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：
10569023
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/10569023
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 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 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.

项目摘要。线粒体呼吸链（RC）疾病是高病态的能量缺乏由所有年龄和系统的异质性病因和表型都非常异构的疾病两个基因组中> 350种不同基因的致病变异。无法治愈，FDA批准，也没有临床试验 - 有验证的RC疾病疗法。作为一定大小的所有人，单一疗法不太可能使所有患者受益，治疗建模对于开发精确药物至关重要，这些药物有意义地改善健康状况分子，生化或临床RC疾病亚型。具体而言，临床前翻译RC病在人类患者细胞和简单动物模型中进行的研究可能有效地识别潜在的治疗引导和特定的机械目标可以有意义地改善整体健康状况。我们独特的集合 “匹配”基于核基因的RC疾病模型集（对于NDUFS2，Nubpl，Surf1，fbxl4，c12orf65， dld）在秀丽隐杆线虫（蠕虫，无脊椎动物）中，遍及3种进化不同的物种，D。rerio（斑马鱼，脊椎动物），和人类患者的成纤维细胞，我们已经验证了一套新方法，我们很强烈旨在进一步利用多物种建模方法。确实，我们已经建立了一个高度的 RC疾病模型中的生产研究计划，以交叉验证多种机械见解并确定有希望的原发性RC疾病的新治疗铅。 NIGMS R35 MIRA支持将使重点基本和翻译的研究计划具有证明的教学机会，这是过去14 国际公认的研究者的年份，以通过识别确定精度线粒体医学潜水RC疾病亚型的中央疾病机制和铅治疗候选物。具体来说，该翻译的研究计划将重点放在利用RC病人细胞和简单动物模型上调查两个总体主题的关键问题。主题1是病理生理研究，涉及4个项目领域：（i）了解不同器官病理生理学的机理基础（ii）在不同的RC疾病中占主导地位线粒体功能，（iii）解密新型翻译后修饰的功能意义，包括N-糖基化，RC疾病中线粒体蛋白的N-糖基化，以及（iv）确定哪种中心营养素 - 传感信号网络（NSSN）节点及其下游生化途径，调节细胞蛋白毒性应激，以治疗靶向特定的RC疾病子集。主题2是治疗建模，涉及3个项目区域：（v）识别最佳营养疗法（大量营养素，维生素，辅助因子）为了改善RC疾病的健康和整体功能，（VI）利用翻译动物和细胞模型用于高通量药物筛查和铅化合物验证，以有效识别高潜力，安全和针对不同RC疾病亚组的精确疗法，以及（vii）确定原发性RC疾病是否是否治疗将改善继发性疾病（例如21三体）或急性RC功能障碍的健康状况。