Development of Novel Synthetic Proteomimetics for Mediating Tauopathy in Alzheimer's Disease

开发介导阿尔茨海默病 Tau 蛋白病的新型合成蛋白质模拟物

• 批准号: 10389502
• 负责人: Mara Fattah
• 金额: $ 4.25万
• 依托单位: NORTHWESTERN 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 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10389502
• 关键词: Address; Affect; Affinity; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Antibodies; Avidity; Binding; Binding Proteins; Biology; Blood - brain barrier anatomy; Blood Circulation; Brain; Cell Survival; Cell model; Cells; Chemicals; Chimeric Proteins; Clinical; Clinical Research; Coculture Techniques; Collaborations; Communication; Communities; Complex; Core Facility; Corpus striatum structure; Data; Degradation Pathway; Dementia; Detection; Development; Disease; Doctor of Philosophy; Dose; Educational workshop; Enzyme Stability; Enzymes; Exhibits; Functional disorder; Future; Goals; Growth; Half-Life; Homeostasis; Hour; Human; Huntington protein; Image; Immune response; Impaired cognition; Impairment; In Vitro; Interdisciplinary Study; Interferometry; Libraries; Liquid substance; MAPT gene; Mediating; Mediation; Methodology; Methylene blue; Modality; Modernization; Modification; Molecular; Molecular Biology; Molecular Conformation; Monitor; Morbidity - disease rate; Mutation; National Research Service Awards; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neuronal Dysfunction; Neurons; Oral; Outcome; Pathogenesis; Pathologic; Patients; Penetration; Peptide Library; Peptides; Performance; Permeability; Persons; Phase; Polymers; Prevention strategy; Property; Protac; Proteins; Proteolysis; Quality Control; Research; Research Personnel; Resistance; Science; Seeds; Stains; Synapses; Tauopathies; Technology; Testing; Therapeutic; Toxic effect; Training; Transgenic Mice; Ubiquitin; Ubiquitination; aging population; amyloid formation; base; brain dysfunction; career; chemical synthesis; cognitive development; density; design; directed differentiation; disability; fluorophore; improved; in vivo; monomer; nanomedicine; nanotherapeutic; neurochemistry; neurotoxicity; novel; novel therapeutics; polymerization; prevent; protein aggregation; protein protein interaction; recruit; side effect; skills; small molecule; structural biology; success; tau Proteins; tau aggregation; tool; ubiquitin-protein ligase; uptake

PROJECT SUMMARY Alzheimer’s Disease (AD) is an incurable, progressive neurodegenerative disease drastically affecting 35 million people worldwide who suffer from dementia and cognitive decline. Recently, microtubule associated protein Tau is believed to be an instrumental inducer in AD, as its misfolding and aggregation disrupts homeostasis and results in widespread neuronal dysfunction. Significant clinical challenges remain in current efforts to cap Tau aggregates from growing or degrading large tangles: a) small molecule approaches have nonspecific binding and resultant side effects, b) antibodies trigger an immune response that necessitates modification for each patient, and c) promising Tau binding peptides have poor cell permeability and are easily degraded. To overcome these challenges, this proposal utilizes a new methodology, the Protein-Like Polymer (PLP) for protecting Tau binding peptides from degradation for their sustained delivery to prevent and cap protofibril formation and degrade larger aggregates from spreading using a proteolysis targeting chimera (PROTAC) PLP approach. This synthetic proteomimetic packages peptides together as high-density brush polymers that are modular, scalable, and rapidly formulated using modern, advanced polymerization strategies to offer multivalency, cell penetration, and specific target binding. PLPs exhibit extended circulation half-life compared to small molecules and linear peptides, maintaining strong bioactivity, cell uptake, and disrupting protein-protein interactions (PPIs). Here, we aim to target Tau in two ways: 1. selectively binding to pre-aggregative Tau to dampen aggregation, and 2. to improve PROTACs enzyme stability and deliverability using a novel proteomimetic bioconjugation strategy. Using Ring Opening Metathesis Polymerization (ROMP), I will develop and optimize a library of Tau binding PLPs and Tau PROTAC PLPS. All PLPs will be rigorously characterized and assessed in in vitro degradation and stability studies, as well as efficacy in relevant Tau expressing cells. I will directly compare the performance of the Tau PLPs in cell viability, cellular uptake, Tau binding, and effect on Tau aggregate formations to the native peptides and their corresponding linear PROTACs. This will be done in collaboration with my co-sponsor, Prof. Richard Morimoto, an expert in proteinopathy molecular biology. My sponsor/co-sponsor and I have devised a training plan at Northwestern to develop my independent resesarch skills as a Chemical Biology PhD candidate. I will conduct this interdisciplinary research at Northwestern, taking advantage of technical training at core facilities to develop skills for both this project (disease cell models, chemical synthesis, advanced imaging) and my future independent research career in neurochemistry. I will simultaneously be improving my oral and written science communication, networking at professional development workshops, and impacting my community. Under Profs. Gianneschi and Morimoto, I will cultivate the skills to be an indispensable nanomedicine researcher. With Kirchstein NRSA Support, I will identify and optimize a chemical biology tool or nanotherapeutic for mediating dysregulated Tau in Alzheimer’s Disease to allay the morbidity of our world’s aging population.

