Targeting Blood-CNS-Barrier in ALS via Apolipoprotein A1

通过载脂蛋白 A1 靶向 ALS 中的血液中枢神经系统屏障

基本信息

批准号：
10680237
负责人：
CESARIO V BORLONGAN
金额：
$ 22.49万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
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：
2023-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10680237
关键词：
ALS patients Age Amyotrophic Lateral Sclerosis Animal Model Antiinflammatory Effect Apolipoprotein A-I Astrocytes Behavioral Blood Blood Vessels Bone Marrow Brain Capillary Endothelial Cell Cell Survival Cell Therapy Cell Transplantation Cell physiology Cells Clinical Trials Competence Data Disease Disease Outcome Disease Progression Endothelial Cells Endothelium Ensure Experimental Designs Future Gender Goals Histology Homeostasis Human Immunohistochemistry Impairment In Vitro Intravenous Longevity Mediating Microglia Microvascular Permeability Motor Neurons Mus Mutant Strains Mice Natural regeneration Neurodegenerative Disorders Neuroglia Outcome PIK3CG gene Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Process Proteins Publications Random Allocation Recovery of Function Reporting Research Design Risk Rodent Model Role Safety Scientific Advances and Accomplishments Signal Transduction Spinal Cord Symptoms Testing Therapeutic Therapeutic Effect Tissues Translating Translations Transplantation Treatment Efficacy Widespread Disease amyotrophic lateral sclerosis therapy astrogliosis blood damage cell injury clinical application efficacy evaluation endothelial stem cell experimental study extracellular vesicles high reward in vitro Model in vivo innovation insight intravenous administration laboratory experiment motor neuron degeneration mouse model neuronal survival neurovascular novel novel therapeutic intervention primary endpoint protein expression regenerative repair strategy repaired reparative process replication factor C restoration superoxide dismutase 1 therapeutic evaluation translational study wortmannin

项目摘要

Project Summary Abstract Amyotrophic lateral sclerosis (ALS) is a fatal disease of widespread motor neuron degeneration in the brain and spinal cord. Progressive impairment of the blood-CNS--barrier (B-CNS-B) represents an additional disease mechanism. Capillary endothelial cell (EC) damage in the CNS has been shown in ALS rodent models and in ALS patients. We demonstrated benefits of intravenously (iv) transplanted human bone marrow-derived endothelial progenitor cells (hBM-EPCs) on functional disease outcomes and motor neurons in an SOD1 mouse model of ALS by attenuating damage to the compromised barrier. Transplanted hBM-EPCs may also exert positive effects by release of extracellular vesicles (EVs) and facilitate restoration of degenerated ECs through delivery of cargo proteins. Apolipoprotein A1 (ApoA1) was determined as the most abundant high-expression protein in EVs and may represent a therapeutically active component for EC-targeted regeneration. We showed that ApoA1 enhanced EC survival in an ALS-like pathologic condition in vitro. The purpose of this project is to determine whether ApoA1 facilitates endothelium homeostasis leading to B-CNS-B repair in ALS. The significant scientific advance of this project is the demonstration that ApoA1 administration elucidates reparative processes in B-CNS-B restoration and promotes motor neuron survival in G93A SOD1 mutant mice. Also, the determination of reparative mechanisms underlying B-CNS-B restoration by assessing ApoA1 effects is the novelty of this project. An important aspect of the proposed study is B-CNS-B restoration in a symptomatic mouse model of ALS with existing barrier damage. Aim 1 will establish therapeutic efficacy of a single iv administration of ApoA1 into symptomatic ALS mice of both genders on B-CNS-B repair by examining behavioral disease outcomes (Aim 1A), functional (Aim 1B) barrier repair, glial cells status (Aim 1C), and motor neuron survival (Aim 1D). Aim 2 will determine the mechanism(s) of ApoA1-mediated vascular repair in symptomatic ALS mice by examining the pathway of this protein on endothelium integrity. This aim will address activity of the ApoA1 protein by impeding the downstream signaling through the cytosolic PI3K/Akt pathway. The effects of inhibiting intracellular signaling will be examined with the same outcomes as described in Aim 1 Sub-aims. Our experimental design to determine the efficacy of ApoA1 administration is a highly translational and innovative mechanism-based approach for repairing the damaged B-CNS-B. Positive project outcomes will evidence the mechanistic role of ApoA1 protein in restoring EC function towards repair of the altered B-CNS-B in ALS. Even if Aim 1 results are negative, probing ApoAI in Aim 2 via inhibitory paradigm will reveal novel ApoAI-based approaches to optimize protein treatment. This study represents a relatively low-risk, but high-reward and innovative protein-mediated therapy for vascular repair in ALS, thereby facilitating translation into a clinical application for ALS patients.

项目摘要摘要肌萎缩性侧索硬化症（ALS）是大脑中广泛运动神经元变性的致命疾病脊髓。血液-CNS的进行性损害 - 级 - B-CNS-B表示另一种疾病机制。 CNS中的毛细血管内皮细胞（EC）损伤已在ALS啮齿动物模型中显示 ALS患者。我们证明了静脉内（IV）移植的人骨骨髓的益处 SOD1小鼠中功能性疾病结果和运动神经元的内皮祖细胞（HBM-EPC） ALS模型通过减轻对障碍的损害的损害。移植的HBM-EPC也可能发挥通过释放细胞外囊泡（EV）的积极影响，并通过促进退化的EC恢复货物蛋白的递送。载脂蛋白A1（APOA1）被确定为最丰富的高表达 EV中的蛋白质，可能代表用于EC靶向再生的治疗活性成分。我们展示了该APOA1在体外在类似ALS的病理状态下增强了EC的生存。这个项目的目的是确定APOA1是否促进内皮稳态，导致ALS的B-CNS-B修复。这该项目的大量科学进步是ApoA1管理阐明的演示 B-CNS-B恢复中的修复过程并促进G93A SOD1突变小鼠中的运动神经元存活。同样，通过评估APOA1效应来确定B-CNS-B恢复基础的修复机制是这个项目的新颖性。拟议的研究的一个重要方面是症状的B-CNS-B恢复现有屏障损坏的ALS的鼠标模型。 AIM 1将建立单个IV的治疗功效通过检查行为，将APOA1用于B-CNS-B修复的两种性别的有症状的ALS小鼠疾病结果（AIM 1A），功能（AIM 1B）屏障修复，神经胶质细胞状态（AIM 1C）和运动神经元生存（目标1D）。 AIM 2将确定有症状的apoA1介导的血管修复的机制 ALS小鼠通过检查该蛋白质对内皮完整性的途径。这个目标将解决 APOA1蛋白通过胞质PI3K/AKT途径阻碍下游信号传导。效果抑制细胞内信号传导将以与AIM 1子AIMS相同的结果进行检查。我们的确定ApoA1给药功效的实验设计是一种高度转化和创新的基于机制的方法来修复受损的B-CNS-B。积极的项目成果将证明 APOA1蛋白在恢复ALS中B-CNS-B改变的EC功能中的机械作用。甚至如果AIM 1结果为负，则通过抑制性范式在AIM 2中探测Apoai将揭示基于Apoai的新型优化蛋白质处理的方法。这项研究代表了一个相对较低的风险，但高回报，并且创新的蛋白质介导的ALS血管修复疗法，从而促进转化为临床申请ALS患者。