Tuesday, July 1, 2025 7/1/2025

Regulation and impact of alternative splicing in biology and disease

Award Number: R35GM145254
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: 08/09/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Regulation and impact of alternative splicing in biology and disease - Pre-mRNA splicing is a fundamental process required for the expression of most metazoan genes. Defects in splicing lead to human genetic disease, and splicing mutations in a number of genes involved in growth control have been implicated in multiple types of cancer. Insights into the basic mechanisms of pre-mRNA splicing and splice site recognition are therefore fundamental to understanding regulated gene expression and human disease. The control of alternative splicing is a highly combinatorial process, where many inputs dictate the splicing outcome for each exon. A critical feature of these regulatory mechanisms is the specific interaction of trans-acting splicing factors with cis-acting RNA elements. We use a highly integrated approach to investigate the molecular mechanisms that regulate pre-mRNA splicing. This includes knockout and knock-in tissue culture models, reconstitution assays using radioligands, transcriptomics, bioinformatics, kinetics, structure- function and biochemical techniques. In the next five years, we aim to address several outstanding challenges in the field, pursuing the following novel research directions. (1) Our demonstration that splicing regulatory proteins display highly position-dependent activities that negatively or positively influence splice site choice changed the way we think about the classical splicing activators (SR proteins) and the classical splicing repressors (hnRNPs). It is now appreciated that the context-dependent activation or repression of U1 snRNP serves as a gateway to allow the abundant U1 snRNP to fulfill its splicing function and its role to protect the pre-mRNA from premature degradation. However, it is not understood how splicing regulators achieve activation or repression of U1snRNP at the 5’ splice site. We aim to dissect the mechanisms of splicing repression by embracing multi-system approaches and by understanding the role of U1 snRNP conformers in mediating spliceosomal assembly. (2) Intron retention is an important alternative splicing pathway that has eluded extensive study. Thus, its regulation is not well-understood. The existence of inefficiently spliced introns within coding exons (exitrons) further highlights the biological importance of understanding when introns are removed efficiently and when they are not. We will decipher the rules of efficient intron removal and investigate the impact of cis-acting elements in this process using synthetic biology approaches. The argument is that the depth of the sequence variation tested in massively parallel reporter assays is far greater than the testing landscape that the human genome offers. Here, we will take advantage of our expertise in experimental molecular biology and bioinformatics. (3) It has become widely appreciated that gene expression events are highly integrated, with evidence suggesting that most pre-mRNA processing occurs co- transcriptionally. Defects in any one of these steps has been linked to disease. However, most published studies evaluate only steady-state levels of gene expression or focus only on a single step. This ignores the dynamics of gene expression steps that collectively contribute to the generation of proteins from mRNAs. Thus, it is unclear how the kinetics of RNA processing and mRNA stability translate into an endpoint gene expression signature. We have established a reliable method to metabolically label nascent RNA, which allows us to track transcripts from synthesis to degradation. Work in this project will probe how steady state mRNA levels are established, how the splicing and translation regulator SRSF1 influences mRNA dynamics and how these processes adjust as a cell undergoes transformation. The goals of our research program are to obtain a better understanding of exon recognition and alternative splicing. The new mechanistic insights will be leveraged to improve strategies to therapeutically target this essential gene expression step.


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: 2025 ( Subtotal = $392,500 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Biomedical Research and Research Training	002	4	6/10/2025	NON-COMPETING CONTINUATION	$392,500
2025	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Biomedical Research and Research Training	001	3	6/9/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Biomedical Research and Research Training	000	3	12/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $392,500

Issue Date FY: 2024 ( Subtotal = $483,657 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Biomedical Research and Research Training	001	3	7/3/2024	SUPPLEMENT FOR EXPANSION	$91,157
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Biomedical Research and Research Training	000	3	6/12/2024	NON-COMPETING CONTINUATION	$392,500
														Subtotal = $483,657

Issue Date FY: 2023 ( Subtotal = $473,877 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Biomedical Research and Research Training	001	2	8/17/2023	SUPPLEMENT FOR EXPANSION	$81,377
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Biomedical Research and Research Training	000	2	6/19/2023	NON-COMPETING CONTINUATION	$392,500
														Subtotal = $473,877

Issue Date FY: 2022 ( Subtotal = $392,500 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Biomedical Research and Research Training	000	1	8/9/2022	NEW	$392,500
														Subtotal = $392,500

Grand Total All Awards = $1,742,534

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Regulation and impact of alternative splicing in biology and disease

Award Number: R35GM145254

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: 08/09/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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