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.

线粒体在细胞代谢和线粒体中扮演基石角色 碎裂，肿胀和损失Cristae，线粒体DNA的表观遗传变化，还原 转运蛋白和线粒体 - 调节的构成之前的组织病理学异常 博士最近的研究表明，线粒体转移可以从生物能中拯救细胞 异常和细胞死亡[1-8]。我们提出了视网膜内皮细胞的归一化 线粒体转移的生物能学可以防止视网膜血管变性，并提供 新颖的DR治疗方法。积累的证据表明视网膜 当糖尿病代谢侮辱既造成视网膜损伤和 通过骨髓来源的循环循环的血管修复细胞的修复，称为CD34+细胞 基于鉴定它们进行隔离的临界表面标记。在健康受试者中，CD34+ 细胞通过迁移和归居到现场的视网膜血管修复过程 内皮损伤，而这种能力在患有血管的糖尿病受试者的CD34+细胞中丧失 并发症。以前，我们证明了带有CD34+细胞的骨髓病理 功能障碍先于糖尿病的视网膜血管变性所必需。 CD34+细胞 通过旁分泌机制修复，最近显示出包括线粒体转移 纳米核或通过细胞外囊泡介导的机制。线粒体的释放 视网膜内皮细胞受损的DNA和蛋白质刺激线粒体生物发生 茎/祖细胞，然后将线粒体转移到受伤的居民细胞上。 损害糖尿病CD34+细胞修复受伤血管细胞能力的改变不是 完全理解，将在此应用中进行研究。是解决的问题之一 在此应用程序中。我们假设视网膜内皮细胞（REC）线粒体受损 由于I）线粒体转移的启动，线粒体和线粒体无法修复 通过CD34+细胞，ii）CD34+细胞线粒体的质量，iii）CD34+细胞感应居民的感应 损伤期间释放的内皮细胞mtDNA/蛋白质。为了检验假设，以下特定 目标将被解决：目标1：确定启动维修的信号和机制 线粒体转移通过线粒体转移受损的视网膜内皮细胞。目标2：检查线粒体 DB/DB小鼠中的糖尿病和非糖尿病供体从CD34+细胞转移。