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Seeds and Strains Derived from Tau Monomer

Tau 单体衍生的种子和菌株

基本信息

批准号：
10058234
负责人：
MARC I DIAMOND
金额：
$ 317.95万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10058234
关键词：
Alzheimer&apos s Disease Amino Acids Animal Model Biosensor Brain Cell Culture Techniques Cell model Cells Chemicals Classification Classification Scheme Clinical Consensus Crosslinker Cryoelectron Microscopy Data Diagnosis Diagnostic Disease Disease Progression Generations Grain Grant Growth Human Individual Mass Spectrum Analysis Methods Modeling Molecular Conformation Mus Mutation Neurons Organism Pathology Patients Pattern Point Mutation Prions Protein Region Publications Recombinants Seeds Solvents Structure System Tauopathies Testing Therapeutic Transgenic Organisms Work accurate diagnosis amyloid structure base brain cell crosslink induced pluripotent stem cell molecular modeling monomer neuropathology novel personalized medicine self assembly structural biology tau Proteins tau aggregation tau conformation unpublished works

项目摘要

PROJECT SUMMARY/ABSTRACT Alzheimer disease (AD) and related tauopathies are major diagnostic, therapeutic, and clinical challenges. Our previous work suggest that different tauopathies are based on unique tau aggregate conformations, or “strains,” and that strain identity predicts specific disease progression patterns in animal models. We hypothesize that distinct, self-propagating tau strains can move between cells of the brain to propagate pathology in humans. Recent publications from our group indicate that tau monomer in fact encodes strains. However this has not been rigorously tested across tauopathies. We will test this idea first by determining whether tau monomer encodes the same sets of strains encoded by larger assemblies in human brain (Aim 1). Next we will use multiplex biosensors to classify monomer from human tauopathies, and determine whether monomer can classify individuals in correlation with neuropathology with the same fidelity as larger assemblies. We will also test the fidelity of strain propagation in human neurons vs. HEK293 cells in comparison those strains isolated directly from human brain (Aim 2). Finally, we use structural biology approaches to determine the conformations of seed-competent monomer. In particular, we will determine whether local structures in tau predict its subsequent assembly into fibrils. This will be based on crosslinking mass spectrometry, molecular modeling, cryoEM, and microcrystallography. We predict that tau monomer will encode strain composition across tauopathies. If we are successful, we anticipate ultimately that it will be possible to classify tauopathies based on the conformation with tau monomer. This could have important implications for accurate diagnosis and personalized therapy.

项目总结/文摘