The role of S1P signaling in surgical cardiac remodeling

S1P信号在外科心脏重塑中的作用

• 批准号: 6956567
• 负责人: MICHAEL J MANN
• 金额: $ 12.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6956567
• 关键词: alcohol phosphotransferase; apoptosis; biomarker; cardiac myocytes; cardiovascular surgery; cell surface receptors; enzyme activity; gene induction /repression; heart failure; laboratory mouse; lysophospholipids; myocardial ischemia /hypoxia; receptor expression; sphingosine; ventricular hypertrophy

DESCRIPTION (provided by applicant): The applicant hopes to establish an investigative program that links the dissection of molecular pathways of cardiomyocyte growth and survival with the development of surgical interventions for heart disease. The rich collaborative environment at UCSF and the support for active involvement in both cardiothoracic surgery and molecular research are expected to foster this goal. The current proposal would help form a basis for such a long term program by demonstrating the feasibility of analyzing cardiomyocyte signaling in the context of an experimental procedure for ischemic heart failure. Early generations of surgical interventions for heart failure, based on left ventricular (LV) geometry, have failed to account for complexities of myocardial biology, including apoptotic loss of cardiomyocytes and progressive thinning and fibrosis of the peri-infarct zone. Sphingosine-1-phosphate (S1P) has been associated both with cellular hypertrophy and with protection from apoptosis in cardiac myocytes. It is therefore hypothesized that a drop in S1P signaling accompanies infarct extension and cardiomyopathy after chronic LV infarction. It is further postulated that therapeutic cardiac remodeling (TCP) achieved via ventricular scar resection is associated with an increase in S1P signaling that leads to a reduction in cardiomyocyte apoptosis and an adaptive hypertrophic response in the remaining myocardium. To test these hypotheses, a mouse model of chronic coronary ligation will be used to analyze S1P receptor 1 (S1Pi) expression and responsiveness, as well as the activity and expression of sphingosine kinase 1 (SphK1), an enzyme that regulates the balance between pro-apoptotic ceramide and anti-apoptotic S1P. This activity will be correlated to cardiomyocyte apoptosis and to changes in LV structure and function. S1P signaling will then be studied in the context of ventricular scar resection, and correlated to changes in ventricular wall structure and function. Finally, pharmacologic stimulation of SphK1 and gene transfer of S1 P! And of SphK1 will test the feasibility of an intra-operative, molecular enhancement of surgical TCR. (End of Abstract)

描述（由申请人提供）： 申请人希望建立一个调查计划，该计划将心肌细胞生长和生存的分子途径与心脏病外科干预的发展联系起来。 UCSF的丰富协作环境以及积极参与心胸外科和分子研究的支持将促进这一目标。当前的建议将通过在实验性缺血性心力衰竭的过程中证明分析心肌细胞信号传导的可行性，有助于为这一长期计划构成基础。基于左心室（LV）几何形状基于心力衰竭的早期手术干预措施未能说明心肌生物学的复杂性，包括心肌细胞的凋亡损失以及渐进式稀疏和累积的纤维化和纤维化。 鞘氨氨酸1-磷酸盐（S1P）既与细胞肥大和免受心肌细胞凋亡的保护有关。因此，假设S1P信号的下降伴随着梗死的延伸和慢性LV梗死后的心肌病。进一步推测，通过心室疤痕切除获得的治疗性心脏重塑（TCP）与S1P信号的增加有关，这会导致剩余心肌中心肌细胞凋亡的降低和适应性肥大反应。为了检验这些假设，将使用慢性冠状结扎的小鼠模型来分析S1P受体1（S1PI）的表达和反应性，以及鞘氨醇激酶1（SPHK1）的活性和表达，该酶是一种调节促脑陶瓷陶瓷和抗抗焦点的平衡之间的平衡。该活性将与心肌细胞凋亡以及LV结构和功能的变化相关。然后，将在心室疤痕切除的背景下研究S1P信号传导，并与心室壁结构和功能的变化相关。最后，S1 P的SPHK1和基因转移的药理刺激！ SPHK1将测试手术TCR的术中分子增强的可行性。 （抽象的结尾）