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Mitochondrial respiratory chain disease mechanistic and therapeutic modeling

Award Number: R35GM134863
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2030

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Mitochondrial respiratory chain disease mechanistic and therapeutic modeling - PROJECT SUMMARY. Primary mitochondrial diseases (PMD) are highly morbid energy deficiency disorders with remarkably heterogeneous etiologies and phenotypes across all ages and systems, caused by pathogenic variants in > 400 different genes across both nuclear and mitochondrial genomes. No cure, FDA-approved, nor clinical trial-validated therapies exist for the indication of PMD. As one-size-fits-all, single therapy is unlikely to benefit all patients, therapeutic modeling is essential to develop precision medicines that significantly improve health in distinct molecular, biochemical, and/or clinical PMD subtypes. Specifically, pre- clinical translational RC disease investigations in human patient cells and simple animal models may efficiently identify potent therapeutic leads, and specific mechanistic targets, to meaningfully improve overall cellular and organismal health. We will exploit for this purpose our unique and growing collection of ‘matched’ nuclear gene-based PMD model sets for complex I (NDUFS2, NUBPL), complex IV (SURF1), multiple respiratory chain complexes (FBXL4, C12ORF65, MT-ARS2), and interacting pathways (DLD, OPA1) in 3 evolutionarily distinct species using C. elegans (worm, invertebrate), D. rerio (zebrafish, vertebrate), and humans (derived cell lines), as well as our newer array of heteroplasmic mtDNA mutant zebrafish and cybrid cell models. Having validated many novel, in vivo approaches to quantify PMD effects on survival and diverse cellular and animal- level functions, we are strongly situated to harness this patented, multi-species preclinical modeling approach to gain further mechanistic insights and identify promising new therapeutic leads for diverse PMD subtypes and secondary mitochondrial disorders. NIGMS R35 MIRA support will enable this basic and translational research program, built over the past 18 years by an established physician-scientist research investigator who has been highly productive and provided many teaching opportunities, to continue to advance the scientific evidence base for precision mitochondrial medicine. Specifically, this translational research program will focus on harnessing PMD cells and simple animal models to investigate key questions across 2 overarching themes. Theme 1 is ‘Pathophysiology Investigations in PMD cell and animal models’, involving 2 project areas: (i) Understanding the mechanistic basis by which distinct organ pathophysiology and metabolic dysfunction predominates in different forms of PMD; and (ii) Determining which central nutrient-sensing signaling network node(s) and downstream biochemical pathways that regulate cellular proteotoxic stress underlie candidate therapies response in specific PMD subsets. Theme 2 is ‘Preclinical therapeutic discovery in PMD cell and animal models’, involving 2 project areas: (iii) Therapeutic target and compound discovery and validation in distinct PMD animal and cell translational disease variant models; and (iv) Identify whether treatments that improve health in genetic-based PMD will improve health in complex disorders with secondary forms of mitochondrial dysfunction that are chronic (eg, Down or Cockayne syndrome) or acute (toxin-induced).


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: 2025 ( Subtotal = $628,340 )
2025	2025	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	002	6	7/16/2025	COMPETING CONTINUATION	$628,340
2025	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	5	11/8/2024	NON-COMPETING CONTINUATION	$0
2025	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	001	5	6/16/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $628,340

Issue Date FY: 2024 ( Subtotal = $580,800 )
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	001	5	5/16/2024	NON-COMPETING CONTINUATION	$58,079
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	5	2/9/2024	NON-COMPETING CONTINUATION	$522,721
														Subtotal = $580,800

Issue Date FY: 2023 ( Subtotal = $840,780 )
2023	2023	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	001	4	5/18/2023	SUPPLEMENT FOR EXPANSION	$10,212
2023	2023	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	4	3/10/2023	NON-COMPETING CONTINUATION	$580,800
2023	2023	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	002	4	6/6/2023	SUPPLEMENT FOR EXPANSION	$249,768
														Subtotal = $840,780

Issue Date FY: 2022 ( Subtotal = $580,800 )
2022	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	001	3	6/24/2022	NON-COMPETING CONTINUATION	$58,078
2022	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	3	2/8/2022	NON-COMPETING CONTINUATION	$522,722
														Subtotal = $580,800

Issue Date FY: 2021 ( Subtotal = $580,800 )
2021	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	2	2/5/2021	NON-COMPETING CONTINUATION	$580,800
														Subtotal = $580,800

Issue Date FY: 2020 ( Subtotal = $440,109 )
2020	2020	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	1	2/25/2020	NEW	$440,109
														Subtotal = $440,109

Grand Total All Awards = $3,651,629

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Mitochondrial respiratory chain disease mechanistic and therapeutic modeling

Award Number: R35GM134863

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2030

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