Generation of Endothelial Cell Memory in Inflammatory Vascular Disease

研究项目摘要：肺动脉高压(PAH)是一种危及生命的疾病 无药可救 以血管细胞过度增殖导致的肺血管严重损害为特征， 包括内皮细胞。这些损伤的主要原因在很大程度上尚不清楚，但几项研究表明 它们是由慢性炎症引起的，例如由曼氏血吸虫感染引起的炎症。~1000万人 感染曼氏沙门氏菌可产生多环芳烃(SCH-PAH)。因此，更好地理解感染是如何促进 血管病变的形成将为寻找治疗PAH的新分子靶点提供见解。 最近，我们报道了在慢性肺损伤中存活的内皮细胞，表现出表达减少的 抗增殖支架蛋白小窝蛋白-1(CAV-1)和对促纤维化的转化生长因子-β信号的反应增强。 转化生长因子-β的激活需要Th2细胞重新进入肺内，这反过来又扩大了耗尽的Cav-1 促进血管内皮细胞的增殖，促进PAH。尽管尚不清楚Cav-1耗尽的内皮细胞如何参与 我们的初步数据表明，凋亡抑制蛋白2(c-IAP2)的表达增强可能 参与这一进程。与此观察一致的是，数据表明曼氏链球菌刺激的内皮细胞 在体外保留体内感染的记忆。具体地说，这种记忆的特征是功能受损 死亡相关受体P2X7，受Cav-1表达控制。因此，我假设，虽然 曼氏杆菌感染导致肺内皮细胞死亡和c-IAP2的分泌，受体细胞产生长时间的 内皮免疫细胞串扰和SCH-PAH发展所需的持久生存记忆。 候选人和机构环境：奥利维拉博士是伊利诺伊大学芝加哥分校初级教员 (UIC)。她获得了免疫生物学博士学位和理学硕士学位。里约联邦大学药理学专业 巴西，德热内卢。作为一名拉丁女性，她成长于不同的文化背景，因此， 了解了多样性如何成为人类体验和存在本身的重要部分。奥利维拉医生的职业生涯 发展计划结合了她从研究生和研究生培训中获得的知识和技术专长 用新的方法和研究主题建立一条独特的轨迹，朝着成为一个完全 独立调查员。具体地说，奥利维拉博士建议提高她的领导技能，增强她的能力 机构间网络，在机构内外提供和组织讲座，并进一步 从事辅导和学生评价工作。为了实现这些目标，奥利维拉博士组建了一个团队， 来自科学和专业成功所需专业知识领域的尊敬的教授们 她的职业发展计划。在环境方面，奥利维拉博士参与了一项广受好评的研究 致力于发现和传播知识的机构。因此，在她的职业成长过程中，Dr。 奥利维拉计划通过让所有声音参与到一个 持续的科学进步和机构卓越所需的包容性和创造性的环境。

Summary of the Research Project: Pulmonary arterial hypertension (PAH) is a life-threatening disease with no cure characterized by severe lesions in the pulmonary vessels due to hyperproliferation of vascular cells, including endothelial cells. The primary cause of these lesions is largely unknown, but several studies indicate they result from chronic inflammation, such as that caused by Schistosoma mansoni infection. ~10 million people infected with S. mansoni develop PAH (Sch-PAH). Thus, a better understanding of how the infection promotes the formation of vascular lesions will provide insights for identifying novel molecular targets for PAH treatment. Recently, we reported that endothelial cells that survive to chronic lung injury, show reduced expression of the anti-proliferative scaffolding protein caveolin-1 (Cav-1) and elevated response to pro-fibrotic TGF-β signaling. Activation of TGF-β requires recruitment of Th2 cells into the lungs, which in turn expands Cav-1 depleted endothelial cells and promote PAH. Although it is unknown how Cav-1-depleted endothelial cells contribute to Sch-PAH, our preliminary data indicate enhanced expression of inhibitor of apoptosis protein 2 (c-IAP2) may participate in this process. In line with this observation, data suggest that S. mansoni-primed endothelial cells retain in vitro a memory of the in vivo infection. Specifically, this memory is characterized by impaired function of the death associated receptor P2X7, which is controlled by Cav-1 expression. Thus, I hypothesize that while S. mansoni infection leads to lung endothelial cell death and secretion of c-IAP2, recipient cells generate a long- lasting survival memory required for endothelial-immune cell crosstalk and the development of Sch-PAH. Candidate & Institutional Environment: Dr. Oliveira is Junior Faculty at the University of Illinois at Chicago (UIC). She earned her Ph.D. in Immunobiology and M.Sc. in Pharmacology from the Federal University of Rio de Janeiro, Brazil. As a Latin woman, she grew up surrounded by different cultural backgrounds, and thus, learned how diversity is a crucial part of the human experience and existence itself. Dr. Oliveira’s career development plan combines the knowledge and technical expertise from her graduate and post-graduate training with novel methodologies and research subjects to build up a unique trajectory toward becoming a fully independent investigator. Specifically, Dr. Oliveira proposes advancing her leadership skills, strengthening her inter-institutional network, providing and organizing lectures inside and outside of her institution, and further engaging in mentoring and student evaluation. To achieve these goals, Dr. Oliveira built a team with distinguished Professors from the areas of expertise needed for both the scientific and professional success of her career development plan. In terms of the environment, Dr. Oliveira is located in an acclaimed research institution dedicated to discovering and distributing knowledge. Thus, along with her professional growth, Dr. Oliveira plans to promote the growth of the academic community as a whole by engaging all voices into an inclusive and creative environment required for continuous scientific progress and institutional excellence.