Immunomodulatory and behavioral effects of CAR T regulatory cell therapy for Alzheimer's Disease”.

CAR T 调节细胞疗法对阿尔茨海默病的免疫调节和行为影响。

基本信息

批准号：
10633721
负责人：
Charles L. Sentman
金额：
$ 24.6万
依托单位：
DARTMOUTH COLLEGE
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：
2023-04-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10633721
关键词：
Acceleration Affect Age Years Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease therapy Amyloid beta-Protein Anti-Inflammatory Agents Area Autologous Behavior Behavioral Binding Brain CAR T cell therapy Cell Therapy Central Nervous System Clinic Clinical Management Cognitive Cognitive deficits Data Dementia Deposition Development Disease Engineering Evaluation Excision FOXP3 gene Fiber Foundations Gliosis Goals Hippocampus Immune Immune response Immune system Impaired cognition Inflammation Inflammation Mediators Inflammatory Laboratories Macrophage Mediating Memory impairment Microglia Mus Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neuroglia Neuronal Dysfunction Neurons Patients Peripheral Production Property Proteins Reaction Regulatory T-Lymphocyte Role Sampling Senile Plaques Site Specificity T-Lymphocyte Subsets Testing Therapeutic Tissues Toxicity Tests abeta accumulation abeta oligomer cancer therapy cellular engineering chimeric antigen receptor clinical candidate cognitive function effector T cell engineered T cells extracellular family management first-in-human frontal lobe genetically modified cells immune modulating agents immunoregulation improved in vivo innovation manufacture mouse model neoplastic cell neuroinflammation neuron loss neuroprotection neurotoxicity novel novel therapeutic intervention novel therapeutics pre-clinical protein aggregation scale up tau Proteins trafficking

项目摘要

Project Summary/Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is one of the primary reasons for memory dysfunction and dementia after 60 years of age. Neuronal dysfunction and death in the frontal cortex and hippocampus, along with glia-mediated neuroinflammation and formation of aberrant protein aggregates and fibrils are hallmarks of AD. Sporadic and familial forms of AD have an overproduction and/or decreased clearance of extracellular amyloid-beta (Aβ) peptides and intraneuronal tangles of twisted tau protein fibers. Neuroinflammation is known to occur in AD, and when associated near Aβ plaques there is a greater neurodegeneration. Furthermore, peripheral immune activity and inflammation can affect inflammation in the CNS. T regulatory cells (Tregs) are a subset of T cells that have inherent anti-inflammatory and immunomodulatory properties. Tregs are found in the CNS under steady state conditions and increase trafficking to regions of CNS inflammation. Less active or decreased numbers of Tregs has been found in AD patients and depletion of Tregs can accelerate cognitive defects in murine AD models. We hypothesize that Tregs expressing chimeric antigen receptors (CARs) with specificity to amyloid-beta (Aβ) will have immunomodulatory activity and improve cognitive function of the 5xFAD B6 mice, a murine AD model. The aim of this proposal is to test the innovative concept that Tregs engineered to express CARs against amyloid-beta will demonstrate immunomodulatory effects in the CNS and in the peripheral tissues resulting in improved cognitive behavior. The data generated will provide key proof-of-concept data to develop this novel therapeutic idea forward.

项目摘要/摘要：阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，这是导致的主要原因之一 60岁以后的记忆功能障碍和痴呆症。额叶皮质的神经元功能障碍和死亡和海马，以及神经胶质介导的神经炎症和异常蛋白聚集体的形成原纤维是AD的标志。广告的零星和家庭形式的生产过多和/或精制扭曲的tau蛋白纤维的细胞外淀粉样β（Aβ）肽和神经元缠结的清除。已知神经炎症发生在AD中，并且当与Aβ斑块附近相关时，就会发生更大的神经变性。此外，周围免疫活性和炎症会影响炎症 CNS。 T调节细胞（Tregs）是遗传抗炎和的T细胞的子集免疫调节特性。 Treg在稳态条件下在中枢神经系统中发现并增加贩运到中枢神经系统炎症区域。在AD患者中发现了较少活跃或改善的Treg，并且 Treg的耗竭可以加速鼠类AD模型中的认知缺陷。我们假设Tregs表达具有特异性淀粉样蛋白β（Aβ）的嵌合抗原受体（CAR）将具有免疫调节活性，并且提高5xFAD B6小鼠的认知功能，一种鼠广告模型。该建议的目的是测试特雷格（Tregs 中枢神经系统和周围组织中的免疫调节作用，导致认知行为改善。这生成的数据将提供关键的概念验证数据，以发展这种新颖的热思想向前。