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.

研究项目的摘要：肺动脉高压（PAH）是一种威胁生命的疾病无法治愈由于血管细胞的过度增殖，其特征是肺部视频中的严重病变，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，但几项研究表明它们是由慢性感染引起的，例如由曼森血吸虫感染引起的。〜1000万人感染了S. Mansoni发展PAH（Sch-Pah）。这是对感染如何促进的更好理解血管病变的形成将为鉴定新的分子靶标提供见解。最近，我们报道了生存为慢性肺损伤的内皮细胞，显示出降低的表达抗增殖的脚手架蛋白小窝蛋白1（CAV-1）和对纤维化TGF-β信号的反应升高。 TGF-β的激活需要将Th2细胞募集到肺部，进而扩展Cav-1耗尽内皮细胞并促进PAH。尽管尚不清楚Cav-1缺乏的内皮细胞有助于 Sch-Pah，我们的初步数据表明凋亡蛋白2（C-IAP2）的抑制剂表达增强了参加此过程。与此观察一致，数据表明S. mansoni-primed内皮细胞保留体内感染的体外记忆。具体而言，此内存的特征是功能受损与死亡相关的接收器P2X7的控制，该接收器由CAV-1表达控制。那我假设曼氏链球菌感染导致肺内皮细胞死亡和C-IAP2的分泌，受体细胞会产生长期内皮免疫细胞串扰和Sch-Pah的发展所需的持久存活记忆。候选人与机构环境：Oliveira博士是伊利诺伊大学芝加哥大学的初级教师（UIC）。她获得了博士学位在免疫生物学和硕士学位里约联邦大学的药理学巴西的德·贾尼罗（De Janeiro）。作为拉丁女人，她长大了，被不同的文化背景所包围，因此了解了人类经验和生存本身的重要组成部分多样性。奥利维拉博士的职业发展计划结合了她的研究生和研究生培训的知识和技术专长通过新颖的方法和研究对象，建立了独特的轨迹，以成为一个完全独立研究者。特别是，奥利维拉博士的提议提高了她的领导能力，增强了她机构间网络，在其机构内外提供和组织讲座，并进一步从事心理和学生评估。为了实现这些目标，奥利维拉博士与杰出的教授与科学和专业成功所需的专业知识领域她的职业发展计划。在环境方面，奥利维拉博士位于一项广受赞誉的研究中致力于发现和分发知识的机构。随着她的专业成长，博士奥利维拉（Oliveira）计划通过使所有声音参与整个学术界的成长持续的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）

Cardiopulmonary Pathogenic Networks: Unveiling the Gut-Lung Microbiome Axis in Pulmonary Arterial Hypertension.

DOI：
10.1164/rccm.202211-2126ed
发表时间：
2023-03-15
期刊：
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
影响因子：
24.7
作者：
Oliveira, Suellen Darc
通讯作者：
Oliveira, Suellen Darc

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.