PREVENTION OF VEIN GRAFT SPASM

预防移植静脉痉挛

• 批准号: 6884077
• 负责人: Colleen M Brophy
• 金额: $ 49.36万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6884077
• 关键词: bioengineering /biomedical engineering; biological signal transduction; biomaterial evaluation; blood vessel transplantation; chimeric proteins; disease /disorder prevention /control; genetically modified plants; heat shock proteins; human tissue; hyperplasia; laboratory rabbit; muscle proteins; muscle relaxing factor; organ culture; phosphorylation; plants; postoperative complications; protein engineering; protein purification; protein structure function; tissue /organ preservation; transfection; vascular smooth muscle; vasospasm

DESCRIPTION (provided by applicant): Vasospasm occurs in the blood vessels used for vascular bypass operations. This spasm is due to impaired relaxation of the smooth muscle. Relaxation is mediated by cyclic nucleotide-dependent signaling pathways. We have demonstrated that the phosphorylation of a small heat shock protein, HSP20 represents a point in which the cyclic nucleotide signaling pathways converge to cause relaxation. The hypotheses of this investigation are that vasorelaxing molecules, engineered to include HSP20 motifs and protein transduction domains, will prevent 1) short term vein graft failure due to vasospasm and 2) long term graft failure by better preservation of the graft during harvest and by the prevention of intimal hyperplasia. The specific aims of this investigation are: #1: Generate recombinant HSP20 linked to a protein transduction domain (PTD) and determine if this engineered protein reverses human vascular smooth muscle spasm ex vivo. #2: Determine the effect of PTD-HSP20 on dynamic cytoskeletal processes relevant to intimal hyperplasia. #3: Determine the feasibility of protein transduction of HSP20 analogues of vein grafts in vivo. The goal of this project is to engineer biomolecules that enhance vein graft preservation by directly introducing the analogues of an endogenous relaxing protein (HSP20) into the smooth muscle. Vein grafts represent an ideal target for these therapeutic approaches in that the graft can be treated ex vivo, thus providing an optimal environment for the localization of engineered protein/peptide therapeutics. This represents a novel approach in that the receptors and signaling cascades are "bypassed" and the effector protein/peptide is directly introduced into the target cell. This represents a "post-genomic" platform for engineering biologically active protein/peptide molecules.

描述（由申请人提供）： 血管痉挛发生在用于血管旁路作战的血管中。这种痉挛是由于平滑肌放松受损。弛豫是由循环核苷酸依赖性信号通路介导的。我们已经证明了小热激蛋白的磷酸化，HSP20代表了一个循环核苷酸信号通路会汇聚以引起松弛的点。这项研究的假设是，设计为包括HSP20基序和蛋白质转导域的血管延迟分子将预防1）1）短期静脉移植物在血管痉挛引起的短期静脉移植失败和2）长期移植物在收获期间通过更好地保存移植物和预防膜超时性增生性超浮肿。这项研究的具体目的是：＃1：生成与蛋白质转导域（PTD）相关的重组HSP20，并确定该设计的蛋白质是否逆转了人体血管平滑肌痉挛的体外。 ＃2：确定PTD-HSP20对与内膜增生有关的动态细胞骨架过程的影响。 ＃3：确定体内静脉移植物HSP20类似物的蛋白质转导的可行性。该项目的目的是通过将内源性松弛蛋白（HSP20）的类似物直接引入平滑肌，从而设计生物分子，从而增强静脉移植物的保存。静脉移植物是这些治疗方法的理想目标，因为可以对移植物进行治疗，从而为工程蛋白/肽治疗剂的定位提供了最佳环境。这代表了一种新颖的方法，因为受体和信号级联是“绕过”的，并且效应蛋白/肽直接引入靶细胞。这代表了工程生物活性蛋白/肽分子的“后基因组”平台。