Mitochondrial respiratory chain disease mechanistic and therapeutic modeling

线粒体呼吸链疾病机制和治疗模型

• 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
• 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

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 在所有年龄段和系统中具有显著不同病因和表型的疾病，由 &gt；350个不同基因在两个基因组中的致病变异。没有治愈方法，FDA批准，也没有临床试验- RC疾病已有经过验证的治疗方法。由于一刀切，单一疗法不太可能惠及所有患者， 治疗建模对于开发有意义的、显著改善健康的精确药物至关重要 分子、生化或临床RC疾病亚型。具体地说，临床前转化性RC病 对人类患者细胞和简单动物模型的研究可能有效地识别出有效的治疗方法 领导和具体的机械性目标，以有意义地改善整体健康。我们独一无二的 基于核基因的RC病模型集(针对NDUFS2、NUBPL、SURF1、FBXL4、C12ORF65、 在线虫(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，在其中我们已经验证了一套新的方法，我们强烈 以进一步利用多物种建模方法。事实上，我们已经建立了高度的 RC疾病模型中的富有成效的研究计划，以交叉验证多种机制见解并确定 有望为原发RC疾病提供新的治疗线索。NIGMS R35 Mira支持将使这一点成为焦点 基础研究和翻译研究计划，具有示范的教学机会，在过去14年中建立 由一位国际公认的研究人员数年来，通过识别 针对不同RC疾病亚型的中心疾病机制和主要候选治疗方法。具体来说， 这项翻译研究计划将专注于利用RC病患者细胞和简单的动物模型 调查两个主要主题的关键问题。主题1是病理生理学调查， 涉及4个项目领域：(I)了解不同器官病理生理学 在不同的RC疾病中占主导地位，(Ii)开发敏感的纳米传感器以非侵入性地在体内定量 线粒体功能，(Iii)破译新的翻译后修饰的功能意义， 包括RC病中线粒体蛋白的N-糖基化，以及(Iv)确定哪种中枢营养物质- 感知信号网络节点(S)及其下游调节细胞的生化通路 蛋白毒性应激，在治疗上针对特定的RC疾病亚群。主题2是治疗建模， 涉及3个项目领域：(5)确认最佳营养疗法(大量营养素、维生素、辅助剂) 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 用于高通量药物筛选和先导化合物验证，以高效识别高效、安全和 对不同的RC疾病亚组进行精确治疗，以及(Vii)确定原发RC疾病 治疗将改善继发性疾病(如21三体)或急性RC功能障碍患者的健康状况。