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Generation of Endothelial Cell Memory in Inflammatory Vascular Disease

炎症性血管疾病中内皮细胞记忆的产生

基本信息

批准号：
10671561
负责人：
Suellen D'Arc dos Santos Oliveira
金额：
$ 16.2万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-27 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10671561
关键词：
Abnormal Endothelial Cell Acute Address Animal Model Anti-Inflammatory Agents Antigens Apoptosis Apoptotic Area Blood Vessels Brazil Caveolins Cell Death Cell Death Induction Cell Survival Cell secretion Cells Cessation of life Characteristics Chicago Chronic Chronic Lung Injury Collaborations Communities Creativeness Cultural Backgrounds Curiosities Cytometry Cytoprotection Data Dedications Development Development Plans Disease Doctor of Philosophy Endothelial Cells Endothelium Environment Evaluation Faculty Fibrosis Functional disorder Generations Goals Growth Human Illinois Immune Immunity Immunobiology Impairment In Vitro Induction of Apoptosis Infection Inflammation Inflammatory Injury Institution Knowledge Leadership Learning Lesion Life Lung Lymphocyte Mediating Memory Mentors Methodology Modeling Molecular Target Mus Parasites Parasitic infection Persons Pharmacology Phase Phenotype Phosphorylation Process Proliferating Pulmonary Fibrosis Pulmonary Heart Disease Pulmonary Inflammation Pulmonary vessels Reporting Research Research Personnel Research Project Summaries Research Subjects Resistance Scaffolding Protein Schistosoma mansoni Schistosoma mansonii infection Signal Transduction Smooth Muscle Myocytes Students Technical Expertise Testing Th2 Cells Therapeutic Embolization Tissues Training Transforming Growth Factor beta Universities Vascular Diseases Vascular Proliferation Vascular remodeling Vesicle Voice Woman career career development caveolin 1 chemokine clinical development cytokine distinguished professor egg experience hypertension treatment imprint in vivo inhibitor inhibitor of apoptosis protein 2 injured insight inter-institutional lectures lung pressure molecular modeling novel overexpression pathogen pharmacologic pre-clinical prevent pulmonary arterial hypertension receptor recruit response skills success superresolution microscopy targeted treatment

项目摘要

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.

研究项目概述：肺动脉高压（PAH）是一种危及生命的疾病，无法治愈其特征在于由于血管细胞的过度增殖导致的肺血管中的严重损伤，包括内皮细胞。这些病变的主要原因在很大程度上是未知的，但一些研究表明，它们由慢性炎症引起，例如由曼氏血吸虫感染引起的炎症。约1000万人感染S. mansoni发展为PAH（Sch-PAH）。因此，更好地了解感染如何促进血管病变的形成将为识别肺动脉高压治疗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，其表达减少，抗增殖支架蛋白小窝蛋白-1（Cav-1）和对促纤维化TGF-β信号传导的升高的反应。 TGF-β的激活需要Th2细胞募集到肺中，这反过来又使Cav-1耗尽的内皮细胞和促进PAH。尽管不清楚Cav-1缺失的内皮细胞如何促进 Sch-PAH，我们的初步数据表明，凋亡抑制蛋白2（c-IAP 2）的表达增强可能参与这个过程。根据这一观察，数据表明，S。曼氏致敏内皮细胞在体外保留体内感染的记忆。具体来说，这种记忆的特点是功能受损死亡相关受体P2X7，其由Cav-1表达控制。因此，我假设， S. mansoni感染导致肺内皮细胞死亡和c-IAP 2分泌，受体细胞产生长- 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：奥利维拉博士是芝加哥伊利诺伊大学的初级教师（UIC）。她获得了博士学位。里约联邦大学免疫生物学硕士和药理学硕士巴西里约热内卢作为一名拉丁妇女，她在不同的文化背景中长大，因此，了解到多样性是人类经验和存在本身的重要组成部分。奥利维拉博士的职业生涯发展计划结合了她在研究生和研究生培训中获得的知识和技术专长通过新颖的方法和研究主题，建立一个独特的轨迹，成为一个全面的独立调查员具体来说，奥利维拉博士建议提高她的领导能力，加强她的领导能力，机构间网络，在其机构内外提供和组织讲座，并进一步参与指导和学生评估。为了实现这些目标，奥利维拉博士建立了一个团队，杰出的教授从专业知识的领域需要为科学和专业的成功，职业发展计划。在环境方面，奥利维拉博士位于一个著名的研究致力于发现和传播知识的机构。因此，随着她的专业成长，博士沿着。奥利维拉计划通过让所有的声音参与到一个这是持续科学进步和机构卓越所需的包容性和创造性环境。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Schistosomiasis-associated pulmonary hypertension unveils disrupted murine gut-lung microbiome and reduced endoprotective Caveolin-1/BMPR2 expression.

DOI：
10.3389/fimmu.2023.1254762
发表时间：
2023
期刊：
FRONTIERS IN IMMUNOLOGY
影响因子：
7.3
作者：
Marinho, Ygor;Villarreal, Elizabeth S.;Aboagye, Sammy Y.;Williams, David L.;Sun, Jun;Silva, Claudia L. M.;Lutz, Sarah E.;Oliveira, Suellen D.
通讯作者：
Oliveira, Suellen D.

Thiostrepton-Nanomedicine, a TLR9 Inhibitor, Attenuates Sepsis-Induced Inflammation in Mice.