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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：
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
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/10389502
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 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

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.

项目总结