VIRAL VECTOR DELIVERY OF ANTISENSE TO ACE MRNA IN CARDIOVASCULAR DISEASE

心血管疾病中 ACE mRNA 反义病毒载体的传递

• 批准号: 6500812
• 负责人: MICHAEL. IAN PHILLIPS
• 金额: $ 22万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6500812
• 关键词: animal tissue; antisense nucleic acid; enzyme activity; familial hypertension; gene therapy; hypertension; laboratory rat; messenger RNA; peptidyl dipeptidase A; pulmonary hypertension; renal hypertension; renin angiotensin system; restenosis; transfection /expression vector

PARENT ABSTRACT - SUBPROJECT ABSTRACT NOT AVAILABLE The long-range goal of this Program Project is to develop viral vector-based gene transfer strategies for treating genetic and acquired cardiopulmonary disorders. To this end, a group of investigators with diverse, yet complementary interdisciplinary interests and expertise has established an integrated research effort that is underscored by a common interest inpracticalapplications of gene therapy. A major focus of the Programis the development of improved methods of gene transfer. Four of the components (Subproject 3, Subproject 4, Subproject and Pilot 2) are primarily focused onthe development of vectors suitable for transduction of terminally differentiated cells. These include two stable expression vectors, Adeno-associated virus (AAV, Subproject 3) and lentivirus (subproject 4), as wellas two transient expression vectors, adenovirus (Ad, Subproject 5) and the entomopoxvirus (EPV, Pilot 2). In each case, the efforts are directed at identifying and circumventing obstacles to the practical applicationof gene therapy, most of which are rooted in the basic biology of the individual virus upon which each vector system is based. Along with the vector development components, there is a strong emphasis on the development of new animal models, including the development of knock-out mouse models for monogenic cardiac (Subproject 1) and pulmonary (Pilot 1, Subproject 2) disorders, and a transgenic model for AAV integration (Subproject 1). The utilization of established models of hypertension and acute lung injury are likewise pivotal for Subprojects 6 and 5, respectively. The program also will investigate the applications of these vector systems to three cardiopulmonary disorders: alpha-1-antitrypsin deficiency (alpha 1AT, Subproject 2), acid maltase deficiency (GAA, Subproject 1) and hypertension (Subproject 6). This will be done by targeting vectors to muscle (Subprojects 1 and 2) and vascular endothelium (Subprogject 6). Additionally, the Program has established a Vector Core Laboratory (Core B) which will supply vectors of uniform and reproducible quality to all subprojects, and investigate improved methods of generating recombinant AAV (rAAV) and adenovirus (Ad) vectors. The Vector Core will also serve as a mechanism to insure rapid exchange of information among all subprojects. Finally, an Administrative Core (Core A) will insure centralized fiscal management and oversight for the subprojects and pilot/feasibility projects.

父级摘要 - 该程序项目的摘要不可用的远程目标是开发基于病毒载体的基因转移策略来治疗遗传和获得的心肺疾病。 为此，一组具有多样化但互补的跨学科利益和专业知识的研究人员建立了一项综合的研究工作，这是由于基因治疗的共同利益而强调的。 该程序的主要重点是发展基因转移方法的发展。 其中四个组件（subproject 3，subproject 4，subproject和Pilot 2）主要集中于适合转导末端分化细胞的矢量的发展。其中包括两个稳定的表达矢量，分别与腺相关病毒（AAV，子标记3）和慢病毒（subproject 4），以及wellas两个瞬时表达矢量，腺病毒（AD，Subproject 5）和Entomopoxvirus（EPV，PILOT 2）。 在每种情况下，努力都旨在识别和规避基因治疗的实际应用障碍，其中大多数植根于每个载体系统所基于的个体病毒的基本生物学。 与矢量发育成分一起，人们非常重视新动物模型的发展，包括开发单基因心脏（subproject 1）和肺动物（Pilot 1，subproject 2）疾病的基因敲除小鼠模型，以及用于AAV集成的转基因模型（Subprothoctiject 1）。 同样，对6和5的高血压和急性肺损伤的既定模型也是关键。 该计划还将研究这些矢量系统对三种心肺疾病的应用：α-1-抗抗蛋白酶缺乏症（Alpha 1AT，subproject 2），酸性麦芽糖酶缺乏症（GAA，subproject 1）和高血压（亚第6）。 这将通过将矢量靶向肌肉（第1和2个）和血管内皮（亚物体6）来完成。 此外，该计划还建立了一个向量核心实验室（核心B），该实验室将为所有副标士提供均匀且可重复的质量的向量，并研究了生成重组AAV（RAAV）和腺病毒（AD）矢量的改进方法。 矢量核心还将作为确保所有次要投影之间信息快速交换的机制。 最后，行政核心（核心A）将确保对子弹和试点/可行性项目的集中财政管理和监督。