Identification of immunotherapeutic targets in cardiovascular disease

心血管疾病免疫治疗靶点的鉴定

• 批准号: 10438856
• 负责人: MATTHEW Ryan BERSI
• 金额: $ 24.9万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-04 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10438856
• 关键词: Acute myocardial infarction; Adoptive Cell Transfers; Age; Allogeneic Bone Marrow Transplantation; Animals; Antibodies; Arthritis; Atomic Force Microscopy; Award; Biological; Blood Vessels; Blood flow; Cardiac; Cardiac Myocytes; Cardiopulmonary; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cause of Death; Cell Adhesion Molecules; Cell Proliferation; Cell model; Cell-Cell Adhesion; Cells; Cessation of life; Cicatrix; Collagen; Combined Modality Therapy; Computational Technique; Computer Models; Congestive Heart Failure; Coronary; Coronary Occlusions; Coronary artery; Coronary heart disease; Cytokine Signaling; Data; Deposition; Development; Disease; Disease Progression; Enzyme-Linked Immunosorbent Assay; Fluorescence-Activated Cell Sorting; Foundations; Funding; Goals; Hematopoietic; Histologic; Hyperplasia; Immune; Immune system; Immunological Models; Immunology; Immunotherapeutic agent; Immunotherapy; Incidence; Inflammation; Inflammatory; Injury; Laboratory Research; Lead; Left; Ligation; Link; Location; Measures; Mechanics; Mediating; Mentors; Modeling; Molecular; Morphology; Mus; Myocardial Infarction; Myofibroblast; Outcome; Pathologic; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Polymerase Chain Reaction; Population; Positioning Attribute; Profibrotic signal; Property; Pulmonary Fibrosis; Research; Role; Signaling Molecule; Site; Smooth Muscle Myocytes; Stents; System; Techniques; Testing; Therapeutic; Time; Tissues; Training; Transgenic Mice; Vascular Smooth Muscle; Ventricular; Wild Type Mouse; Work; aortic valve disorder; base; biomechanical model; body system; cadherin-11; calcification; candidate identification; cardiovascular injury; career; comorbidity; computer framework; coronary artery occlusion; coronary fibrosis; coronary vasculature; cytokine; dimorphism; efficacy evaluation; femoral artery; heart function; immunomodulatory therapies; immunoregulation; in silico; in vitro Assay; injured; mortality; myocardial injury; neointima formation; novel; optimal treatments; percutaneous coronary intervention; predictive modeling; prevent; rational design; recruit; response; response to injury; restenosis; restoration; soft tissue; treatment strategy; ultrasound; vascular injury

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.

项目摘要。 心肌梗塞（MI）和新内膜增生（NH）是冠状动脉患者的常见合并症 心脏病 - 一个阴险的病，包括所有心血管疾病（CVD）相关的大多数 死亡。急性MI之后，冠状动脉的阻塞会导致持续的心脏纤维化和IM- 配对心脏功能。冠状动脉血流的恢复通常是通过放置支架来实现的，但是 过度的细胞内膜和病理NH的形成仍然很高。那，最佳治疗策略 急性MI必须集中于减少心脏纤维化和新内膜形成。越来越多的证据表明 炎症调节了CVD的进展，但很少的工作集中在目标免疫的发展上 调节疗法。因此，该提案的目标是：1）开发新型实验和组成 识别和评估CVD中有针对性的免疫治疗策略的方法和评估2） 建立一个集中的培训期，将使Bersi博士拥有过渡到一个的专业知识 独立研究职位。在物质K99阶段，Bersi博士将研究细胞的表达如何 细胞粘合剂蛋白钙粘蛋白11（CDH11）中的细胞谱系中调节注射和组织重塑 与Mi和NH相关的Eling（AIM 1）。通过利用CDH11的免疫调节潜力，他将 在伴随汽车后，将组织特异性重塑与免疫细胞定位和细胞因子分泌相关联 双血管损伤。免疫介导的胶原蛋白沉积的实验信息计算模型和 平滑肌细胞增殖将用于识别组织的一级分子和细胞驱动因素 特定的伤害反应（AIM 2）。在独立的R00阶段，Bersi博士将利用硅 产生新型免疫治疗假设的模型（AIM 2），并将通过AS-评估模型预测 在病理组织还原方面理性设计的免疫治疗效率 在MI和NH中进行重塑（AIM 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和 计算建模，需要其他知性和技术培训以实现他的职业目标 调查CVD中力学与炎症之间的多尺度关系。快乐的人和 哈里森实验室是获得诸如Merryman博士是心肺机械专家之类的培训的理想位置。 Anobiology和Harrison博士是心血管免疫学和药理学专家。接受的培训 在整个奖项中 由CVD中的机械，建模和炎症的多方面，R01资助的研究实验室。在 摘要，Bersi博士将利用此K99/R00奖来建立多尺度实验和计算技术 - 为了指导合理发现和评估免疫治疗策略 炎症性心血管疾病。该项目将奠定基础，用于使用目标免疫疗法 CVD中的派，将定义Bersi博士长期职业的轨迹。