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Drivers of Repeat Instability in Myotonic Dystrophy

Award Number: K08AR087002
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Drivers of Repeat Instability in Myotonic Dystrophy - Project Summary Myotonic dystrophy type 1 (DM1) is a progressive neuromuscular disorder caused by an expanded CTG repeat tract in the DMPK gene, leading to RNA toxicity and widespread tissue dysfunction. Germline and somatic repeat instability are key contributors to disease onset and progression, yet the molecular mechanisms driving these processes remain poorly understood. To investigate drivers of germline and somatic instability, this project leverages a novel CRISPR-Cas9 knock-in allelic series of mice (Dmpk-KI) which contain 400-5000 CTG repeats in the endogenous mouse locus. These mice faithfully recapitulate human DM1 genetics and demonstrate many features consistent with DM1 symptoms in human patients. Leveraging modern-day long-read sequencing (LRS) technologies, we can systematically investigate factors influencing repeat instability. Specific Aim 1 will determine how parental sex and age impact germline instability, and also look at methylation signatures around the CTG repeat. Each of these focus areas has implications for congenital DM1, the most severe form of the disease. Specific Aim 2 will evaluate somatic expansion across multiple tissues, with a focus on R-loop formation as a potential driver of instability in post-mitotic cells. All work will be conducted in a highly collaborative environment, under the primary mentorship of Dr. Charles Thornton, a renowned expert in the field with over 30 years of working on DM1. By integrating cutting-edge sequencing and molecular biology techniques, this work will provide critical insights into mechanisms of DM1 and inform therapeutic strategies aimed at stabilizing expanded repeats. In parallel, this project serves as a career development platform, fostering expertise in animal models of neuromuscular disease, LRS, molecular genetics, and bioinformatics, all of which are critical skill gaps. This will be accomplished through formal and informal coursework at the University of Rochester, attending targeted symposia focused on LRS, and close relationships with my mentors and advisors. The proposed research and training will prepare me to lead larger studies on DM1 instability, and independently investigate mechanisms and treatments for other pediatric neuromuscular and repeat expansion 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 = $166,396 )
2026	2026	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	4/29/2026	NEW	$0
2026	2026	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	4/21/2026	NEW	$166,396
														Subtotal = $166,396

Grand Total All Awards = $166,396

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Drivers of Repeat Instability in Myotonic Dystrophy

Award Number: K08AR087002

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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