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.

所有的生物都会遇到各种各样的新陈代谢和环境压力，并形成了各种促进生存的应激反应机制。在细菌中，主要的应激反应机制是由警报蛋白(P)ppGpp的积累触发的“严格反应”。它协调了广泛的转录变化，以促进压力生存。后生动物基因组编码细菌斑点的同源物-MESH1-在体外可以降解ppGpp，并在功能上补充大肠杆菌中的斑点。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，这使哺乳动物细胞中MESH1的功能和相关底物(S)变得神秘。最近，我们的研究表明，MESH1是第一个胞内NADPH磷酸酶，对铁性下垂是必不可少的。铁下垂是一种新发现的细胞死亡形式，其特征是铁依赖和脂质过氧化。铁下垂时MESH1的诱导导致NADPH和GSH的耗竭。因此，MESH1的基因缺失有力地保护了细胞免受铁下垂的侵袭。由于铁下垂参与了阿尔茨海默病和阿尔茨海默病相关痴呆(AD/ADRD)等神经退行性疾病中神经细胞的死亡，我们推测小分子MESH1抑制剂抑制铁下垂可能对AD/ADRD中的神经细胞有保护作用。为了验证我们的假设，我们组建了一个具有互补专业知识的综合科学团队，并提出了以下两个具体目标：首先，我们将开发和优化从前两个经过验证的HIT化合物衍生的小分子MESH1抑制剂。接下来，我们将确定MESH1抑制剂在培养细胞和器官型AD/ADRD脑片培养模型中阻断铁下垂的活性和特异性。总的来说，该提案的成功执行将确定MESH1和铁下垂的新型化学抑制剂，以改善与年龄相关的AD/ADRD患者的治疗结果。