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Identifying tissue-specific interactions to bridge mechanisms underlying muscle degeneration in Congenital Disorders of Glycosylation and Dystroglycanopathies

Award Number: F31HD117499
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Identifying tissue-specific interactions to bridge mechanisms underlying muscle degeneration in Congenital Disorders of Glycosylation and Dystroglycanopathies - Both Congenital Disorders of Glycosylation (CDGs) and dystroglycanopathies are clinically heterogenous, multisystem disorders that can lead to severe progressive neural and muscular degeneration, which deleteriously impacts quality of life and is frequently lethal. CDGs are marked by disrupted glycan biosynthesis, while dystroglycanopathies stem from disrupted glycosylation of dystroglycan (DG), a critical transmembrane receptor that anchors the intracellular cytoskeleton to the surrounding extracellular matrix. Post-translational modifications, such as glycosylation, are critical for skeletal muscle development, growth, and homeostasis, so it is not surprising that disrupted glycosylation can lead to disease. Healthy muscle also requires the development of neuromuscular junctions (NMJs), which contain cell-matrix adhesion complexes replete with glycosylated proteins, for neuromuscular crosstalk to occur. In the context of CDGs and dystroglycanopathies, it is still unknown whether muscle tissue or neural tissue degenerates first, driving disease progression. Important questions that remain unanswered include: (1) which tissue or tissues that express genes associated with dystroglycanopathy should be targeted to mitigate degeneration and disease progression, and (2) which aspects of neuromuscular degeneration are specifically due to the disruption of DG glycosylation versus disruption of other proteins. The ability to address these questions has been hindered by the lack of viable vertebrate models to facilitate the discovery of tissue-specific impacts of disrupted glycosylation on cell-matrix adhesion throughout embryonic development and disease progression. To address this, I have generated a zebrafish model through CRISPR/Cas9 gene editing of a known dystroglycanopathy gene, dolichol-phosphate mannosyltransferase subunit 3 (dpm3), which assists in the generation of a foundational mannose residue as a building block for the glycosylation of DG. Importantly, my model recapitulates the phenotypic variation and disease progression observed in human dpm3 patients. Through use of dpm3 zebrafish mutants, as well as dpm3;dg double mutants, I have developed models to elucidate which aspects of Dpm3 function are DG- dependent and DG-independent in disease progression. I propose to use these models to address my long- term goal of elucidating tissue-specific impacts of glycosylation during neuromuscular development and homeostasis. I will leverage my unique genetic model to accomplish two aims: (1) Elucidate tissue-specific roles for dpm3 during development and homeostasis, and (2) Determine which aspects of Dpm3 protein function are dependent on versus independent of dystroglycan. Completing these aims will provide a critical foundation for understanding the basic biology underlying abnormal neuromuscular development in CDGs and dystroglycanopathies, serving as a basis for identifying future therapeutic targets and significantly impacting the field of neuromuscular development and homeostasis.


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 = $22,943 )
2026	2026	UNIVERSITY OF MAINE SYSTEM	5717 CORBETT HALL	ORONO	ME	04469	PENOBSCOT	USA	Child Health and Human Development Extramural Research	001	2	3/24/2026	NON-COMPETING CONTINUATION	$2,644
2026	2026	UNIVERSITY OF MAINE SYSTEM	5717 CORBETT HALL	ORONO	ME	04469	PENOBSCOT	USA	Child Health and Human Development Extramural Research	000	2	1/7/2026	NON-COMPETING CONTINUATION	$20,299
														Subtotal = $22,943

Issue Date FY: 2024 ( Subtotal = $34,007 )
2024	2024	UNIVERSITY OF MAINE SYSTEM	5717 CORBETT HALL	ORONO	ME	04469	PENOBSCOT	USA	Child Health and Human Development Extramural Research	000	1	9/17/2024	NEW	$34,007
														Subtotal = $34,007

Grand Total All Awards = $56,950

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Identifying tissue-specific interactions to bridge mechanisms underlying muscle degeneration in Congenital Disorders of Glycosylation and Dystroglycanopathies

Award Number: F31HD117499

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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