# Mitochondrial respiratory chain disease mechanistic and therapeutic modeling

> **NIH NIH R35** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $440,109

## Abstract

PROJECT SUMMARY. 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 effici...

## Key facts

- **NIH application ID:** 9850902
- **Project number:** 1R35GM134863-01
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** MARNI J FALK
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $440,109
- **Award type:** 1
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850902

## Citation

> US National Institutes of Health, RePORTER application 9850902, Mitochondrial respiratory chain disease mechanistic and therapeutic modeling (1R35GM134863-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9850902. Licensed CC0.

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