Protein Homeostasis and Proteotoxicity Mechanisms

蛋白质稳态和蛋白质毒性机制

• 批准号: 10430286
• 负责人: JONATHAN LIN
• 金额: $ 32.78万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10430286
• 关键词: Affect; Alleles; Apoptosis; Area; Arsenic; Autophagocytosis; Autopsy; Biochemical; Brain; Brain region; Cell Death; Cells; Chemicals; Clinic; Clinical; Data; Degradation Pathway; Development; Dimerization; Disease; Environment; Environmental Monitoring; Environmental Risk Factor; Enzymes; Exposure to; Firearms; Florida; Fruit; Genetic Transcription; Genotype; Goals; Hippocampus (Brain); Histologic; Homeostasis; Human; Impairment; Ingestion; Lead; Link; London; Mediating; Midbrain structure; Molecular; Molecular Chaperones; Molecular Genetics; Neocortex; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Occupational Exposure; PERK kinase; Paint; Pathogenicity; Pathology; Patients; Persons; Pharmacology; Phosphotransferases; Progressive Supranuclear Palsy; Property; Protein-Serine-Threonine Kinases; Proteins; Recombinants; Research; Resistance; Risk; Role; Signal Transduction; Speed; Tauopathies; Testing; Therapeutic; Toxin; Translations; base; brain tissue; cell growth regulation; endoplasmic reticulum stress; environmental agent; environmental chemical; epidemiology study; genetic risk factor; genome wide association study; human stem cells; improved; inhibitor; insight; misfolded protein; multicatalytic endopeptidase complex; nerve stem cell; neuron loss; novel therapeutic intervention; novel therapeutics; polypeptide; prevent; programs; protein degradation; protein folding; protein misfolding; proteostasis; proteotoxicity; response; risk variant; small molecule; stem cells; tau Proteins; transcriptome sequencing

Protein misfolding arises in many neurodegenerative diseases. The mechanisms by which protein misfolding causes cell death and disease are poorly understood. The broad, long-term research objectives are: 1) to decipher the cellular, molecular, and genetic mechanisms that cause neurodegeneration, and 2) to develop new therapies to prevent and treat neurodegenerative diseases through correction of cellular protein misfolding in people. The Unfolded Protein Response (UPR) is a conserved intracellular signal transduction mechanism essential for cellular protein homeostasis. The UPR activates transcriptional programs that induce chaperones, protein folding enzymes, and protein degradation pathways (proteasome and autophagy). The UPR also regulates the speed of translation to match the amount of newly synthesized polypeptides to cellular protein folding capacity. If protein misfolding persists, the UPR triggers apoptosis. The UPR may be a potential pathomechanism underlying diseases arising from protein misfolding. PERK encodes a serine/threonine kinase that regulates the UPR. In people, GWAS identified PERK as a genetic risk factor for the tauopathy neurodegenerative disease, Progressive Supranuclear Palsy (PSP). This research investigates how PERK causes PSP in these Specific Aims. Aim 1 will investigate PERK's role in mediating neurodegeneration caused by environmental chemical toxins that increase risk of tauopathy. PERK activity will be assessed in human stem cell-derived neurons treated with PSP-linked agents. Small molecule proteostasis agents will be tested for their efficacy in rescuing neuronal damage linked to environment agents. Aim 2 will analyze the enzymatic properties of PERK heterodimers compared to homodimers. Isogenic stem cell-derived neurons will be employed. In parallel, recombinant PERK heterodimers will be generated and characterized using small molecule heterodimerizering compounds. Aim 3 will investigate the molecular and biochemical basis for selective tau neuropathology in the brain. Postmortem human brain tissues from vulnerable and resistant brain regions will be compared for UPR activity. Genotyped brain cases will be examined to see how risk PERK allele expression affects tau neuropathology. PERK is an essential regulator of protein quality in cells, and human PERK alleles are genetic risk factors for tauopathy neurodegeneration. These studies will have a positive impact by elucidating fundamental molecular pathomechanisms of PERK signaling in PSP. These studies may also reduce the clinical burden of PSP and related tauopathy neurodegenerative diseases by development of novel therapeutic strategies based on pharmacologic regulation of cellular protein quality homeostasis.

蛋白质错误折叠发生在许多神经退行性疾病中。蛋白质错误折叠会导致细胞死亡和疾病的机制知之甚少。广泛的长期研究目标是：1）破译导致神经变性的细胞，分子和遗传机制，以及2）开发新的疗法，以通过纠正人们的细胞蛋白质折叠折扣来预防和治疗神经退行性疾病。展开的蛋白质反应（UPR）是一种保守的细胞内信号转导机制，对细胞蛋白稳态必不可少。 UPR激活了诱导伴侣，蛋白质折叠酶和蛋白质降解途径（蛋白酶体和自噬）的转录程序。 UPR还调节翻译速度，以使新合成的多肽的量与细胞蛋白折叠能力相匹配。如果蛋白质错误折叠持续存在，则UPR会触发凋亡。 UPR可能是由蛋白质错误折叠引起的潜在的病理机理。 PERK编码调节UPR的丝氨酸/苏氨酸激酶。在人们中，GWAS将PERK鉴定为tauopathy神经退行性疾病，进行性核上麻痹（PSP）的遗传危险因素。这项研究调查了PERK如何在这些特定目标中引起PSP。 AIM 1将调查PERK在调解中的作用 由环境化学毒素引起的神经变性，这些毒素会增加tauopathy的风险。 PERK活性将在用PSP连接剂处理的人类干细胞衍生的神经元中评估。小分子蛋白抑制剂将在挽救与环境药物相关的神经元损伤方面的功效测试。 AIM 2将分析与同二聚体相比，PERK异二聚体的酶促性能。将采用等源干细胞衍生的神经元。同时，将使用小分子异二聚体化合物生成重组PERK异二聚体。 AIM 3将研究大脑中选择性TAU神经病理学的分子和生化基础。将比较来自脆弱和抗性大脑区域的尸体人类脑组织的UPR活性。将检查基因分型的大脑病例，以了解风险振兴等位基因表达如何影响tau神经病理学。 PERK是细胞中蛋白质质量的重要调节剂，人类PERK等位基因是Tauopathy神经变性的遗传危险因素。这些研究将通过阐明PSP中PERK信号传导的基本分子病理机制产生积极的影响。这些研究还可以通过基于细胞蛋白质质量稳态的药理调节来开发新型的治疗策略来减少PSP和相关的Tauopathy神经退行性疾病的临床负担。