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From cells to complex syndromes: using networks to understand heterogeneity in TDP-related frontotemporal degeneration and aging

从细胞到复杂综合征：利用网络了解 TDP 相关额颞叶退化和衰老的异质性

基本信息

批准号：
10261330
负责人：
MURRAY GROSSMAN
金额：
$ 246.77万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10261330
关键词：
Adopted Advisory Committees Aging Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Animal Disease Models Animal Model Area Autopsy Biological Markers Biometry Brain Brain region Cell model Cells Clinical Clinical Pathology Collection Complex DNA Dementia Development Diagnosis Discipline Disease Disease Progression Elements Ensure Experimental Models Family Frontotemporal Lobar Degenerations Functional disorder Genetic Genetic Transcription Goals Heterogeneity Human Image Knowledge Lead Life Mediating Microscopic Molecular Nerve Degeneration Nervous System Physiology Neurons Outcome Pathologic Pathology Pathway Analysis Patients Pattern Prognosis Program Research Project Grants Progressive Disease Property RNA-Binding Proteins Resources Role Science Syndrome System Transact Translating Work age related emotion dysregulation experimental study frontotemporal degeneration frontotemporal lobar dementia-amyotrophic lateral sclerosis grasp human disease improved in vivo innovation insight language impairment limbic-predominant age-related TDP-43 encephalopathy longitudinal course motor disorder multidisciplinary neural network novel programs protein TDP-43 relating to nervous system single-cell RNA sequencing symposium therapy development tool treatment trial

项目摘要

Frontotemporal degeneration (FTD) is an understudied clinical neurodegenerative condition that is the most common dementia after Alzheimer disease (AD) in people younger than 65. The most common pathology associated with FTD is frontotemporal lobar degeneration due to transactive DNA/RNA binding protein of ~43 kD (TDP-43 (FTLD-TDP), and this is also the underlying pathology in the vast majority of patients who have co-occurring amyotrophic lateral sclerosis (FTD-ALS) spectrum disorders as well as a critical force in age- related disorders such as limbic-predominant age-related TDP-43 encephalopathy (LATE). Since discovering a role for TDP-43 pathology in human disease, important progress has been made in experimental cellular and animal models of disease. However, the human brain has many unique properties associated with distinctly human clinical disorders that are not easily replicated in these experimental models. Major gaps in knowledge thus constrain the development of disease-modifying treatment trials. Among these is our limited knowledge of the pathophysiologic consequences of the accumulation and progression of abnormal TDP-43 at a molecular level. At a microscopic level, a major limitation is that most patients with accumulating TDP-43 have sporadic disease that can be identified reliably only at autopsy, although ~20% of cases have familial FTLD (fFTLD) with known pathology during life. We are limited at translating this knowledge to a macroscale level where FTLD- TDP pathology is manifested in humans with heterogeneous clinical features as diverse as emotional dysregulation and impaired language both with and without a motor disorder. Moreover, there is limited knowledge of the factors contributing to the highly varying rates of disease progression. In five novel, independent but synergistic Projects and five Cores that support each of the Projects, this unique, multidisciplinary, Program Project Grant (PPG) adopts the innovative perspective of investigating the TDP-43-associated breakdown of neural networks at molecular, microscopic and macroscale levels in humans. We hypothesize that our novel, well-integrated, network perspective will fill major gaps in knowledge by elucidating mechanistic insights into the pathophysiology of abnormal TDP-43 and the associated pattern of disease progression, and offer a fresh perspective on the identification of accumulating TDP-43 pathology during life and its longitudinal course. This proposal is consistent with the highest priorities for FTD at the 2019 Alzheimer’s Disease and Related Disorders (ADRD) summit. By focusing on disruption of neural networks at molecular, microscopic and macroscale levels of brain functioning, our multidisciplinary network approach will elucidate the pathophysiology and spread of abnormal TDP-43 in humans, and examine the consequences of TDP-43 pathology for clinical disease during life in dementia and aging using fresh approaches to improve our mechanistic understanding of TDP-43 pathology in humans while maintaining the highest level of scientific rigor and contributing to urgent clinical needs such as treatment trials.

额颞叶变性（FTD）是一种尚未得到充分研究的临床神经退行性疾病