Identification of immunotherapeutic targets in cardiovascular disease

项目摘要。 心肌梗死（MI）和新生内膜增生（NH）是冠心病患者的常见合并症， 心脏病-一种潜伏的疾病，包括大多数与心血管疾病（CVD）相关的疾病， mortality.急性心肌梗死后，冠状动脉血管闭塞导致持续性心脏纤维化和心肌梗死。 配对心功能冠状动脉血流的恢复通常通过支架置入来实现，但 过度的细胞向内生长和病理性NH形成仍然很高。因此，最佳治疗策略 急性心肌梗死必须集中于减少心脏纤维化和新生内膜形成。越来越多的证据表明 炎症调节心血管疾病的进展，但很少有工作集中在发展有针对性的免疫， 调节疗法因此，本建议的目标是：1）开发新的实验和计算机， 确定和评估CVD中靶向免疫治疗策略的方法; 2） 建立一个集中的培训期，使Bersi博士具备过渡到 独立研究立场。在指导K99阶段，Bersi博士将研究细胞的表达如何- 细胞粘附蛋白钙粘蛋白-11（CDH 11）在不同的细胞谱系中调节炎症和组织重塑， 与MI和NH相关的eling（目的1）。通过利用CDH 11的免疫调节潜力，他将获得- 将组织特异性重塑与伴随的CAR后的免疫细胞定位和细胞因子分泌相关， 血管损伤免疫介导的胶原蛋白沉积的实验信息计算模型， 平滑肌细胞增殖将用于鉴定组织的主要分子和细胞驱动因素， 特异性损伤反应（目标2）。在独立R 00阶段，Dr. Bersi将使用拟定的计算机模拟 模型，以产生新的免疫假说（目标2），并将评估模型预测， 评估合理设计的免疫治疗对减少病理组织的功效 MI和NH中的重构（目的3）。尽管Bersi博士在软组织生物力学方面具有重要的专业知识， 计算建模，额外的智力和技术培训将需要实现他的职业目标 研究CVD中力学和炎症之间的多尺度关系。快乐人和 哈里森实验室是获得此类培训的理想场所，因为梅里曼博士是心肺机械方面的专家。 哈里森博士是心血管免疫学和药理学方面的专家。接受的培训 在整个奖项将允许博士贝尔西成功过渡到一个独立的研究职位，并领导 一个多方面的，R 01资助，研究实验室专注于力学，建模，和炎症心血管疾病。在 总之，Bersi博士将利用这个K99/R 00奖建立多尺度实验和计算技术， 以指导免疫治疗策略的合理发现和评估， 炎症性心血管疾病该项目将为使用靶向免疫疗法奠定基础- 这将决定Bersi博士长期职业生涯的轨迹。

Project Summary. Myocardial infarction (MI) and neointimal hyperplasia (NH) are common comorbidities in patients with coronary heart disease - an insidious condition that comprises the majority of all cardiovascular disease (CVD)-related mortality. Following acute MI, occlusion of the coronary vasculature leads to persistent cardiac fibrosis and im- paired cardiac function. Restoration of coronary blood flow is often achieved by stent placement, but rates of excessive cellular ingrowth and pathologic NH formation remain high. Thus, optimal treatment strategies for acute MI must focus on reducing both cardiac fibrosis and neointima formation. Increasing evidence suggests inflammation regulates CVD progression, but little work has focused on the development of targeted immuno- modulatory therapies. Therefore, the objectives of this proposal are: 1) develop novel experimental and compu- tational approaches to identify and evaluate targeted immunotherapeutic treatment strategies in CVD and 2) establish a concentrated period of training that will equip Dr. Bersi with the expertise needed to transition to an independent research position. In the mentored K99 phase, Dr. Bersi will investigate how expression of the cell- cell adhesion protein cadherin-11 (CDH11) in diverse cellular lineages regulates inflammation and tissue remod- eling associated with MI and NH (Aim 1). By leveraging the immunomodulatory potential of CDH11, he will cor- relate tissue-specific remodeling with immune cell localization and cytokine secretion following concomitant car- diovascular injury. Experimentally-informed computational models of immune-mediated collagen deposition and smooth muscle cell proliferation will be used to identify the primary molecular and cellular drivers of tissue- specific injury responses (Aim 2). In the independent R00 phase, Dr. Bersi will utilize the proposed in silico models to generate novel immunotherapeutic hypotheses (Aim 2) and will evaluate model predictions by as- sessing the efficacy of rationally-designed immunotherapeutic treatments on the reduction of pathologic tissue remodeling in MI and NH (Aim 3). Though Dr. Bersi has significant expertise in soft tissue biomechanics and computational modeling, additional intellectual and technical training will be needed to realize his career goals of investigating the multiscale relationship between mechanics and inflammation in CVD. The Merryman and Harrison labs are ideal locations to acquire such training as Dr. Merryman is an expert in cardiopulmonary mech- anobiology and Dr. Harrison is an expert in cardiovascular immunology and pharmacology. The training received throughout this award will allow Dr. Bersi to successfully transition to an independent research position and lead a multi-faceted, R01-funded, research laboratory focused on mechanics, modeling, and inflammation in CVD. In summary, Dr. Bersi will utilize this K99/R00 award to establish multiscale experimental and computational tech- niques in order to guide the rational discovery and assessment of immunotherapeutic treatment strategies in inflammatory cardiovascular disorders. This project will lay the foundation for the use of targeted immunothera- pies in CVD and will define the trajectory of Dr. Bersi’s long-term career.