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A pilot study to investigate the contribution of alternative splicing to sex biases of aging related phenotypes

Award Number: R03AG067071
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2023

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A pilot study to investigate the contribution of alternative splicing to sex biases of aging related phenotypes - Project Summary/Abstract Alternative splicing is a fundamental gene regulatory mechanism that allows cells to significantly diversify their protein products. Splicing defects, often caused by mutations that disrupt the function of RNA-binding proteins (RBPs), which regulate splicing, have increasingly been implicated in aging-related disorders including cancer and neurodegenerative disease. Yet, despite this emerging pattern, few splicing factors have been studied with regard to aging and aging-related disease. The long-term goal of this project is to begin to elucidate how aberrant splicing that results from the dysfunction of a highly conserved RBP, leads to abnormal aging phenotypes. To this end, the highly conserved splicing factor Caper will be used as a model. Caper is required for the development and maintenance of Drosophila sensory neurons, and for adult locomotor behavior. Our preliminary data show that caper dysfunction leads to a shortened lifespan and a decline in locomotor behavior that is exacerbated with age. Moreover, these aging phenotypes show a strong sex bias, where males are more affected than females. Such sex biases are often seen in aging-related diseases, but the underlying mechanism for such sex biases remains unknown. Though little is known about the function of the human caper ortholog, the human caper ortholog, RBM39, is implicated in cancer progression and is expressed throughout the nervous system. The research proposed within this application will test the following hypotheses: (1) Caper regulates the maintenance of neurons in the adult brain and nervous system; (2) caper is differentially spliced in males compared to females; (3) Caper regulates sex-specific splicing during aging. Using the highly tractable model, Drosophila, we will utilize immunofluorescence to examine various markers of brain anatomy, apoptosis and mitochondrial markers over time in adult flies to determine if caper dysfunction results in neurodegeneration. We will use differential gene expression and spliceform analyses to determine whether caper itself is differentially spliced in aging male versus female flies, and if caper regulates differential splicing of other genes in aging male versus female flies. Finally, we will perform a pilot genetic screen to identify genes that interact with caper to regulate aging phenotypes. The outcomes of this study will establish the foundation for a more comprehensive research program aimed at using caper as a model for aging and sex biases in aging-related disease. Since aberrant alternative splicing has emerged as a common theme in various aging disorders, the knowledge gained from this study has broad implications for understanding and treating such 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: 2024 ( Subtotal = -$568 )
2024	2021	THE REGENTS OF THE UNIVERSITY OF COLORADO	1420 AUSTIN BLUFFS PKWY	COLORADO SPRINGS	CO	80918	EL PASO	USA	Aging Research	000	2	12/7/2023	NON-COMPETING CONTINUATION	-$568
														Subtotal = -$568

Issue Date FY: 2021 ( Subtotal = $72,000 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	1420 AUSTIN BLUFF PKWY CH209	COLORADO SPRINGS	CO	80918	EL PASO	USA	Aging Research	000	2	3/31/2021	NON-COMPETING CONTINUATION	$72,000
														Subtotal = $72,000

Issue Date FY: 2020 ( Subtotal = $72,000 )
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	1420 AUSTIN BLUFF PKWY CH209	COLORADO SPRINGS	CO	80918	EL PASO	USA	Aging Research	000	1	6/1/2020	NEW	$72,000
														Subtotal = $72,000

Grand Total All Awards = $143,432

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A pilot study to investigate the contribution of alternative splicing to sex biases of aging related phenotypes

Award Number: R03AG067071

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2023

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