Metabolic regulation of MODS in pediatric mitochondrial disorders

小儿线粒体疾病中 MODS 的代谢调节

基本信息

批准号：
10744903
负责人：
Shilpa Iyer
金额：
$ 67.35万
依托单位：
UNIVERSITY OF ARKANSAS AT FAYETTEVILLE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10744903
关键词：
Address Affect Age Biochemistry Bioenergetics Biological Markers Brain Cardiac Myocytes Categories Cell Culture Techniques Cell Death Cell Differentiation process Cell model Cell physiology Cells Child Childhood Chronic Clinical Communities Complex DNA DNA Sequence Alteration Data Defect Diagnosis Disease Event Exhibits Experimental Designs Fibroblasts Frequencies Functional disorder Gastrointestinal tract structure Generations Genetic Genomics Health Heart Human Impairment Injury Intervention Kidney Life Link Medical Genetics Membrane Potentials Metabolic Metabolic Control Metabolic Diseases Metabolic stress Metabolism Mission Mitochondria Mitochondrial DNA Mitochondrial Diseases Morphology Multiple Organ Failure Muscle NADH Neurons Nuclear Organ Organ failure Outcome Oxidation-Reduction Oxidative Stress Pathogenicity Pathway interactions Patients Phenotype Physiology Play Polyamines Process Production Putrescine Regulation Research Respiration Respiratory Chain Role Severities Severity of illness Skin Stress Symptoms Testing Therapeutic Tissues Toxic effect United States National Institutes of Health Variant Virus Diseases biological adaptation to stress cell type comparison control current pandemic fighting improved in vivo Model indexing induced pluripotent stem cell interest metabolic rate metabolomics mitochondrial dysfunction mitochondrial genome mitochondrial membrane mortality mouse model next generation sequencing novel personalized medicine personalized strategies podocyte polycation pre-clinical response skin disorder stem cell biology stem cells stressor therapeutic candidate

项目摘要

PROJECT SUMMARY Devastating human primary mitochondrial disorders are caused by pathogenic mtDNA variants and frequently evolve into organ failures referred to, as mitochondrial-induced multiple organ dysfunction syndrome (MIMODS). The underlying pathophysiologic mechanisms are more complex than a mere decrease in ATP pro- duction and very little is known about these complex processes in a tissue-specific manner. There is thus an urgent unmet need to assess the impact of the widespread mitochondrial dysfunction in multiple tissues leading to MIMODS. We have demonstrated deleterious outcomes of widespread mitochondrial dysfunction (lowered bioenergetics health index, abnormal mitochondrial morphology, elevated putrescine levels) in multiple pediat- ric PMD dermal fibroblasts carrying unique pathogenic mtDNA variants. Based on our findings, we hypothesize that elevated putrescine levels cause oxidative stress response and widespread mitochondrial dysfunction that contributes to MIMODS in cellular models of primary mitochondrial disorders. Our collaborative team will de- sign experiments and build upon established expertise in mitochondrial genetics and physiology, stem cell biol- ogy and differentiation, next-generation sequencing analysis and metabolite profiling to address the following research aims: In Aim 1, we will comprehensively assess mitochondrial dysfunction in twenty pediatric diseased fibroblasts with a confirmed diagnosis of PMDs, along with five age matched controls. We will assess the oxida- tive stress markers, NAD/NADH redox biochemistry, metabolomics, mitochondrial respiration and morphology. In aim 2, we will seek to understand tissue-specific abnormalities associated with mitochondrial dysfunction in neurons, cardiomyocytes and podocytes. In aim 3, we will assess the effect of targeted interventions of reducing oxidative stress and improving mitochondrial respiration in multiple differentiated cell types that exhibit ele- vated putrescine levels; and in multiple tissues from preclinical mouse models of PMD. The completion of these aims will contribute to a newer understanding of putrescine metabolism in multiple energy-intensive cell types derived from patients with pediatric PMD and its role in triggering MIMODS. In the long-term, our studies have the potential to develop strategies for individualized testing of patient cells with candidate therapeutics to drive rational, personalized therapies.

项目概要毁灭性的人类原发性线粒体疾病是由致病性 mtDNA 变异引起的，并且经常发生演变成器官衰竭，称为线粒体诱导的多器官功能障碍综合征（MIMODS）。潜在的病理生理机制比单纯的 ATP 亲和性降低更为复杂。诱导，但人们对组织特异性方式的这些复杂过程知之甚少。因此有一个迫切需要评估多种组织中广泛存在的线粒体功能障碍的影响，但这一需求尚未得到满足到 MIMODS。我们已经证明了广泛的线粒体功能障碍（降低多种儿科疾病的生物能学健康指数、线粒体形态异常、腐胺水平升高） ric PMD 真皮成纤维细胞携带独特的致病性 mtDNA 变异。根据我们的发现，我们假设腐胺水平升高会导致氧化应激反应和广泛的线粒体功能障碍有助于原发性线粒体疾病细胞模型中的 MIMODS。我们的协作团队将签署实验并建立在线粒体遗传学和生理学、干细胞生物学方面的既定专业知识基础上生物学和分化、下一代测序分析和代谢物分析，以解决以下问题研究目标：在目标 1 中，我们将全面评估 20 名儿科疾病患者的线粒体功能障碍确诊患有 PMD 的成纤维细胞，以及五名年龄匹配的对照。我们将评估氧化活性应激标记、NAD/NADH 氧化还原生物化学、代谢组学、线粒体呼吸和形态。在目标 2 中，我们将寻求了解与线粒体功能障碍相关的组织特异性异常。神经元、心肌细胞和足细胞。在目标 3 中，我们将评估有针对性的干预措施的效果，以减少多种分化细胞类型中的氧化应激和改善线粒体呼吸改变腐胺水平；以及 PMD 临床前小鼠模型的多个组织中。这些工作的完成目标将有助于对多种能量密集型细胞类型中的腐胺代谢有新的认识来自儿科 PMD 患者及其在触发 MIMODS 中的作用。从长远来看，我们的研究开发利用候选疗法对患者细胞进行个体化测试的策略的潜力合理的、个性化的治疗。