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手术的血管中。这种痉挛是由于平滑肌松弛受损所致。松弛由环核苷酸依赖性信号通路介导。我们已经证明，一个小的热休克蛋白，热休克蛋白20的磷酸化代表了一个点，其中的环核苷酸信号通路收敛，导致松弛。本研究的假设是，血管舒张分子，包括HSP 20基序和蛋白转导结构域，将防止1）短期静脉移植失败由于血管痉挛和2）长期移植失败，通过更好地保存移植物在收获过程中，并通过防止内膜增生。本研究的具体目的是：#1：产生与蛋白质转导结构域（PTD）连接的重组HSP 20，并确定这种工程蛋白是否能逆转离体人血管平滑肌痉挛。#2：确定PTD-HSP 20对与内膜增生相关的动态细胞骨架过程的影响。#3：确定静脉移植物的HSP 20类似物在体内蛋白转导的可行性。该项目的目标是设计生物分子，通过直接将内源性松弛蛋白（HSP 20）的类似物引入平滑肌来增强静脉移植物的保存。静脉移植物代表了这些治疗方法的理想靶标，因为移植物可以离体处理，从而为工程化蛋白质/肽治疗剂的定位提供了最佳环境。这代表了一种新的方法，因为受体和信号级联被“绕过”，效应蛋白/肽被直接引入靶细胞。这代表了用于工程化生物活性蛋白质/肽分子的“后基因组”平台。