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

基本信息

批准号：
10680372
负责人：
Mara Fattah
金额：
$ 4.41万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
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/10680372
关键词：
Address Affect Affinity Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Antibodies Avidity Binding Binding Proteins Biology Blood - brain barrier anatomy Brain Cell Survival Cell model Cells Chemicals Chimeric Proteins Circulation 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 gene Image Immune response Impaired cognition Impairment In Vitro Interdisciplinary Study Interferometry Investments Libraries Liquid substance MAPT gene Maps 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 Stains Synapses Tauopathies Testing Therapeutic Toxic effect Training Transgenic Mice Ubiquitin Ubiquitination Writing aging population amyloid formation brain dysfunction career chemical synthesis copolymer 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 tau mutation technology platform tool ubiquitin-protein ligase uptake

项目摘要

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.

项目概要阿尔茨海默病 (AD) 是一种无法治愈的进行性神经退行性疾病，影响着 3500 万人最近，世界范围内患有痴呆症和认知能力下降的人发现了微管相关蛋白 Tau。被认为是 AD 的重要诱导剂，因为它的错误折叠和聚集会破坏体内平衡，导致广泛的神经元功能障碍，目前限制 Tau 的努力仍然面临重大的临床挑战。来自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以及由此产生的副作用，b）抗体触发免疫反应，需要对每个抗体进行修改 c)有前途的Tau结合肽细胞渗透性差且容易降解的问题需要克服。针对这些挑战，该提案采用了一种新的方法，即类蛋白聚合物 (PLP) 来保护 Tau 结合肽免于降解，以持续递送以防止和限制原纤维的形成和使用蛋白水解靶向嵌合体 (PROTAC) PLP 方法降解较大的聚集体，防止其扩散。合成蛋白质模拟将肽包装在一起作为高密度刷状聚合物，这些聚合物是模块化的、可扩展的、并使用现代、先进的聚合策略快速配制，以提供多价、细胞渗透、与小分子和线性相比，PLP 具有更长的循环半衰期。肽，保持强大的生物活性、细胞摄取并破坏蛋白质-蛋白质相互作用 (PPI)。我们的目标是通过两种方式靶向 Tau：1. 选择性地与聚集前的 Tau 结合以抑制聚集，2. 使用新型蛋白质模拟生物共轭策略提高 PROTAC 酶的稳定性和递送能力。使用开环复分解聚合 (ROMP)，我将开发和优化 Tau 结合库 PLP 和 Tau PROTAC PLPS 将经过严格的表征和体外降解评估。稳定性研究，以及相关 Tau 表达细胞的功效，我将直接比较性能。 Tau PLP 在细胞活力、细胞摄取、Tau 结合以及对 Tau 聚集体形成的影响方面的研究天然肽及其相应的线性 PROTAC 将与我的共同发起人合作完成。 Richard Morimoto 教授，蛋白质病分子生物学专家，我和我的资助者/共同资助者。在西北大学制定了一项培训计划，以培养我作为化学生物学博士的独立研究技能我将利用西北大学的技术培训进行这项跨学科研究。开发该项目技能的核心设施（疾病细胞模型、化学合成、高级成像）以及我未来在神经化学方面的独立研究生涯，我将同时提高我的口语和能力。书面科学交流、专业发展研讨会上的网络以及影响我的在 Gianneschi 和 Morimoto 教授的带领下，我将培养成为不可或缺的纳米医学的技能。借助 Kirchstein NRSA 支持，我将确定并优化化学生物学工具或纳米治疗方法。调解阿尔茨海默病中 Tau 蛋白失调，从而降低世界人口老龄化的发病率。