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Mitochondrial respiratory chain disease mechanistic and therapeutic modeling

线粒体呼吸链疾病机制和治疗模型

基本信息

批准号：
10343742
负责人：
MARNI J FALK
金额：
$ 58.08万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10343742
关键词：
Acute Affect Age Animal Model Area Basic Science Biochemical Biochemical Pathway Caenorhabditis elegans Cell model Cells Clinical Clinical Trials Collection Disease Disease model Down Syndrome Educational process of instructing Etiology FDA approved Fibroblasts Functional disorder Genes Genetic Diseases Genome Health Human International Invertebrates Investigation Lead Macronutrients Nutrition Medicine Methodology Mitochondria Mitochondrial Proteins Modeling Molecular National Institute of General Medical Sciences Nuclear Nutritional Support Organ Pathogenicity Patients Phenotype Post-Translational Protein Processing Precision therapeutics Research Research Personnel Respiratory Chain Signal Transduction Stress System Therapeutic Validation Variant Vitamins Zebrafish base cofactor detection of nutrient disorder subtype effective therapy glycosylation high-throughput drug screening improved in vivo insight nanosensors novel novel therapeutics pre-clinical precision medicine programs proteotoxicity therapeutic candidate therapeutic target translational research program

项目摘要

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 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.

项目总结。线粒体呼吸链（RC）疾病是高度病态的能量缺乏症