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p38 MAPK activation as a therapeutic target for Friedreich ataxia

p38 MAPK 激活作为 Friedreich 共济失调的治疗靶点

基本信息

批准号：
10641939
负责人：
ROBERT B WILSON
金额：
$ 58.74万
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：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641939
关键词：
Affect Afferent Neurons Antioxidants Ataxia Biogenesis Cardiac Myocytes Cardiomyopathies Cells Chronic Clinical Trials Complement Complex DNA Damage Defect Degenerative Disorder Disease Drug Targeting Environment Enzymes Exhibits Feedback Fibroblasts Friedreich Ataxia Functional disorder Genes Genetic Goals Growth Human In Vitro Inherited Investigational Therapies Iron Length Link Lipid Peroxidation MAP Kinase Gene Mission Mitochondria Mitochondrial Matrix Modeling Mutation National Heart, Lung, and Blood Institute National Institute of Neurological Disorders and Stroke Oxidative Stress Pathogenesis Pathway interactions Pharmaceutical Preparations Phenotype Prosthesis Proteins Public Health Research Role Secondary to Sulfur System Telomere Shortening Testing Therapeutic Therapeutic Effect Therapeutic Intervention Time United States National Institutes of Health Whole Organism Zebrafish autosome biological adaptation to stress cell type clinical development frataxin genetic approach in vivo induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes inhibitor mitochondrial dysfunction model organism mouse model p38 Mitogen Activated Protein Kinase response screening small molecule telomere therapeutic target

项目摘要

PROJECT SUMMARY/ABSTRACT There are no approved therapies for the autosomal-recessive neuro- and cardio-degenerative disorder Friedreich ataxia (FA). FA is caused by hypomorphic mutations in the gene encoding the protein frataxin. Frataxin localizes to the mitochondrial matrix and functions in the biogenesis of iron-sulfur-clusters (ISCs), which are important prosthetic groups for both intra- and extra-mitochondrial enzymes. We found that the p38 MAP kinase stress- response pathway is constitutively hyperactivated in FA cells, likely as a result of ongoing oxidative stress and/or an ongoing DNA damage response (DDR). Our working hypothesis is that chronic hyperactivation of the p38 pathway, which modulates a key protein in the ISC biogenesis complex, is part of a maladaptive feedback loop that further suppresses ISC biogenesis in FA cells; hence, inhibition of the p38 pathway, or of its activation, counteracts the deleterious effects of decreased frataxin function. Our preliminary studies have implicated lipid peroxidation and telomere damage in FA pathogenesis, both of which activate p38, and both of which are consequences of ISC deficiency. We hypothesize that ISC biogenesis in FA cells will be increased, and FA- associated defects ameliorated, by (i) inhibition of p38 and/or MK2, which links p38 to ISC biogenesis; or (ii) a reduction in p38 activation, either through a decrease in oxidative stress (particularly lipid peroxidation) or a decrease in the DDR (particularly secondary to critical telomere shortening). Complemented by genetic approaches, we will test compounds that are known to target these pathways, allowing us to elucidate the roles of these pathways in FA pathogenesis while simultaneously advancing our overall goal of identifying and prioritizing compounds for potential clinical development. Our Specific Aims are: Aim 1. To use fibroblast models to interrogate the interrelated roles of the p38-MAPK pathway, oxidative stress, and DNA damage in the pathogenesis of FA, and to test relevant drugs and drug targets for amelioration of FA-associated defects. We will test our hypothesis that constitutive hyperactivation of the p38 pathway in FA cells represents a maladaptive feedback loop, and that inhibiting this pathway counteracts the deleterious effects of decreased frataxin function, thereby ameliorating FA-associated defects. Using a combination of genetic and small-molecule approaches, we will test the effects of antioxidants, anti-DDR agents, and p38/MK2 inhibition on p38 activation, ISC biogenesis, and FA-associated defects. Aims 2 and 3. To use FA iPSC- derived cardiomyocytes and sensory neurons (Aim 2), and FA zebrafish (Aim 3), to test our hypotheses in affected cell types in vitro and in vivo. Using a combination of genetic and small-molecule approaches, we will test the effects of antioxidants, anti-DDR agents, and p38/MK2 inhibition on p38 activation, ISC biogenesis, and FA-associated defects validated in these models. We anticipate a significant positive impact: our preliminary studies already link these pathways to FA pathophysiology, and compounds targeting these pathways have been developed and, in some cases, are already in clinical trials for other disorders.

项目总结/文摘