell types. We will also perform mechanistic assessments of cis-regulatory SNP:isoform associations by introducing SNPs into isogenic iPSCs, and study their effects in isogenic iPSC-derived neural cells. The quantitative isoform maps generated here will allow us to address major outstanding questions regarding control of isoform expression in the brain, and in ASD cases in particular, which is instrumental in unravelling the neurobiological mechanisms of genetic risk for ASD. Our data and results will provide an invaluable resource to the community, and widely applicable to other neurodevelopmental and psychiatric disorders.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $763,265 )
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	1	8/20/2026	NEW	$763,265
														Subtotal = $763,265

Grand Total All Awards = $763,265

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Characterization of splicing and isoform dysregulation in ASD at cellular resolution

Award Number: R01MH140323

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/18/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer