Development of MESH1 inhibitors to treat ferroptosis-associated neurodegeneration

开发 MESH1 抑制剂来治疗铁死亡相关的神经变性

• 批准号: 10432233
• 负责人: Jen-Tsan Ashley Chi
• 金额: $ 42.78万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10432233
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; American; Amyloid beta-Protein Precursor; Antioxidants; Bacteria; Biological; Brain; Cell Death; Cells; Cellular Stress; Chemicals; Clinical; Complement; Cultured Cells; Data; Deferoxamine; Dependence; Development; Disease; Elderly; Escherichia coli; Excision; Exhibits; Fatty Acids; Frontotemporal Dementia; Funding; Future; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Genome; Goals; Healthcare; Homologous Gene; Huntington Disease; Huntington gene; Hydrolase; In Vitro; Indoles; Iron; Iron Chelating Agents; Ligands; Ligase; Lipid Peroxidation; Lipoxygenase Inhibitors; Literature; Mammalian Cell; Medical; Metabolic stress; Modeling; Molecular; Mus; NADP; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oleic Acids; Organism; Patient-Focused Outcomes; Pharmaceutical Preparations; Phenotype; Phosphoric Monoester Hydrolases; Play; Population; Production; Property; Proteins; Reactive Oxygen Species; Regulation; Reporting; Research; Role; Slice; Specificity; Spottings; Stress; Stress and Coping; Structure; Structure-Activity Relationship; Testing; Therapeutic; Toxic effect; Transfection; Treatment outcome; Work; age related; analog; base; biological adaptation to stress; clinical development; coping mechanism; design; effective intervention; efficacy study; experimental study; gene gun; glutathione peroxidase; improved; in silico; inhibitor; insight; knock-down; neuron loss; novel; nutrient deprivation; pharmacophore; preclinical study; preservation; prevent; public health relevance; response; safety study; screening; small molecule; tau mutation; therapy development; treatment strategy

All living organisms encounter a wide variety of metabolic and environmental stress and have developed various stress-response mechanisms that promote survival. In bacteria, the main stress-response mechanism is the “stringent response” which is triggered by the accumulation of the alarmone (p)ppGpp. It orchestrates extensive transcriptional changes to promote stress survival. Metazoan genomes encode a homolog of bacterial SpoT—MESH1—that can hydrolyze ppGpp in vitro and functionally complements SpoT in E. coli. However, neither a homolog of the (p)ppGpp synthetase nor (p)ppGpp itself has been found in metazoans, mystifying the function and relevant substrate(s) of MESH1 in mammalian cells. Recently, our research has revealed that MESH1 is the first cytosolic NADPH phosphatase that is essential for ferroptosis. Ferroptosis is a newly- recognized form of cell death which is characterized by iron dependency and lipid peroxidation. The induction of MESH1 under ferroptosis contributes to NADPH and GSH depletion. Therefore, genetic removal of MESH1 robustly protects cells from ferroptosis. As ferroptosis is involved in neuronal cell death in neurodegenerative diseases, such as Alzheimer's Disease and Alzheimer's Disease Related Dementias (AD/ADRD), we hypothesize that inhibition of ferroptosis by small molecule MESH1 inhibitors may protect neurons from ferroptosis in AD/ADRD. To test our hypothesis, we assemble an integrative scientific team with complementary expertise and propose the following two specific aims: First, we will develop and optimize small molecule MESH1 inhibitors derived from the top two validated hit compounds. Next, we will determine the activity and specificity of MESH1 inhibitors to block ferroptosis in cultured cells and in organotypic brain slice culture models of AD/ADRD. Collectively, the successful execution of the proposal will identify novel chemical inhibitors of MESH1 and ferroptosis to improve treatment outcomes for patients with age-related AD/ADRD.

所有生物体都会遇到各种各样的代谢和环境压力，并发展出各种促进生存的压力反应机制。在细菌中，主要的应激反应机制是由报警素(p)ppGpp的积累引发的“严格反应”。它协调广泛的转录变化以促进压力生存。后生动物基因组编码细菌 SpoT 的同源物 MESH1，它可以在体外水解 ppGpp，并在功能上补充大肠杆菌中的 SpoT。然而，在后生动物中既没有发现 (p)ppGpp 合成酶的同源物，也没有发现 (p)ppGpp 本身，这使得 MESH1 在哺乳动物细胞中的功能和相关底物变得神秘。最近，我们的研究表明 MESH1 是第一个对于铁死亡至关重要的胞质 NADPH 磷酸酶。铁死亡是一种新认识的细胞死亡形式，其特征是铁依赖性和脂质过氧化。 MESH1 在铁死亡下的诱导导致 NADPH 和 GSH 消耗。因此，MESH1 的基因去除可以强有力地保护细胞免于铁死亡。由于铁死亡与神经退行性疾病（例如阿尔茨海默病和阿尔茨海默病相关痴呆（AD/ADRD））中的神经细胞死亡有关，我们假设小分子 MESH1 抑制剂抑制铁死亡可能会保护 AD/ADRD 中的神经元免受铁死亡的影响。为了检验我们的假设，我们组建了一个具有互补专业知识的综合科学团队，并提出以下两个具体目标：首先，我们将开发和优化源自前两种经过验证的命中化合物的小分子 MESH1 抑制剂。接下来，我们将确定 MESH1 抑制剂在培养细胞和 AD/ADRD 器官型脑切片培养模型中阻止铁死亡的活性和特异性。总的来说，该提案的成功执行将确定 MESH1 和铁死亡的新型化学抑制剂，以改善与年龄相关的 AD/ADRD 患者的治疗结果。