Stem Cell-Derived Exosomes, MrgD and Vascular Cognitive Impairment in Aging

干细胞衍生的外泌体、MrgD 和衰老过程中的血管认知障碍

• 批准号: 10737100
• 负责人: Yagna Jarajapu
• 金额: $ 45.76万
• 依托单位: NORTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737100
• 关键词: APP-PS1; Adult; Affect; Age; Aging; Agonist; Agreement; Alzheimer' s Disease; Antioxidants; Attenuated; Bioenergetics; Blood Vessels; Blood flow; Brain; CD34 gene; Cell Communication; Cells; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Dementia; Development; Elderly; Endothelium; Exhibits; Functional disorder; G-Protein-Coupled Receptors; Glycolysis; Hematopoietic stem cells; Homeostasis; Human; Impaired cognition; Impairment; Individual; Inflammatory; Mediating; Mediator; MicroRNAs; Microvascular Dysfunction; Mitochondria; Molecular; Mus; Oxidative Phosphorylation; Oxygen; Pathology; Peptides; Persons; Pharmacology; Phenotype; Play; Regulation; Renin-Angiotensin System; Risk; Role; Senility; Testing; Transgenic Mice; Vascular Cognitive Impairment; Vascular Dementia; Vascular Diseases; Vascular Endothelium; Vesicle; aging brain; angiogenesis; brain endothelial cell; cerebral microvasculature; cerebrovascular; cognitive function; cognitive performance; druggable target; endothelial regeneration; exosome; hematopoietic stem cell aging; in vivo; middle age; nanosized; nanovesicle; neurovascular coupling; new therapeutic target; novel; pharmacologic; prevent; receptor; response; senescence; stem cell aging; stem cell exosomes; stem cells; transcriptome sequencing; vascular cognitive impairment and dementia

Stem Cell-Derived Exosomes, MrgD and Vascular Cognitive Impairment in Aging Abstract Cerebrovascular dysfunction in aging increases risk for the development of cognitive decline and Alzheimer’s disease. Adult hematopoietic stem/progenitor cells (HSCs) play an important role in maintaining vascular homeostasis. Our novel preliminary studies identified that exosomes, nanovesicles, derived from HSCs of Older subjects (Old-HSC-Exos) induced dysfunction the human brain microvascular endothelial cells (BMECs) characterized by impaired mitochondrial bioenergetics and attenuated angiogenesis. In agreement with these findings, brain microvessels (BMVs) from Old mice showed imbalance in mitochondrial bioenergetics compared to the Young- BMVs. Furthermore, we have discovered that activation of Mas-related G-protein coupled receptor, D (MrgD) reversed age-associated impairment in bioenergetics in BMVs. This proposal tests the hypothesis that HSC-derived exosomes from Older individuals induce imbalance in the mitochondrial bioenergetics and impair cerebrovascular function resulting in cognitive decline. We further hypothesize that activation of MrgD is novel pharmacological approach for the treatment of vascular dementia. We will evaluate molecular cargo in the exosomes derived from Young and Old individuals by RNAseq analysis and determine the mitochondrial functions of selected molecules in the brain MVECs and BMVs. The potential of Mrgd activator Alamandine in reversing the detrimental effects of Old-HSC-Exos in the endothelial mitochondria and BMVs. We’ll determine the detrimental effects of Old-HSC-Exos in murine BMVs and test their potential to induce vascular dementia and cognitive decline in the Young and Old mice. The potential benefits of MrgD activators in Old-HSC-Exos-induced vascular dementia will be evaluated in vivo. Lastly, pharmacology of MrgD activators will be evaluated in APP/PS1 mice. If carried out successfully, this proposal will provide proof-of-concept for a novel role of HSC-exosomes in the pathology of vascular dementia and for MrgD as a promising target for the treatment.

干细胞衍生的外泌体，MRGD和血管认知障碍 抽象的 脑血管功能障碍在衰老中增加了认知能力下降和 阿尔茨海默氏病。成人造血干/祖细胞（HSC）在 维持血管稳态。我们的新型初步研究表明，外泌体， 纳米植物，源自老年受试者的HSC（旧HSC-exos）诱导功能障碍 人脑微血管内皮细胞（BMEC），其特征是线粒体受损 生物能和血管生成减弱。与这些发现一致，大脑微血管 （BMV）来自老鼠的旧小鼠，与年轻人相比，线粒体生物能力失衡 BMV。此外，我们发现MAS相关G蛋白的激活耦合 受体，D（MRGD）反转BMV中生物能力的年龄相关损伤。 该提案检验了以下假设，即来自老年人的HSC衍生的外泌体影响 线粒体生物能学的失衡和损害脑血管功能，导致脑血管功能 认知能力下降。我们进一步假设MRGD的激活是新型药理 治疗血管痴呆的方法。我们将评估分子货物 通过RNASEQ分析源自年轻人和老年人的外泌体，并确定 脑MVEC和BMV中选定分子的线粒体功能。潜力 MRGD激活剂Alamandine在逆转内皮中旧的HSC-exos的有害影响 线粒体和BMV。我们将确定旧hsc-exos在鼠中的不利影响 BMV并测试其诱导年轻人和认知能力下降的潜力 老鼠。 MRGD激活剂在旧HSC诱导的血管痴呆中的潜在益处 将在体内进行评估。最后，将在APP/PS1中评估MRGD激活剂的药理学 老鼠。如果成功执行，该提案将为新的作用提供概念概念 血管性痴呆病理和MRGD的HSC外观测体是有希望的目标 治疗。

项目成果

Early onset of aging phenotype in vascular repair by Mas receptor deficiency.

Mas 受体缺陷导致血管修复中早期出现衰老表型。

• DOI: 10.1007/s11357-021-00473-4
• 发表时间: 2022
• 期刊: GeroScience
• 影响因子: 5.6
• 作者: Vasam,Goutham;S,ShrinidhJoshi;Miyat,SuYamin;Adam,Hashim;Jarajapu,YagnaP
• 通讯作者: Jarajapu,YagnaP

Methods for Studying the Role of RAAS in the Modulation of Vascular Repair-Relevant Functions of Stem/Progenitor Cells.

研究 RAAS 在干细胞/祖细胞血管修复相关功能调节中的作用的方法。

• DOI: 10.1007/978-1-4939-7030-8_4
• 发表时间: 2017
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Jarajapu,YagnaPR

Angiotensin-(1-7) Restores Gut Barrier Integrity and Ameliorates Systemic Inflammation in Aging.

血管紧张素-(1-7) 恢复肠道屏障完整性并改善衰老过程中的全身炎症。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Chittimalli,Kishore;Jahan,Jesmin;Sakamuri,Anil;Jarajapu,YagnaP
• 通讯作者: Jarajapu,YagnaP