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Targeted delivery of a proangiogenic and promyogenic protein for regeneration of diabetic ischemic limbs

靶向递送促血管生成和促肌生成蛋白以促进糖尿病缺血肢体的再生

基本信息

批准号：
10616819
负责人：
Jianjun Guan
金额：
$ 58.25万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-02 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10616819
关键词：
Acceleration Blood Platelets Cell Survival Cell membrane Cell physiology Cellular Metabolic Process Clinical Diabetic mouse Diameter Diffusion Encapsulated Endothelial Cells Endothelium Engineering Environment Exhibits Fibrosis Glucose Growth Factor Hyperglycemia Impairment Inferior Inflammation Injections Ischemia Limb Salvage Limb structure Membrane Modeling Morphogenesis Mus Muscle Cells Muscle Fibers Muscle function Myoblasts Natural regeneration Peptides Phosphotransferases Principal Investigator Proliferating Property Protein Engineering Proteins Reporting Signal Pathway Skeletal Muscle Testing Therapeutic Effect Time Tissues Treatment Efficacy Tube Vascularization angiogenesis blood perfusion cell motility controlled release critical limb Ischemia density diabetic diabetic patient effective therapy efficacy testing functional improvement improved innovation limb amputation limb ischemia migration mortality myogenesis nanoparticle novel novel strategies preservation programs repaired satellite cell targeted delivery

项目摘要

Program Director/Principal Investigator (Last, First, Middle): GUAN, JIANJUN Project Summary Diabetic patients with critical limb ischemia (CLI) have significantly high rates of limb amputation and mortality. CLI is featured by extremely low blood perfusion and degenerated skeletal muscle. Accordingly, regeneration of vasculature and skeletal muscles will salvage the limbs. Yet the poor endothelial and skeletal muscle cell survival, and inferior cell functions under the hyperglycemia and ischemic conditions of diabetic CLI impair the limb repair. Currently, there is no effective treatment available although growth factor therapy represents a promising strategy. However, growth factor therapy has relatively low therapeutic efficacy in regenerating both vasculature and skeletal muscles, as multiple growth factors are simultaneously needed for vascularization and myogenesis, and these cannot be readily delivered by current approaches. In this project, we propose to use a novel TRIM72 protein with both pro-angiogenic and pro-myogenic properties to regenerate vasculature and skeletal muscles in diabetic CLI. The TRIM72 will be engineered to have longer retention time (slower diffusion rate) in ischemic tissue, thus exhibiting longer therapeutic effect. To deliver the engineered TRIM72 (ETRIM72), it will be encapsulated into ischemic limb-targeting nanoparticles, followed by delivering via clinically attractive IV injection. The nanoparticles will then predominantly accumulate in the ischemic limbs and gradually release ETRIM72. The released protein will promote vascularization and myogenesis by (1) improving the survival of endothelial cell and skeletal muscle cell through cell membrane repair, and activation of cell survival kinase; and (2) stimulating endothelial cell and skeletal muscle cell migration and morphogenesis under the hyperglycemia and ischemic conditions of diabetic CLI. In our preliminary studies, we have developed ETRIM72 by genetically fusing TRIM72 with peptide CSTSMLKAC that targets ischemic environment of ischemic limbs. This first version of ETRIM72 was able to retain in the ischemic limbs significantly longer than TRIM72. After IV injection of ischemic limb-targeting, ETRIM72-releasing nanoparticles, the released ETRIM72 significantly promoted regeneration of both vasculature and skeletal muscles in diabetic ischemic limbs. The function of TRIM72 in promoting vascularization and myogenesis under hyperglycemia and ischemic conditions has not been reported before. Based on our preliminary studies, we hypothesize that controlled release of ETRIM72 will simultaneously increase endothelial and skeletal muscle cell survival, migration and morphogenesis under hyperglycemia and ischemic conditions, leading to accelerated regeneration of both vasculature and skeletal muscles in diabetic ischemic limbs. Aim #1 will test the hypothesis that optimal ETRIM72 release profiles will significantly promote survival, migration and morphogenesis of endothelial cells and myoblasts under high glucose and ischemic conditions. Aim #2 will test efficacy of the ETRIM72-releasing nanoparticles using diabetic murine limb ischemia model. This project is innovative because it engineers a novel proangiogenic and promyogenic protein to simultaneously regenerate vasculature and skeletal muscles in diabetic ischemic limbs. The longer tissue retention time of the engineered protein, together with localized and controlled release are expected to significantly improve therapeutic efficacy. OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page Continuation Format Page

项目主任/首席研究员（后、一、中）：关建军