Correction of diabetic retinopathy by mitochondrial transfer

通过线粒体转移纠正糖尿病视网膜病变

• 批准号: 10658455
• 负责人: Maria Bartolomeo Grant
• 金额: $ 57.12万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-05-01
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658455
• 关键词: Address; Binding; Bioenergetics; Biogenesis; Blood Vessels; Bone Marrow; CD34 gene; Carrier Proteins; Cell Death; Cells; Crista ampullaris; Diabetes Mellitus; Diabetic Retinopathy; Disease; Early Diagnosis; Early treatment; Endoplasmic Reticulum; Endothelial Cells; Endothelium; Energy-Generating Resources; Epigenetic Process; Functional disorder; Growth Factor; Homing; Immunotherapy; Impairment; In Vitro; Injury; Intervention; Mediating; Metabolic; Metabolism; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins; Nanotubes; Pathogenesis; Pathology; Patients; Play; Process; Proteins; Regulation; Retina; Role; Signal Transduction; Site; Surface; Swelling; Symptoms; Testing; Withdrawal; bevacizumab; bone repair; cell injury; db/db mouse; diabetic; directed differentiation; endothelial stem cell; extracellular vesicles; in vivo; injured; injury and repair; macular edema; migration; neovascular; new therapeutic target; non-diabetic; novel; novel strategies; paracrine; prevent; remediation; repair function; repaired; reparative capacity; restoration; retinal damage; stem cells; vascular injury

Mitochondria play cornerstone role in cellular metabolism and mitochondrial fragmentation, swelling and loss of cristae, epigenetic changes in mitochondrial DNA, reduction of transport proteins, and mitochondria-ER regulation precede histopathological abnormalities in DR. Recent studies demonstrate that mitochondrial transfer can rescue cells from bioenergetic abnormalities and cell death [1-8]. We propose that normalization of retinal endothelial cell bioenergetics by mitochondrial transfer can prevent retinal vascular degeneration and provide a novel breakthrough approach to treatment of DR. Accumulating evidence suggests that retinal vascular degeneration occurs when diabetic metabolic insult causes both retinal damage and defective repair by bone marrow-derived circulating vascular reparative cells, called CD34+ cells based on the critical surface marker that identifies them for isolation. In healthy subjects, CD34+ cells participate in the retinal vascular repair process by migrating and homing to the site of endothelial injury, while this capability is lost in CD34+ cells from diabetic subjects with vascular complications. Previously, we demonstrated that bone marrow pathology with CD34+ cell dysfunction precedes and is necessary for retinal vascular degeneration in diabetes. CD34+ cells repair by paracrine mechanism and was recently shown to include mitochondrial transfer nanotunnels or through extracellular vesicles-mediated mechanism. Release of mitochondrial DNA and proteins by damaged retinal endothelial cells stimulate mitochondrial biogenesis in stem/progenitor cells followed by the transfer of mitochondria to the injured resident cells. Alterations that impair the ability of diabetic CD34+ cells to repair injured vascular cells are not completely understood and will be studied in this application. is one of the questions addressed in this application. We hypothesize that retinal endothelial cells (REC) mitochondria are damaged and mitochondria are not repaired because of deficiency in i) initiation of mitochondrial transfer by CD34+ cells, ii) quality of CD34+cell mitochondria, and iii) the CD34+ cells sensing of resident endothelial cell mtDNA/proteins released during injury. To test hypothesis, the following Specific Aims will be addressed: Aim 1: To determine the signals and mechanisms that initiate repair of damaged retinal endothelial cells by mitochondrial transfer. Aim 2: To examine the mitochondrial transfer by CD34+ cells from diabetic and nondiabetic donors in db/db mice.

线粒体在细胞代谢中起基石作用， 嵴断裂、肿胀和缺失，线粒体DNA的表观遗传变化， 转运蛋白的表达，以及Escheria-ER调节先于组织病理学异常， 博士最近的研究表明，线粒体转移可以拯救细胞的生物能量， 异常和细胞死亡[1-8]。我们认为视网膜内皮细胞的正常化 通过线粒体转移的生物能量学可以防止视网膜血管变性， 新的突破性方法来治疗DR。积累的证据表明，视网膜 当糖尿病代谢损伤引起视网膜损伤和视网膜坏死时， 骨髓来源的循环血管修复细胞（称为CD 34+细胞）的缺陷修复 根据关键的表面标记来识别它们以进行隔离。在健康受试者中，CD 34 + 细胞参与视网膜血管修复过程，通过迁移和归巢的网站， 血管内皮损伤，而这种能力在来自患有血管内皮损伤的糖尿病受试者的CD 34+细胞中丧失。 并发症以前，我们证明了骨髓病理学与CD 34+细胞， 功能障碍先于糖尿病视网膜血管变性并且是糖尿病视网膜血管变性所必需的。cd 34+细胞 通过旁分泌机制进行修复，最近显示包括线粒体转移 纳米隧道或通过细胞外囊泡介导的机制。线粒体释放 受损视网膜内皮细胞的DNA和蛋白质刺激线粒体生物合成， 干/祖细胞，随后将线粒体转移到受损的驻留细胞。 损害糖尿病CD 34+细胞修复受损血管细胞能力的改变并不 完全理解，并将在本申请中进行研究。这是一个需要解决的问题 在这个应用中。我们假设视网膜内皮细胞（REC）线粒体受损， 并且线粒体由于i）线粒体转移起始的缺陷而不能修复 ii）CD 34+细胞线粒体的质量，和iii）CD 34+细胞对驻留的细胞的敏感性。 内皮细胞线粒体DNA/蛋白质在损伤过程中释放。为了检验假设，以下具体 目的1：确定启动修复的信号和机制， 通过线粒体转移损伤视网膜内皮细胞。目的2：检测线粒体 通过db/db小鼠中来自糖尿病和非糖尿病供体的CD 34+细胞转移。