Cerebral endothelial cells derived exosomes as a therapy for cognitive impairment in aged diabetic rats

脑内皮细胞衍生的外泌体作为老年糖尿病大鼠认知障碍的治疗方法

• 批准号: 10601114
• 负责人: LI ZHANG
• 金额: $ 35.86万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601114
• 关键词: Acceleration; Address; Adult; Aging; Bioinformatics; Blood - brain barrier anatomy; Blood Vessels; Brain; Cells; Cerebrovascular Disorders; Cerebrum; Clinical; Cognitive Therapy; Cognitive deficits; Combined Modality Therapy; Communication; Couples; Data; Dementia; Development; Diabetes Mellitus; Elderly; Endothelium; Exhibits; Extravasation; Functional disorder; Funding; Genes; Harvest; Hippocampus; Human; Impaired cognition; Impairment; Individual; Measures; Mediating; Metabolic Diseases; MicroRNAs; Microarray Analysis; Myelogenous; Niacinamide; PTEN gene; Physiological; Play; Population; Proteins; Rattus; Rodent; Role; Streptozocin; Testing; Therapeutic; Therapeutic Effect; Thrombosis; Thrombospondin 1; Vascular Patency; aged; aging population; angiogenesis; blood-brain barrier crossing; brain endothelial cell; cerebrovascular; cognitive function; diabetes mellitus therapy; diabetic; diabetic rat; endothelial dysfunction; endothelial stem cell; engineered exosomes; exosome; extracellular vesicles; improved; innovation; intercellular communication; intravenous administration; middle age; nano; nanosized; nerve stem cell; neurogenesis; novel; pre-clinical; response

Abstract: Diabetes mellitus (DM) induces cerebral vascular dysfunction and impairs the hippocampal neurogenesis, resulting in cognitive decline. Cerebral angiogenesis couples with neurogenesis. Molecules that mediate the interaction between cerebral endothelial cells and neural stem cells in particular in DM have not been fully investigated. Cerebral endothelial cells constitutively release exosomes, which mediate intercellular communication. Our preliminary data demonstrated that exosomes derived from dysfunctional cerebral endothelial cells of DM rats communicate with neural stem cells and inhibit neurogenesis. Importantly, administration of exosomes isolated from cerebral endothelial cells (CE-exo) of healthy adult brain to DM rats robustly improved cognitive function and minimized DM-induced cerebral endothelial cell dysfunction and DM- impaired hippocampal neurogenesis. In this application, we therefore, propose to develop cerebral endothelial exosomes as a mechanism-based therapy for DM-induced cognitive decline in the aged rats. There are three Aims. Aim 1 tests the hypothesis that CE-exo treatment reduces cognitive deficits in the DM rat. Aim 2 tests the hypothesis that CE-exo treatment improves cerebral vascular patency and integrity, and promotes neurogenesis in the aged-DM rat. Aim 3 tests the hypothesis that engineered exosomes carrying elevated selective miRNAs have enhanced effects on cerebral vascular function and neurogenesis as well as cognitive function. These studies will provide preclinical evidence for developing CE-exo as an innovative treatment for DM-induced cognitive dysfunction.

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