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Unraveling the Impact of Alternative Splicing on RNA-Binding Protein Function Using Integrative Machine Learning

Award Number: R01GM164526
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/10/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Unraveling the Impact of Alternative Splicing on RNA-Binding Protein Function Using Integrative Machine Learning - Project Summary Alternative splicing (AS) is a major driver of transcriptomic and proteomic complexity, yet its impact on the structure and function of RNA-binding proteins (RBPs), key regulators of gene expression, RNA metabolism, and cellular homeostasis, remains poorly understood. Many RBP genes undergo extensive AS, producing multiple isoforms whose individual roles in health and disease are largely uncharacterized. Elucidating the functional consequences of alternative RBP isoforms is essential to understanding post-transcriptional regulation and may reveal new mechanisms of disease and therapeutic intervention. The primary objective of this project is to develop integrative machine learning methods characterizing alternatively spliced isoforms of RBPs and their functions, and to experimentally validate these methods on a set of medically relevant RBPs. By combining transcriptomic, proteomic, interactomic, and structural data with advanced deep learning and semi-supervised learning techniques, this study will systematically characterize RBP isoforms that are likely to produce functional, biologically relevant proteins. In Aim 1, we will develop novel machine learning strategies to predict the physiological stability of alternative RBP isoforms by leveraging experimentally and computationally obtained knowledge on the RBPs. In Aim 2, we will introduce the concept of an alternative splicing impact factor to quantify the functional effects of AS events on RNA-binding capacity, using a semi-supervised approach to expand predictions of RNA-binding sites. In Aim 3, we will apply these tools to a curated set of medically relevant RBPs and perform isoform-specific biochemical and RNA-binding experiments to validate model predictions. This work will produce a comprehensive, experimentally grounded framework to interpret the biological consequences of RBP isoform diversity and will identify new isoform-specific mechanisms relevant to human health and disease.


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 = $431,535 )
2026	2026	WORCESTER POLYTECHNIC INSTITUTE	100 INSTITUTE RD	WORCESTER	MA	01609	WORCESTER	USA	Biomedical Research and Research Training	000	1	8/7/2026	NEW	$431,535
														Subtotal = $431,535

Grand Total All Awards = $431,535

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Unraveling the Impact of Alternative Splicing on RNA-Binding Protein Function Using Integrative Machine Learning

Award Number: R01GM164526

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/10/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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