项目摘要 阿尔茨海默氏病（AD）是一种无法治愈的，进行性的神经退行性疾病，对3500万 全球患有痴呆症和认知能力下降的人。最近，微管相关的蛋白质tau 人们认为这是广告中的工具，因为它的错误折叠和聚集破坏了体内平衡和 导致宽度神经元功能障碍。目前努力限定tau的临床挑战仍然存在 从生长或降解大缠结的聚集体：a）小分子方法具有非特异性结合 b）抗体触发了每种必要修改的免疫响应 患者和c）承诺tau结合肽的渗透性较差，并且很容易降解。克服 这些挑战，该提案利用一种新方法，即蛋白质样聚合物（PLP）来保护tau 降解中结合肽的持续递送，以预防和限制原纤维形成和 使用蛋白水解靶向嵌合体（Protac）PLP方法来降解较大的聚集体。这 合成蛋白质含量包装作为模块化，可扩展，可扩展的高密度刷子聚合物一起 并使用现代的高级聚合策略迅速制定，以提供多价，细胞渗透， 和特定的目标结合。与小分子和线性相比，PLP暴露了延长的循环半衰期 肽，保持强大的生物活性，细胞摄取和破坏蛋白质 - 蛋白质相互作用（PPI）。这里， 我们的目标是通过两种方式靶向tau：1。选择性地结合到凝集前的tau与Damen聚集的结合，2。 使用一种新型的蛋白质生物缀合策略来改善Protac酶的稳定性和递送。 使用打开环的聚合聚合（ROMP），我将开发并优化一个tau结合的库 PLP和tau Protac PLP。所有PLP将在体外降解中严格表征和评估 和稳定性研究，并有效地在相关的TAU表达细胞中。我将直接比较性能 细胞活力，细胞摄取，tau结合以及对tau骨料形成的影响 天然胡椒及其相应的线性protac。这将与我的共同赞助商合作完成 理查德·莫里莫托（Richard Morimoto）教授，蛋白质病分子生物学专家。我的赞助商/共同赞助商和我有 在西北部制定了一个培训计划，以发展我的独立Ressesarch技能作为化学生物学博士学位 候选人。我将利用在西北地区进行这项跨学科研究 这两个项目的核心设施（疾病细胞模型，化学合成，高级成像） 以及我未来独立的神经化学研究生涯。我只会改善我的口头， 书面科学沟通，在专业发展研讨会上的网络，并影响我 社区。在教授下。 Gianneschi和Morimoto，我将培养这种技能，成为必不可少的纳米医学 研究员。借助Kirchstein NRSA支持，我将识别并优化化学生物学工具或纳米治疗工具 为了介导阿尔茨海默氏病的失调tau，以使我们世界老龄化的所有发病率。