CAREER: A Lipid Based, Gene Delivery System for Proliferative Vascular Diseases

职业：用于增殖性血管疾病的基于脂质的基因传递系统

• 批准号: 9874631
• 负责人: Ravi Bellamkonda
• 金额: $ 20万
• 依托单位: Case Western Reserve University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=9874631&HistoricalAwards=false
• 关键词: CAREER; Lipid; Based; Gene; Delivery

9874631BellamkondaThis CAREER proposal presents a novel combination of educational and research initiatives in biomedical engineering in general and molecular tissue engineering in particular. The principal investigator holds a joint appointment in the Schools of Engineering and Medicine at Case Western Reserve University, and over a four year period, he proposes a program of teaching and research that will involve students and faculty from both the schools. The unifying theme of the program is the development, application and dissemination of interdisciplinary expertise on adapting biomaterials technologies as enabling tools to facilitate molecular level tissue engineering.The four educational initiatives proposed are a) application of modern teaching methodologies to engineering education, b) curriculum revision and development, c) outreach programs for area high school students focussing on recruitment of women into engineering, and d) mentoring of bioengineering majors. All of the initiatives mentioned above are strong integrated with the research initiatives proposed.The research initiatives proposed focus on the application of biomaterials based, drug delivery technology for the in vivo delivery of therapeutic genes to improve transfection efficiency and duration of transgene expression in vivo. In particular, the research targets proliferative vascular disorders which account for 10%-15% of all fatalities in America today. Proliferative vascular diseases are common after angioplasty, stent or graft placement or in peripheral vascular diseases. This proposal outlines a novel, versatile drug delivery system for the continuous, local, perivascular delivery of genetic agents to the arterial wall. Lipid based microcylinders can be fabricated of differing lengths and provide corresponding periods of slow release of genetic agents. It is proposed to deliver genetic agents via non-viral means to circumvent the safety issues associated with adenoviral mediated gene transfer.It is proposed to use an organ culture system and mathematical modeling to study and optimize the kinetics of reporter gene delivery using non-viral lipid- and peptide-DNA complexes to the arterial wall. Efficiency of transfection and duration of transgene expression will be quantified in vitro in the organ culture system. Once the kinetics of gene deposition in the arterial wall are optimized, endothelial nitric oxide synthase containing plasmids will be complexed to polylysine peptides and continuously delivered to an artery previously injured by a balloon catheter in a rodent model of peripheral restenosis. When complete, this project will shed new light on using continuous gene delivery to improve efficiency, duration of gene expression and the therapeutic outcome of delivering inhibitors of smooth muscle cell proliferation, continuously and perivascularly. It will also influence recruitment and retention of women into engineering, and impart critical biomaterials, molecular, and gene manipulation skills to undergraduate and graduate students in biomedical engineering.

9874631 Bellamkonda这个职业生涯的建议提出了一个新的组合，教育和研究计划，在生物医学工程一般和分子组织工程，特别是。 首席研究员在凯斯西储大学的工程和医学学院担任联合职务，在四年的时间里，他提出了一项教学和研究计划，该计划将涉及两所学校的学生和教师。 该计划的统一主题是开发，应用和传播跨学科的专业知识，使生物材料技术成为促进分子水平组织工程的工具。提出的四项教育倡议是a）现代教学方法在工程教育中的应用，B）课程修订和开发，c）面向地区高中生的外联方案，重点是招收妇女进入工程专业，以及d）指导生物工程专业的学生。 上述所有举措都与拟议的研究举措紧密结合。拟议的研究举措侧重于应用基于生物材料的药物递送技术在体内递送治疗性基因，以提高转染效率和转基因体内表达的持续时间。 特别是，该研究针对的是增殖性血管疾病，占当今美国所有死亡人数的10%-15%。 扩张性血管疾病在血管成形术、支架或移植物放置后或在外周血管疾病中是常见的。 该提案概述了一种新型的，多功能的药物输送系统，用于连续的，局部的，血管周围的遗传物质输送到动脉壁。 基于脂质的微圆柱体可以制造成不同的长度，并提供遗传剂的相应的缓慢释放期。 建议通过非病毒手段传递基因制剂以规避腺病毒介导的基因transfer. It的安全性问题，建议使用器官培养系统和数学建模来研究和优化使用非病毒脂质-和肽-DNA复合物的报告基因传递到动脉壁的动力学。 将在器官培养系统中体外定量转染效率和转基因表达的持续时间。 一旦基因沉积在动脉壁中的动力学被优化，含有内皮型一氧化氮合酶的质粒将与多聚赖氨酸肽复合，并连续递送到外周再狭窄啮齿动物模型中先前被球囊导管损伤的动脉。完成后，该项目将为使用连续基因递送来提高效率、基因表达的持续时间以及连续和血管周围递送平滑肌细胞增殖抑制剂的治疗结果提供新的思路。 它还将影响工程领域女性的招聘和保留，并向生物医学工程领域的本科生和研究生传授关键的生物材料、分子和基因操纵技能。