Administrative Supplement (Undergraduate Summer Research Experiences) - Mitochondrial respiratory chain disease mechanistic and therapeutic modeling

行政补充（本科生暑期研究经历）-线粒体呼吸链疾病机制和治疗模型

• 批准号: 10809930
• 负责人: MARNI J FALK
• 金额: $ 1.02万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 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/10809930
• 关键词: Acute; Administrative Supplement; 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; Productivity; Research; Research Personnel; Respiratory Chain; Signal Transduction; Stress; System; Therapeutic; Validation; Variant; Vitamins; Zebrafish; cofactor; detection of nutrient; disorder subtype; effective therapy; experience; glycosylation; high-throughput drug screening; improved; in vivo; insight; nanosensors; novel; novel therapeutics; parent grant; pre-clinical; precision medicine; programs; proteotoxicity; summer research; therapeutic candidate; therapeutic target; translational research program; undergraduate student

PROJECT SUMMARY (PARENT GRANT). 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.

项目摘要（家长资助）。线粒体呼吸链（RC）疾病发病率高