Multilineage DAmFRET to investigate AD/ADRD protein phase behavior in neural tissue models

多谱系 DAmFRET 研究神经组织模型中 AD/ADRD 蛋白相行为

基本信息

批准号：
10583428
负责人：
Randal Arthur Halfmann
金额：
$ 20.63万
依托单位：
STOWERS INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583428
关键词：
Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Amyloid Astrocytes Bacterial Artificial Chromosomes Behavior Brain Cell Communication Cell Nucleus Cell Volumes Cells Cerebrum Chromosomal Stability Clinical Clone Cells Coculture Techniques Complex Cytoplasm Data Dementia Dependence Engineering Etiology Flow Cytometry Fluorescence Fluorescence Resonance Energy Transfer Future Genotype Homeostasis Human Kinetics Measurement Microglia Microscopy Molecular Nerve Degeneration Neuroglia Neurons Organoids Paint Pathogenicity Patients Phase Phase Transition Phenotype Physical condensation Physiological Population Proteins RNA-Binding Proteins Reporter System Thermodynamics Tissue Model Transfection Transgenes Variant Work biophysical techniques brain cell brain tissue cell type comorbidity experimental study fluorophore induced pluripotent stem cell liquid dynamics mutant neural prevent promoter protein TDP-43 protein aggregation protein expression proteostasis self assembly tool transcriptome sequencing transcriptomics

项目摘要

Project Summary/Abstract Alzheimer's Disease and Related Dementias (AD/ADRD) are the most common forms of dementia. No treatments exist to stop or prevent them. AD/ADRD are caused in part by the aggregation of one, or more often a combination of, specific proteins. TDP-43 is one of a handful of such proteins. It characteristically transitions from a dynamic liquid phase of assembly to a rigid and pathogenic phase in a large fraction of dementia cases. This transition occurs against a backdrop of progressive changes in the interactions between different cell types in the brain. An interdependence of these molecular and cellular changes likely determines the clinical courses of AD/ADRD, but to understand that interdependence, we need new tools with which to compare protein phase transitions and their corresponding phenotype effects in the context of interacting brain cell types. We propose here to develop such a tool by modifying a cell-based biophysical method, Distributed Amphifluoric FRET (DAmFRET) for use in human induced pluripotent stem cell (hiPSC)-derived brain tissue models (Aim 1). We will simultaneously use DAmFRET to develop TDP-43 as a reporter of cell type-specific differences in the homeostasis of protein phase transitions (Aim 2). By completing these aims, we will have created and validated a uniquely powerful tool for better understanding the complex molecular and cellular causes of AD/ADRD.

项目摘要/摘要阿尔茨海默氏病和相关痴呆症（AD/ADRD）是最常见的痴呆形式。不存在治疗以阻止或阻止它们。 AD/ADRD部分是由一个或更频繁的汇总引起的特定蛋白质的组合。 TDP-43是少数此类蛋白质之一。它的特征是过渡从组装的动态液相到大部分痴呆病例中的刚性和致病相。这种过渡是在不同单元之间相互作用的渐进变化的背景下发生的大脑中的类型。这些分子和细胞变化的相互依赖性可能决定了临床 AD/ADRD的课程，但要了解相互依存，我们需要使用新工具来比较在相互作用的脑细胞中，蛋白质相变及其相应的表型效应类型。我们在这里建议通过修改基于细胞的生物物理方法（分布）来开发这种工具用于人类诱导的多能干细胞（HIPSC）衍生的脑组织的二氧化精神（Damfret）模型（目标1）。我们将同时使用Damfret开发TDP-43作为细胞类型特异性的记者蛋白质相跃迁的稳态差异（AIM 2）。通过完成这些目标，我们将拥有创建并验证了一种独特的功能工具，以更好地理解复杂的分子和细胞广告/adrd的原因。