Administrative Supplement - Mitochondrial respiratory chain disease mechanistic and therapeutic modeling

行政补充-线粒体呼吸链疾病机制和治疗模型

基本信息

批准号：
10798475
负责人：
MARNI J FALK
金额：
$ 24.98万
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/10798475
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 glycosylation high-throughput drug screening improved in vivo insight nanosensors novel novel therapeutics parent grant pre-clinical precision medicine programs proteotoxicity therapeutic candidate therapeutic target translational research program

项目摘要

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) 疾病的发病率很高。能量缺乏症在各个年龄段都有着巨大的异质性病因和表型系统，由两个基因组中超过 350 个不同基因的致病变异引起，无法治愈，FDA-。对于 RC 疾病，目前尚无经批准且经临床试验验证的疗法，因此单一疗法是一刀切的。虽然不太可能使所有患者受益，但治疗模型对于开发有意义的精准药物至关重要改善不同分子、生化或临床 RC 疾病亚型（特别是临床前）的健康。在人类患者细胞和简单动物模型中进行转化 RC 疾病研究可能会有效确定有效的治疗线索和具体的机制目标，以有意义地改善整体健康状况。我们独特的“匹配”核基因 RC 疾病模型集（用于 NDUFS2、NUBPL、SURF1、 FBXL4、C12ORF65、DLD）跨越 3 个进化上不同的物种。秀丽隐杆线虫（蠕虫、无脊椎动物）、斑马鱼（斑马鱼、脊椎动物）和人类患者成纤维细胞，我们在其中验证了一套新颖的事实上，我们有能力进一步利用多物种建模方法。在 RC 疾病模型中建立了一个高效的研究项目，以交叉验证多个机制见解并确定针对原发性 RC 疾病的有前景的新治疗线索。支持将使这一基础和转化研究项目的重点通过教学得以体现由国际公认的调查员在过去 14 年中创造的机会，以推进通过识别核心疾病机制和领先的治疗候选药物进行精准线粒体医学具体而言，该转化研究计划将重点关注如何利用 RC。疾病患者细胞和简单的动物模型，以研究两个总体主题的关键问题。主题 1 是病理生理学研究，4 个项目领域：(i) 了解机制基础不同的器官病理生理学在不同的 RC 疾病中占主导地位，(ii) 发展敏感纳米传感器非侵入性地量化体内线粒体功能，（iii）破译功能 RC 中线粒体蛋白的新型翻译后修饰（包括 N-糖基化）的重要性 (iv) 确定哪个中央营养感应信号网络 (NSSN) 节点及其调节细胞蛋白毒性应激的下游生化途径，以特定的治疗目标 RC 疾病子集。主题 2 是治疗建模，涉及 3 个项目领域：(v) 识别最佳方案。营养疗法（大量营养素、维生素、辅因子）可改善 RC 的健康和整体功能 (vi) 利用转化动物和细胞模型进行高通量药物筛选和先导研究化合物验证，有效识别针对不同 RC 疾病的高效、安全和精准的疗法 (vii) 确定原发性 RC 疾病治疗是否会改善患有以下疾病的健康继发性（如 21 三体性）或急性 RC 功能障碍。