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Cellular basis for cancer treatment related GDF15 expression and the regulation of skeletal muscle fibrosis and neuromuscular integrity.

Award Number: R01CA290724
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Cellular basis for cancer treatment related GDF15 expression and the regulation of skeletal muscle fibrosis and neuromuscular integrity. - ABSTRACT One of the great achievements in medical sciences is the improved survival rate among children diagnosed with cancer. Although estimates indicate the 5-year survival rate of children diagnosed with a malignancy is near 80%, most of these individuals prior to the age of 40 demonstrate indices of physical limitation normally associated with the elderly population. Among the treatments received by pediatric cancer patients is multimodal fractionated x-ray irradiation and chemotherapy. Both induce genotoxic stress that eliminates proliferative cancer cells; however, multifarious direct and indirect effects of radiation and chemotherapy can negatively impact normal tissue growth and maintenance especially in actively growing populations. Phenotypes observed earlier in pediatric cancer survivors is the accelerated onset of frailty indices such as neuromuscular decline. In a murine model, we find weeks after image guided pediatric fractionated x-ray irradiation of hindlimbs reduced skeletal muscle fiber size, impaired neuromuscular function, fibrosis, and activation of stress related p53 gene expression. Among the p53 regulated genes elevated weeks after pediatric fractionated radiation is Growth Differentiation Factor 15 (GDF15), a regulator of food intake and body weight in response to stressors such as cancer therapies. Single cell RNA sequencing (scRNASeq) analysis revealed radiation induced GDF15 expression was restricted to muscle resident endothelial cells. Also, we identified a subpopulation of neuromuscular junction associated muscle resident mesenchymal progenitor cells expressing the receptor tyrosine kinase Ret that is implicated in mediating GDF15 activity. We find in our murine model of multimodal pediatric cancer treatment and survivorship, deficits in body weight gain and exacerbation of neuromuscular related phenotypes observed with fractionated radiation alone. Therefore, our long-term goal is to rigorously characterize the mechanisms whereby treatment related GDF15 expression impacts neuromuscular related phenotypes in our murine model of multimodal pediatric cancer therapy and survivorship. Ideally, such insight would be used to uncover interventions to attenuate pediatric cancer treatment related neuromuscular decline that increases morbidity and burdens survivors. To accomplish our objectives, we will utilize, assessment of skeletal muscle integrity, neuromuscular function, imaging analysis, mouse genetics, scRNAseq analysis, flow cytometry, gene expression analysis, pharmacological treatments, and measures of body weight and food intake. The specific aims of this proposal are 1) determine if endothelial cell specific loss of p53 or GDF15 knockout impacts pediatric cancer treatment related fibrosis and neuromuscular deficits, and 2) examine whether Ret activity regulates pediatric cancer treatment related fibrosis and neuromuscular deficits.


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 = $583,677 )
2026	2026	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Treatment Research	000	3	3/5/2026	NON-COMPETING CONTINUATION	$583,677
														Subtotal = $583,677

Issue Date FY: 2025 ( Subtotal = $420,083 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Treatment Research	000	2	3/10/2025	NON-COMPETING CONTINUATION	$378,075
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Treatment Research	001	2	9/25/2025	NON-COMPETING CONTINUATION	$42,008
														Subtotal = $420,083

Issue Date FY: 2024 ( Subtotal = $344,059 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Treatment Research	000	1	3/11/2024	NEW	$344,059
														Subtotal = $344,059

Grand Total All Awards = $1,347,819

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Cellular basis for cancer treatment related GDF15 expression and the regulation of skeletal muscle fibrosis and neuromuscular integrity.

Award Number: R01CA290724

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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