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

• 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
• 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

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.

项目摘要/摘要 糖尿病期间的血管损伤和疾病导致末期功能障碍（肾功能衰竭，失明， 截肢）和心血管疾病，可大大降低患者的生活质量和预期寿命。 拟议的工作旨在开发新的疗法，以预防和阻止 工程纳米颗粒能够有效地递送蛋白质疗法。血管损伤的主要原因 是蛋白质糖化，是葡萄糖与蛋白质的共价附着 产品和蛋白质灭活。特别是蛋白质CD59，膜攻击的关​​键调节剂 复合物（MAC），无处不在，人CD59非常容易受到糖基化渗透的影响 在糖尿病期间。人类和实验研究强调了CD59糖化 - 灭活，完成失调和组织中的MAC沉积。因此，递送外源性， 耐糖化的CD59可以挽救完成调节，并减轻完成介导的血管 糖尿病的损伤，但由于快速清除率和该蛋白质的非特异性血清结合而具有挑战性。 此外，输送策略将需要实现广泛的细胞向趋势（红细胞，内皮和 上皮细胞）和高输送效率。这项工作的目的是设计纳米颗粒（NP）以启用 使用基于脂质的NP改善蛋白质的小鼠CD59在体内有效静脉注射递送 药代动力学。我们假设CD59的纳米颗粒递送会减轻心血管疾病和 CD59缺乏症的糖尿病小鼠的内皮功能障碍。在AIM 1中，NP将被优化 生物相容性，蛋白质负荷，最少的非特异性摄取和体外递送。然后，优化的NP将是 在AIM 2中评估了用于预防动脉粥样硬化的生物分布和治疗效率 糖尿病，CD59缺陷动物的功能障碍和组织完成沉积。成功完成 这项工作可以验证CD59作为停止和预防糖尿病血管并发症的临床策略。 申请人加里·刘（Gary Liu）旨在领导实验室作为首席研究员。他未来的研究目标之一是 开发新的糖尿病微血管并发症的疗法。该博士后奖学金包括（1） 糖尿病的教学训练，其并发症，内分泌学和生物信息学； （2）科学培训 糖尿病动物模型和量化心血管疾病和内皮功能障碍的方法，以及 （3）负责任的研究的专业发展和培训，为职业做准备 首席研究员。培训将在罗伯特·兰格博士实验室的科赫学院进行，该研究所将 提供所需的材料，设备和智力专业知识，以进行拟议的工作。