权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Engineered nanoparticles to rescue complement dysfunction and vascular disease during diabetes

工程纳米颗粒可挽救糖尿病期间的补体功能障碍和血管疾病

基本信息

批准号：
10470753
负责人：
Gary Liu
金额：
$ 6.98万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-09 至 2023-09-08
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10470753
关键词：
Address Advanced Glycosylation End Products Amputation Animal Model Animals Apolipoprotein E Arterial Fatty Streak Artificial nanoparticles Atherosclerosis Binding Binding Proteins Biodistribution Bioinformatics Biological Assay Biological Availability Blindness Blood Blood Circulation Blood Vessels Cardiovascular Diseases Carrier Proteins Cells Chronic Clinic Clinical Complement Complement Inactivators Complement Membrane Attack Complex Complications of Diabetes Mellitus Confocal Microscopy Deposition Development Diabetes Mellitus Diabetic Angiopathies Diabetic mouse Dose Drug Kinetics Endocrinology Endothelial Cells Engineering Epithelial Cells Equipment Erythrocytes Exhibits Fellowship Filtration Flow Cytometry Fluorescence Frequencies Functional disorder Glucose Glutamine Goals Half-Life Histidine Human Hyperglycemia In Vitro Institutes Intravenous Kidney Kidney Failure Kinetics Knock-out Knockout Mice Label Lead Life Expectancy Lipid Bilayers Lipids Lysine Mediating Mediator of activation protein Membrane Lipids Methods Microvascular Dysfunction Molecular Weight Mus Nanotechnology Organ Pathogenesis Patients Phagocytes Pharmaceutical Preparations Post-Translational Protein Processing Preparation Principal Investigator Property Protein Engineering Proteins Quality of life Radiolabeled Regulation Resistance Risk Scintillation Counting Serum Serum Proteins Streptozocin Surface Testing Tissues Training Treatment Efficacy Tropism Vascular Diseases Visual impairment Work biomaterial compatibility cardiovascular endothelium career clinical translation crosslink cytotoxicity diabetic efficacy evaluation endothelial dysfunction experimental study glycation glycemic control improved in vivo in vivo Model lipid nanoparticle lipophilicity macrophage monocyte nanoparticle nanoparticle delivery novel therapeutics prevent protein function responsible research conduct therapeutic protein uptake vascular injury von Willebrand Factor

项目摘要

PROJECT SUMMARY/ABSTRACT Vascular injury and disease during diabetes lead to end-organ dysfunction (kidney failure, blindness, amputation) and cardiovascular disease that profoundly reduces patient quality of life and life expectancy. The proposed work seeks to develop new therapeutics to prevent and arrest diabetic vascular disease, by engineering nanoparticles to enable efficient delivery of a protein therapeutic. A major cause of vascular injury is protein glycation, the covalent attachment of glucose to proteins that leads to advanced glycation end- products and protein inactivation. In particular, the protein CD59, the key regulator of the membrane attack complex (MAC), is ubiquitously expressed, and human CD59 is uniquely susceptible to glycation-inactivation during diabetes. Human and experimental studies underscore the connection between CD59 glycation- inactivation, complement dysregulation, and MAC deposition in tissues. Therefore, delivery of exogenous, glycation-resistant CD59 could rescue complement regulation and mitigate complement-mediated vascular injury in diabetes, but is challenging due to rapid clearance and non-specific serum-binding of this protein. Moreover, a delivery strategy would need to achieve broad cell tropism (red blood cells, endothelial and epithelial cells) and high delivery efficiency. The goal of this work is to engineer nanoparticles (NPs) to enable efficient intravenous delivery of mouse CD59 in vivo using lipid-based NPs to improve protein pharmacokinetics. We hypothesize that nanoparticle delivery of CD59 will mitigate cardiovascular disease and endothelial dysfunction in diabetic mice with CD59 deficiency. In Aim 1, NPs will be optimized for biocompatibility, protein loading, minimal non-specific uptake, and delivery in vitro. Optimized NPs will then be evaluated in Aim 2 for biodistribution and therapeutic efficacy in preventing atherosclerosis, endothelial dysfunction, and tissue complement deposition in diabetic, CD59-deficient animals. Successful completion of this work could validate CD59 delivery as a clinical strategy to halt and prevent diabetic vascular complications. The applicant, Gary Liu, aims to lead a lab as a principal investigator. One of his future research aims is to develop new therapies for diabetic microvascular complications. This postdoctoral fellowship includes (1) didactic training in diabetes, its complications, endocrinology, and bioinformatics; (2) scientific training in diabetic animal models and methods for quantifying cardiovascular disease and endothelial dysfunction, and (3) professional development and training in the responsible conduct of research in preparation for a career as a principal investigator. Training will occur at the Koch Institute of MIT in Dr. Robert Langer’s lab, which will provide the materials, equipment, and intellectual expertise necessary to carry out the proposed work.

项目总结/摘要糖尿病期间的血管损伤和疾病导致终末器官功能障碍（肾衰竭，失明，截肢）和心血管疾病，严重降低患者的生活质量和预期寿命。的拟议的工作旨在开发新的治疗方法来预防和阻止糖尿病血管疾病，工程化纳米颗粒以实现蛋白质治疗剂的有效递送。血管损伤的主要原因是蛋白质糖化，葡萄糖与蛋白质的共价连接，导致晚期糖化末端- 产物和蛋白质失活。特别是，蛋白质CD 59，膜攻击的关键调节因子，复合物（MAC）广泛表达，人CD 59对糖基化失活特别敏感在糖尿病期间。人体和实验研究强调了CD 59糖基化- 失活、补体失调和组织中MAC沉积。因此，外源性，抗糖基化CD 59可以拯救补体调节，减轻补体介导的血管内皮细胞损伤。糖尿病中的损伤，但由于这种蛋白的快速清除和非特异性血清结合而具有挑战性。此外，递送策略将需要实现广泛的细胞向性（红细胞、内皮细胞和内皮细胞）。上皮细胞）和高递送效率。这项工作的目标是设计纳米颗粒（NPs），使用基于脂质的NP在体内有效静脉内递送小鼠CD 59以改善蛋白质药代动力学我们假设纳米颗粒递送CD 59将减轻心血管疾病， CD 59缺乏的糖尿病小鼠的内皮功能障碍。在目标1中，NP将被优化，生物相容性、蛋白负载、最小非特异性摄取和体外递送。优化的NP将被在目标2中评价了在预防动脉粥样硬化、内皮功能障碍和组织补体沉积。成功完成这项工作可以验证CD 59递送作为阻止和预防糖尿病血管并发症的临床策略。申请人，加里刘，旨在领导一个实验室作为首席研究员。他未来的研究目标之一是开发糖尿病微血管并发症的新疗法。该博士后奖学金包括（1）糖尿病及其并发症、内分泌学和生物信息学方面的教学培训;（2）糖尿病动物模型和用于量化心血管疾病和内皮功能障碍的方法，以及 (3)专业发展和培训，负责进行研究，为职业生涯做准备，首席调查员培训将在麻省理工学院科赫研究所罗伯特·兰格博士的实验室进行，提供开展拟议工作所需的材料、设备和知识专长。