. Mitochondrial respiratory chain (RC) diseases are highly morbid energy deficiency disorders with remarkably heterogeneous etiologies and phenotypes across all ages and systems, caused by pathogenic variants in > 350 different genes across both genomes. No cure, FDA-approved, nor clinical trial- validated therapies exists for RC diseases. As one-size-fits-all, single therapy is unlikely to benefit all patients, therapeutic modeling is essential to develop precision medicines that meaningful improve health in distinct molecular, biochemical, or clinical RC disease 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 health. With our unique collection of ?matched? nuclear gene-based RC disease model sets (for NDUFS2, NUBPL, SURF1, FBXL4, C12ORF65, DLD) across 3 evolutionarily distinct species in C. elegans (worm, invertebrate), D. rerio (zebrafish, vertebrate), and human patient fibroblasts in which we have validated a suite of novel methodologies, we are strongly situated to further harness a multi-species modeling approach. Indeed, we have established a highly productive research program in RC disease models to cross-validate multiple mechanistic insights and identify promising new therapeutic leads for primary RC diseases. NIGMS R35 MIRA support will enable focus of this basic and translational research program with demonstrated teaching opportunities, as built over the past 14 years by an internationally-recognized investigator, to advance precision Mitochondrial Medicine by identifying central disease mechanisms and lead therapeutic candidates for diverse RC disease subtypes. Specifically, this translational research program will focus on harnessing RC disease patient cell and simple animal models to investigate key questions across 2 overarching themes. Theme 1 is Pathophysiology Investigations, involving 4 project areas: (i) Understanding the mechanistic basis by which different organ pathophysiology predominates in distinct RC diseases, (ii) Developing sensitive nanosensors to non-invasively quantify in vivo mitochondrial functions, (iii) Deciphering the functional significance of novel post-translational modifications, including N-glycosylation, of mitochondrial proteins in RC disease, and (iv) Determining which central nutrient- sensing signaling network (NSSN) node(s), and their downstream biochemical pathways that regulate cellular proteotoxic stress, to therapeutically target in specific RC disease subsets. Theme 2 is Therapeutic Modeling, involving 3 project areas: (v) Recognizing the optimal nutritional therapies (macronutrients, vitamins, cofactors) to improve health and overall function in RC disease, (vi) Harnessing translational animal and cellular models for high-throughput drug screening and lead compound validation, to efficiently identify highly potent, safe, and precision therapies for distinct RC disease subgroups, and (vii) Identifying whether primary RC disease treatments will improve health in disorders with secondary (such as Trisomy 21) or acute RC dysfunction.

Public Health Relevance

. Mitochondrial respiratory chain (RC) disease is a highly heterogeneous, multi- systemic genetic disorder affecting all organs and ages. Translational RC disease investigations in human cell and simple animal models may identify effective therapies, and specific mechanisms, to improve overall health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
5R35GM134863-02
Application #
10114297
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ansong, Charles Kwaku
Project Start
2020-03-01
Project End
2025-02-28
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19146