Neural Stem Cell-derived EVs for Improving Aged Brain Function

神经干细胞衍生的 EV 可改善老年脑功能

基本信息

批准号：
10670802
负责人：
ASHOK K SHETTY
金额：
$ 57.69万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10670802
关键词：
Adenosine Monophosphate Age Months Age-associated memory impairment Aging Allogenic Anti-Inflammatory Agents Autophagocytosis Benchmarking Brain Brain region CSF1R gene Cells Cognitive Data Dementia Diet Dose Effectiveness Ensure FRAP1 gene Family Female Future Gene Expression Goals Hippocampus Homeostasis Human Impaired cognition Inflammasome Intervention Intranasal Administration Measures Medial Mediating Membrane Memory Memory impairment MicroRNAs Microglia Mitochondria Mus Neurons Nucleic Acids Outcome Pathway interactions Phenotype Prefrontal Cortex Property Protein Kinase Proteins Proteomics Regimen Research Rodent Model Role Signal Pathway Signal Transduction Synapses Testing Therapeutic Time age related aged aging brain behavior test brain tissue cell type clinical translation cognitive function combat effectiveness evaluation efficacy testing extracellular vesicles functional improvement human old age (65+)improved induced pluripotent stem cell inhibitor male marenostrin middle age mouse model nerve stem cell neurobehavioral test neurogenesis neuroinflammation neuroprotection novel strategies prevent therapeutically effective transcriptome sequencing uptake virtual

项目摘要

Project Summary This project's primary goal is to develop a non-invasive, extracellular vesicle (EV) therapy for maintaining better cognitive and memory function in old age. The project proposes to examine the effectiveness of intranasal (IN) administration of EVs generated from human induced pluripotent stem cell (hiPSC)-derived neural stem cells (hNSCs) for improving cognitive and memory function in a mouse model of aging. RNA-seq and proteomic studies have confirmed the presence of miRNAs and proteins having neuroprotective, antiinflammatory, and neurogenic properties in hNSC-EVs. Preliminary studies have suggested that IN administration of hNSC-EVs results in their uptake by microglia and neurons in all brain regions and leads to improved cognitive function in middle-aged mice, in association with diminished neuroinflammation, adenosine monophosphate-activated protein kinase (AMPK) activation, mammalian target of rapamycin (mTOR) inhibition, enhanced autophagy, and improved neurogenesis. Therefore, the rationale for the proposed approach is that the miRNA and protein cargo of hNSC-EVs would activate beneficial signaling pathways in target cells such as microglia, neurons, and neural stem cells in the aged brain, which, in turn, would reduce neuroinflammation, enhance neuronal function and neurogenesis, and thereby improve cognitive and memory function. The project will test the hypothesis that IN administration of hNSC-EVs in early or late middle age will maintain better cognitive function in old age, and hNSC-EV administration in old age will reverse cognitive dysfunction. Furthermore, it is envisaged that functional improvements with hNSC- EV treatment in the aged brain will involve modulation of activated microglia with inhibition of NLRP3 inflammasomes, AMPK activation, improved mitochondrial function, mTOR inhibition, enhanced autophagy, improved neurogenesis, and reduced synapse loss. Using a mouse model of aging, this project will first investigate the effectiveness of EVs administered in the early or late middle age to prevent cognitive and memory dysfunction in old age (Specific Aim 1). In Specific Aim 2, the effect of EVs administered in old age for reversing cognitive and memory dysfunction will be measured. Then, to understand the role of microglial modulation in hNSC-EV-mediated improved cognitive function, the effects of microglia depletion at the time of EV administration will be examined in both middle-aged and aged mice (Specific Aim 3). Since microglia depletion in the aged mice improves cognitive function, any additive effects of hNSC-EV treatment over the effects of microglia depletion would suggest that hNSC-EVs also act on other neural cell types or pathways to mediate therapeutic benefits. Two regions of the brain, the hippocampus, and the medial prefrontal cortex (mPFC), will be analyzed in male and female aged mice. The proposed studies are highly relevant for preventing and treating age-related cognitive and memory impairments in old age.

项目摘要该项目的主要目标是开发一种无创的细胞外囊泡（EV）治疗以维持更好的认知和记忆功能在老年中。该项目建议检查由人类诱导的多能干细胞（HIPSC）衍生的鼻内（IN）给药神经干细胞（HNSC）用于改善小鼠衰老模型中的认知和记忆功能。 RNA-seq 蛋白质组学研究已经证实存在具有神经保护性的miRNA和蛋白质， HNSC-EV中的抗炎和神经源特性。初步研究表明 HNSC-EV的给药会导致小胶质细胞和神经元在所有大脑区域的吸收，并导致随着神经炎症的减少，中年小鼠的认知功能提高了，腺苷一磷酸激活的蛋白激酶（AMPK）活化，雷帕霉素的哺乳动物靶标（MTOR）抑制作用，增强自噬和改善的神经发生。因此，建议的方法是HNSC-EV的miRNA和蛋白质货物将激活有益的信号传导靶细胞中的小胶质细胞，神经元和神经干细胞等靶细胞中的途径，而这些途径又将减少神经炎症，增强神经元功能和神经发生，从而改善认知和记忆功能。该项目将检验以下假设。中年或晚年将在老年保持更好的认知功能，而旧时HNSC-ev给药年龄会逆转认知功能障碍。此外，可以预见的是，HNSC-的功能改进老年大脑中的EV处理将涉及调节活化的小胶质细胞并抑制NLRP3 炎症，AMPK激活，改善线粒体功能，mTOR抑制作用，增强自噬，改善了神经发生，并减少了突触丧失。使用鼠标衰老模型，该项目将首先调查在中年或晚期服用的电动汽车的有效性，以防止认知和老年记忆功能障碍（特定目标1）。在特定的目标2中，EV在老年时的影响为了逆转认知和记忆功能障碍。然后，了解小胶质细胞的作用 HNSC-eV介导的改善认知功能的调节，小胶质细胞耗竭时的影响将在中年和老年小鼠中检查电动汽车给药（特定目标3）。由于小胶质细胞老年小鼠的耗竭可改善认知功能，HNSC-eV治疗对小胶质细胞耗竭的作用表明HNSC-EV还对其他神经细胞类型或通往的途径作用调解治疗益处。大脑的两个区域，海马和内侧前额叶皮层（MPFC）将在男性和女性老年小鼠中进行分析。拟议的研究对预防和治疗老年与年龄有关的认知和记忆障碍。