CARDIAC ISCHEMIA AND HSPS

心脏缺血和 HSPS

基本信息

批准号：
7154082
负责人：
Wolfgang H Dillmann
金额：
$ 32.43万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-12-01 至 2008-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7154082
关键词：
Adenovirus Vector Adenoviruses Animal Model Apoptosis Calcium Cardiac Cardiac Myocytes Cell Death Cell Nucleus Cells Cellular Structures Clinical Code Condition Confocal Microscopy Contractile Proteins Crystallins Cultured Cells Cytoskeleton Disease Dose Evaluation Family member Future Grant HSPB1 gene Heart Heat shock proteins Heat-Shock Proteins 70 Heterotopic Transplantation Human In Situ Infarction Infection Injury Investigation Ischemia Knockout Mice Lead Mediating Microtubules Mus Muscle Muscle Cells Myocardial Myocardial Ischemia Myocardial Stunning Myocardial dysfunction Necrosis Perfusion Phosphorylation Phosphotransferases Physiological reperfusion Protein Family Proteins Rattus Reaction Time Recovery of Function Regional Perfusion Reperfusion Therapy Research Personnel Rodent Shock Simulate Structure Transgenic Mice Transgenic Organisms Viral Vector base heat-shock factor 1 improved in vivo insight mutant novel novel strategies papillary muscle preconditioning protective effect response size transgene expression vector

项目摘要

Ischemic heart disease is a significant clinical problem and results obtained during the previous grant period show that increased expression of specific heat shock proteins (HSP) exerts a protective effect against ischemia-reperfusion (Ism-Reper) induced myocardial injury. Important questions related to the protective effects of HSPs against Ism-Reper induced myocardial injury remain unanswered. We will determine in Aim I if small HSPs, aB-crystallin and HSP27, have a protective effect against Ism-Reper induced injury by themselves, in combination with each other, and with HSP70 family members. Adenoviral vectors expressing the small HSPs aB-crystallin and HSP27 at high levels upon infection of cardiac myocytes have been generated and show a protective effect in preliminary studies. In addition, transgenic mice expressing aB-crystallin and HSP27in their hearts are available for these studies. In Aim II we will determine the basis for protective effects of specific HSPs like the inducible HSP70 (HSP70i), the constitutive HSP70, and the small HSPs aB-crystallin and HSP27 against Ism-Reper induced injury especially cell death by apoptosis and necrosis and decreased myocardial function. Preliminary findings indicate that increased expression of HSP70i hasa protective effect against Ism-Reperinduced apoptosis mediated cell death. Our preliminary findings using confocal microscopy showing that increased expression of small HSPs leadsto protection of specific cytoskeletal structures against ischemia-induced injury will also be further explored. In Aim III, we would like to investigate novel approaches to apply the protective effect of HSPs against Ism-Reper induced injury to the clinical situation. Our very recent findings indicate that 80-90% of myocytes can be infected by adenoviral vectors expressing specific HSPs after perfusion of hearts. Such hearts and myocytes or muscle strips derived from them are used to determine the dose response and time course of protective effects of specific HSPs against Ism-Reper. Results obtained from these investigations of protective effects of specific HSPs against Ism-Reper induced myocardial injury may lead in the future to new treatment strategies for ischemic heartdisease.

缺血性心脏病是一个重大的临床问题，并且在上一个赠款期间获得的结果时期表明，特异性热激蛋白（HSP）的表达增加具有保护作用反对缺血 - 重新灌注（ISM-REPER）诱导的心肌损伤。与 HSP对ISM-Reper诱导的心肌损伤的保护作用尚未得到解答。我们将在目标I中确定小型HSP，AB-Crystallin和HSP27是否具有针对ISM-Reper的保护作用自行诱发伤害，彼此结合，以及HSP70家庭成员。腺病毒载体在感染后高水平表达小型HSP AB-晶状体和HSP27 心肌细胞已经产生，并在初步研究中表现出保护作用。此外，表达AB-晶状体蛋白和HSP27的转基因小鼠可用于这些研究。目标 II我们将确定特定HSP（例如诱导HSP70（HSP70I））的保护作用的基础，本构型HSP70以及针对ISM-Reper诱导损伤的小型HSP AB-晶状体和HSP27 尤其是细胞凋亡和坏死和心肌功能降低的细胞死亡。初步发现表明HSP70I HASA保护作用的表达增加了对ISM再生凋亡的表达介导的细胞死亡。我们使用共聚焦显微镜的初步发现表明增加了针对特定细胞骨架结构对缺血诱导的特定细胞骨架结构的保护表达伤害也将进一步探索。在AIM III中，我们想调查应用新颖的方法 HSP对ISM-Re-Reper诱导临床状况的损伤的保护作用。我们最近的调查结果表明，80-90％的肌细胞可以被表达特定的腺病毒载体感染灌注后HSP。使用了从中得出的心脏，心肌或肌肉条确定特定HSP对ISM-Reper的保护作用的剂量响应和时间过程。从这些针对ISM reper的特定HSP的保护作用的研究中获得的结果诱导的心肌损伤可能会导致缺血性心脏疾病的新治疗策略。