Dissecting the Molecular Link Between Stroke, Actin, and Alzheimer's Disease

剖析中风、肌动蛋白和阿尔茨海默病之间的分子联系

基本信息

批准号：
10772704
负责人：
Claudia Fallini
金额：
$ 41.37万
依托单位：
UNIVERSITY OF RHODE ISLAND
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：
2023-09-22 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10772704
关键词：
Actins Acute Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Biochemical Biological Assay Biological Models Black race Blood Cell Nucleus Cell physiology Cells Cessation of life Characteristics Chromatin Chromatin Structure Chronic Communities Complex Coupling Cytoplasm Cytoskeleton Cytoskeleton Alteration DNA Data Defect Dementia Diagnosis Disease Disease Progression Economic Burden Elderly Event Exposure to Extracellular Matrix Focal Adhesions Foundations Future Gene Expression Genetic Transcription Glucose Health Hispanic Homeostasis Human Huntington Disease Hypoxia In Vitro Induced pluripotent stem cell derived neurons Injury Intervention Ischemia Ischemic Stroke Knowledge Lead Link Mechanics Microscopy Molecular Nerve Degeneration Neurites Neurodegenerative Disorders Neurons Nuclear Nuclear Lamina Nuclear Pore Nuclear Pore Complex Nuclear Proteins Nuclear RNA Outcome Oxidative Stress Oxygen Pathogenicity Pathologic Pathway interactions Population Predisposition Process Proteins RNA RNA metabolism RNA-Binding Proteins Regulation Reperfusion Injury Reperfusion Therapy Research Risk Secondary to Series Stress Stress Fibers Stroke Structure Testing Therapeutic Tissues Transcriptional Regulation Validation age related biomarker development cell fixing cellular imaging cellular pathology cofilin dementia risk deprivation design disability endoplasmic reticulum stress epidemiology study excitotoxicity frontotemporal lobar dementia amyotrophic lateral sclerosis improved in vitro Model in vivo Model induced pluripotent stem cell innovation insight neuroinflammation neuron loss neuronal survival novel nucleocytoplasmic transport post stroke premature protein TDP-43 protein aggregation protein structure reduce symptoms resilience response rho GTP-Binding Proteins socioeconomics stressor stroke model stroke outcome therapeutic biomarker therapeutic target

项目摘要

PROJECT SUMMARY Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide, posing a grave socioeconomic burden on the elderly population. Studies have shown a strong increase in the risk of developing dementia after the occurrence of a stroke. Following a stroke, surviving neurons undergo numerous challenges, such as neuroinflammation, endoplasmic reticulum (ER) stress, and cytoskeletal rearrangements. These cellular processes are also characteristics of neurodegenerative diseases such as AD, suggesting overlapping cellular and molecular mechanisms in both stroke and AD that lead to negative neuronal outcomes. However, there remains a knowledge gap in understanding how early and transient molecular events occurring after acute hypoxia and glucose deprivation cause long lasting neuronal damage that leads to AD-like neurodegeneration. We hypothesize that ischemia-induced transient changes in the actin cytoskeleton homeostasis have long-term impacts on the structure and/or function of the nucleus, nuclear lamina, and nuclear pore via the activation of mechanosensitive pathways, affecting neuronal health and survival. Supporting this hypothesis, we and others have found that drastic alterations to actin homeostasis alters the integrity of the nuclear pore complex (NPC), a structure that has been implicated in the degenerative pathway of many neurodegenerative diseases, including AD. NPCs are connected to the cytoskeleton via the linker of nucleoskeleton and cytoskeleton (LINC) complex, which relays mechanical tension from the extracellular matrix and cytoskeleton to the nucleus and DNA. Our aims are as followed: Aim 1: Does IRI cause nuclear injury via mechanosensitive pathways in iPSC-derived hCNs? We hypothesize that ischemia-induced cytoskeletal rearrangements lead to long lasting alterations in functional stability of the nuclear lamina, NPC, and chromatin structure via the mechanosensitive pathways. We will use induced pluripotent stem cell (iPSC)-derived neurons exposed to ischemic stress to determine the mechanistic connection between actin rearrangements, mechanical tension via the LINC complex, and NPC integrity. Aim 2: Do IRI-induced cytoskeletal alterations impact neuronal resilience to stress? We hypothesize that ischemia-induced changes to the NPC and chromatin reduce neuronal resilience to age-related stressors, leading to premature degeneration. Using iPSC-derived neurons, we will determine to what extent ischemic stress alters neuronal transcriptional regulation leading to a reduced resilience to normal age-related stressors. At the end of this proposed research, we will have determined the fundamental cellular and molecular mechanisms that regulate long-term neuronal survival after an ischemic stroke. These novel insights will provide the necessary foundations for future studies using in vivo models of stroke and AD, thus opening the way for the identification of new potential therapeutic targets and biomarkers for both improving stroke outcomes and for early AD diagnosis and intervention.

项目概要阿尔茨海默病（AD）是世界范围内最常见的神经退行性疾病，给人们带来了严重的健康问题研究表明，南方老年人口的负担大幅增加。中风发生后，幸存的神经元会发生大量的痴呆。挑战，例如神经炎症、内质网（ER）应激和细胞骨架重排。这些细胞过程也是 AD 等神经退行性疾病的特征，表明中风和 AD 中的细胞和分子机制重叠，导致负神经然而，在了解早期和短暂的分子结果方面仍然存在知识差距。急性缺氧和葡萄糖剥夺后发生的事件会导致长期持续的神经元损伤，从而导致我们捕捉到了缺血引起的肌动蛋白的短暂变化。细胞骨架稳态对细胞核的结构和/或功能具有长期影响，核通过激活机械敏感途径，影响神经元健康和核孔我们和其他人发现肌动蛋白稳态发生了巨大变化，支持了这一假设。改变核孔复合体 (NPC) 的完整性，该结构与退行性病变有关许多神经退行性疾病（包括 NPC）的通路通过细胞骨架连接。核骨架和细胞骨架 (LINC) 复合物的连接体，传递机械张力我们的目标如下：目标 1：IRI 是否通过 iPSC 衍生的 hCN 中的机械敏感途径引起核损伤？证实缺血诱导的细胞骨架重排会导致功能的长期持续改变我们将通过机械敏感途径来确定核纤层、NPC 和染色质结构的稳定性。诱导多能干细胞（iPSC）衍生的神经元暴露于缺血应激以确定其机制肌动蛋白重排、通过 LINC 复合体的机械张力和 NPC 完整性之间的联系。目标 2：IRI 诱导的细胞骨架改变是否会影响神经元对压力的恢复能力？缺血引起的 NPC 和染色质变化会降低神经元对年龄相关压力源的恢复能力，使用 iPSC 衍生的神经元，我们将确定缺血的程度。压力会改变神经转录调节，导致对正常年龄相关压力源的抵抗力降低。在这项拟议的研究结束时，我们将确定基本的细胞和分子这些新颖的见解将揭示调节缺血性中风后长期神经元存活的机制。为未来使用中风和 AD 体内模型进行研究提供必要的基础，从而打开识别新的潜在治疗靶点和生物标志物以改善中风的方法结果以及早期 AD 诊断和干预。