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Cell-type-specific dysregulation and genetic control of alternative polyadenylation in neurodegeneration

Award Number: K99AG095208
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/15/2025
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Cell-type-specific dysregulation and genetic control of alternative polyadenylation in neurodegeneration - PROJECT SUMMARY/ABSTRACT Alternative polyadenylation (APA) is the fundamental mechanism for 3’ UTR choice during mRNA maturation, directly affecting mRNA localization, translation, and stability. Proper control of 3’UTR choice is crucial in the brain, especially for precise localization of stable mRNAs in highly structured and compartmentalized neurons. mRNA metabolism and processing is dysregulated in both Alzheimers’ disease (AD) and Parkinson’s disease (PD). mRNA processing is altered by alpha-synuclein and cell-type-specific 3’UTR choice is critical for the proper function of key neurodegenerative genes. Therefore, there is a critical need to understand APA in neurodegenerative disease. In addition, genetic variants controlling 3’UTR choice may explain specific disease risk loci that are not explained by other molecular quantitative trait loci (QTLs), providing mechanisms for disease risk. As the immediate molecular effects of 3’UTRs are encoded through its sequence, there is also an important opportunity to determine and potentially modulate the molecular cascade downstream of variants regulating 3’UTR choice in disease. My objective is to determine the role of APA in neurodegenerative disease and in disease risk. My overall goal is to close the gap in mapping altered molecular processes in neurodegenerative disease, map genetic risk for disease onto mRNA molecular phenotypes, and understand the roles of the downstream mechanisms of 3’UTR choice in neurodegenerative disease. I will repurpose 3’-biased single-nucleus RNA-seq from over 350 post-mortem human brain samples to map APA at the single-cell level in neurodegenerative diseases. I will develop a method for identifying differential APA, determine disease-specific and shared changes across cell types in AD and PD, and predict regulators of APA choice in health and in disease. To investigate the genetic control of 3’UTR choice, I will identify both 3’UTR QTLs (3’aQTLs) and expression QTLs at the single-cell level. I will determine the extent to which 3’aQTLs overlap with other molecular QTLs and identify neurodegenerative disease risk loci acting through 3’aQTLs. I will extend this work in my independent phase to understand how the immediate molecular consequences of 3’UTR choice impact neurodegenerative diseases and disease risk. I will work with my mentor Dr. Shamil Sunyaev; my co-mentors, Dr. Vikram Khurana and Dr. Rudolph Tanzi; and my technical support and advisory committee, Dr. Evan Macosko, Dr. David Bennett, and Dr. Chris Cassa to carry out my proposed research and training plan. I will gain experience in complex disease genetics, statistical genetics, and variant effect prediction. I will audit relevant courses in my training period to bridge the gap in my training on neurodegenerative diseases and genetics. I will receive additional mentoring from Dr. Vikram Khurana on PD biology, genetics, and mRNA processing. I will also receive mentoring and technical support from Dr. Rudolph Tanzi and Dr. David Bennett on neuropathology and AD biology and genetics.


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 = $125,901 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	2	5/12/2026	NON-COMPETING CONTINUATION	$125,901
														Subtotal = $125,901

Issue Date FY: 2025 ( Subtotal = $125,901 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	1	8/15/2025	NEW	$125,901
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	001	1	8/27/2025	NEW	$0
														Subtotal = $125,901

Grand Total All Awards = $251,802

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Cell-type-specific dysregulation and genetic control of alternative polyadenylation in neurodegeneration

Award Number: K99AG095208

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/15/2025

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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