Correction of diabetic retinopathy by mitochondrial transfer

通过线粒体转移纠正糖尿病视网膜病变

基本信息

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
项目类别：
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

项目摘要

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发挥基石作用破碎、嵴肿胀和丢失、线粒体 DNA 的表观遗传变化、减少转运蛋白和线粒体 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将细胞从生物能中拯救出来异常和细胞死亡[1-8]。我们建议视网膜内皮细胞的正常化通过线粒体转移的生物能学可以预防视网膜血管变性并提供治疗 DR 的突破性新方法。越来越多的证据表明，视网膜当糖尿病代谢损伤导致视网膜损伤和骨髓来源的循环血管修复细胞（称为 CD34+ 细胞）的缺陷修复基于识别它们进行隔离的关键表面标记。在健康受试者中，CD34+ 细胞通过迁移和归巢到视网膜血管修复的部位来参与视网膜血管修复过程。内皮损伤，而患有血管疾病的糖尿病受试者的 CD34+ 细胞则丧失了这种能力并发症。之前，我们证明了 CD34+ 细胞的骨髓病理学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。 CD34+细胞通过旁分泌机制进行修复，最近被证明包括线粒体转移纳米隧道或通过细胞外囊泡介导的机制。线粒体的释放受损视网膜内皮细胞的 DNA 和蛋白质刺激线粒体生物发生干/祖细胞，然后将线粒体转移到受伤的常驻细胞。损害糖尿病 CD34+ 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应用程序中进行研究。是所讨论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) 线粒体转移起始的缺陷，线粒体未得到修复通过 CD34+ 细胞，ii) CD34+细胞线粒体的质量，以及 iii) 驻留者的 CD34+ 细胞感知损伤期间释放的内皮细胞线粒体 DNA/蛋白质。为了检验假设，具体如下将解决的目标：目标 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。目标2：检查线粒体由来自糖尿病和非糖尿病供体的 CD34+ 细胞转移到 db/db 小鼠中。