Discovery of druggable pathways that prevent cell death caused by proteotoxic stress

发现可预防蛋白毒性应激引起的细胞死亡的药物途径

• 批准号: 9124060
• 负责人: Terry Justin Rettenmaier
• 金额: $ 5.43万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9124060
• 关键词: Address; Affect; Age; Aging; Alzheimer' s Disease; Amyloid beta-Protein; Autopsy; Binding Proteins; Biochemistry; Biological Assay; Biology; Brain; Caenorhabditis elegans; Cell Death; Cell physiology; Cells; Chemicals; Complex; Cyclic Peptides; Cyclization; DNA; Defect; Development; Disease; Ensure; Future; Genes; Genetic; Genetic Code; Genetic Screening; Goals; Health; Human; Huntington Disease; Kinetics; Lead; Lewy Bodies; Libraries; Link; Lipid Binding; Mediating; Modeling; Molecular Mechanisms of Action; Neurodegenerative Disorders; Neurons; Organism; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Patients; Peptide Library; Peptides; Pharmaceutical Preparations; Point Mutation; Proteins; Protocols documentation; Qualifying; Research; Resistance; Saccharomyces cerevisiae; Societies; Stress; Substrate Specificity; Symptoms; Technology; Therapeutic; Toxic effect; Vesicle; Work; Yeast Model System; Yeasts; alpha synuclein; analog; base; chemical synthesis; design; experience; improved; intein; mitochondrial dysfunction; new therapeutic target; next generation; overexpression; polyglutamine; prevent; protective effect; protein TDP-43; protein folding; protein misfolding; public health relevance; research study; risk variant; screening; small molecule; synucleinopathy; tandem mass spectrometry; therapeutic development; therapeutic target; trafficking; unnatural amino acids; yeast genetics; yeast protein

 DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a progressive neurodegenerative disorder (ND) that afflicts more than 6 million people worldwide. This number will continue to rise in the coming years as the average age of our society increases. While several risk genes are known to predispose to PD, we still incompletely understand this complex disease and, as a consequence, there are no therapies that slow the progression of this debilitating and ultimately fatal disease. To address this issue, many research groups have searched for new therapeutic targets using simple organisms to model PD pathogenesis. Our lab has previously used the yeast Saccharomyces cerevisiae to pinpoint the cellular functions that mediate the toxicity of the misfolded proteins that cause neurodegenerative disorders, including PD (α-syn), Alzheimer's (Aβ), Huntington's (polyQ), and ALS (TDP-43). Genetic screens against this yeast α-syn model have identified suppressors of toxicity that are also protective in neurons. A previous screen of genetically encoded cyclic peptides revealed the presence of a druggable target that protects both yeast and C. elegans neurons from α-syn toxicity, but the mechanism of action of these compounds remains unknown. Aim 1 of the current proposal seeks to identify the mechanistic target(s) of these bioactive cyclic peptides using modern chemical biology approaches, including photocrosslinking and cellular thermal shift assays. In Aim 2, I propose to leverage the genetic tractability of yeast to determine which cellular pathways are necessary and/or sufficient for the protective effect of the cyclic peptides. Finally, in Aim 3 I will leverage recent advances in the technology for screening large libraries o genetically encoded cyclic peptides to develop more efficacious analogs as candidate therapeutics for the treatment of PD and other synucleinopathies. Overall, these studies aim to unveil a new candidate therapeutic target for PD, establish its cellular context, and develop next-generation cyclic peptides that may form the basis of a new class of disease-modifying drugs for PD.

 描述（由申请人提供）：帕金森病（PD）是一种进行性神经退行性疾病（ND），困扰着全球超过600万人。随着我国社会平均年龄的增长，这一数字在今后几年将继续上升。虽然已知几种风险基因易患PD，但我们仍然不完全了解这种复杂的疾病，因此，没有任何疗法可以减缓这种使人衰弱并最终致命的疾病的进展。为了解决这个问题，许多研究小组已经寻找新的治疗靶点，使用简单的生物体来模拟PD发病机制。我们的实验室以前使用酵母酿酒酵母来确定介导导致神经退行性疾病的错误折叠蛋白质毒性的细胞功能，包括PD（α-syn），阿尔茨海默病（Aβ），亨廷顿病（polyQ）和ALS（TDP-43）。针对这种酵母α-syn模型的遗传筛选已经确定了在神经元中也具有保护作用的毒性抑制剂。先前对基因编码的环肽的筛选揭示了一个可保护酵母和C。elegans神经元的α-syn毒性，但这些化合物的作用机制仍然未知。本提案的目的1旨在使用现代化学生物学方法（包括光交联和细胞热位移测定）鉴定这些生物活性环肽的机制靶标。在目标2中，我建议利用酵母的遗传易处理性来确定哪些细胞途径对于环肽的保护作用是必要的和/或足够的。 最后，在目标3中，我将利用用于筛选遗传编码的环肽的大型文库的技术的最新进展来开发更有效的类似物作为用于治疗PD和其他突触核蛋白病的候选治疗剂。总的来说，这些研究旨在揭示PD的新候选治疗靶点，建立其细胞背景，并开发下一代环肽，这些环肽可能构成一类新的PD疾病修饰药物的基础。