Hypoxic inflammation, pulmonary hypertension, and HO-1

缺氧性炎症、肺动脉高压和 HO-1

基本信息

批准号：
7681167
负责人：
SALLY H Harrison Huntoon
金额：
$ 12.86万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-19 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7681167
关键词：
1-Phosphatidylinositol 3-Kinase Acute Adenovirus Vector Animals Anti-Inflammatory Agents Anti-inflammatory Antioxidants Bilirubin Biliverdine Blood Vessels Boston Breathing Carbon Monoxide Cells Childhood Chronic Clinical Research Commit Communication Cultured Cells Cytokine Receptors Data Development Disease Education Employee Strikes Enzymes Experimental Designs Exposure to Ferritin Gene Expression Gene Transfer Goals Heart Heme Histologic Hospitals Hour Hypoxia In Vitro Infiltration Inflammation Inflammatory Inflammatory Response International Investigation Iron Knockout Mice Knowledge Laboratories Lead Lung Lung Inflammation MAP Kinase Gene Mediating Medicine Mentors Molecular Molecular and Cellular Biology Mus Nitric Oxide Pathogenesis Pediatric Hospitals Physicians Physiology Play Process Production Property Proteins Pulmonary Hypertension Research Research Personnel Review Literature Right Ventricular Hypertrophy Role Scientist Shock Signal Pathway Signal Transduction Smooth Muscle Myocytes Stimulus Testing Time Transgenic Mice Vascular Endothelial Cell Vascular remodeling Vasodilator Agents Ventricular Wild Type Mouse Work Workplace adenoviral-mediated career chemokine clinical practice cytokine heme oxygenase-1 in vivo meetings monocyte neutralizing antibody neutrophil programs protective effect response skills vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): My long-term career goal is to combine clinical practice as a pediatric intensivist, laboratory investigation directed toward answering questions raised at the bedside about the cellular and molecular mechanisms of disease, and education and mentoring of trainees in both the clinical and research arenas into long-term, fulfilling career in academic medicine. In the next five years, I hope to strengthen my skills as a pediatric intensivist but I am also committed to devoting the majority of my time to acquire the necessary skills and knowledge in order to succeed as an independent physician-scientist. Specifically, I intend to develop my technical and experimental design skills in the laboratory, increase my knowledge of basic molecular and cellular biology and animal physiology through course work, and enhance my analytical and communication skills through literature review and presentations of my data in the forums of laboratory, division, hospital, and international meetings. The environment for working toward these goals will be in the laboratory of Dr. Stella Kourembanas, a lung and vascular biologist at Children's Hospital Boston who studies the effects of hypoxia on the vasculature in order to understand the pathogenesis of hypoxia-induced pulmonary hypertension (PHTN). Exposure to chronic hypoxia causes inflammatory cell infiltrate and cytokine/chemokine expression in the lung which may play a role in a number of disease processes. Heme oxygenase-1 (HO-1) is a hypoxia-inducible enzyme with actions that protect against hypoxic inflammation and PHTN. My long-term research goal is to understand the mechanisms by which hypoxia causes PHTN and HO-1 protects against PHTN. i hypothesize that cytokines and chemokines released during hypoxic inflammation trigger changes of the pulmonary vasculature that lead to PHTN and that HO-1 interferes with the signaling mechanisms by which hypoxia induces this inflammatory cytokine and chemokine release. The specific aims of the proposed project are (i) to determine whether inflammation plays a causative role in the development of hypoxic PHTN, (ii) to investigate the mechanisms by which HO-1 inhibits inflammatory gene expression induced by hypoxia, and (iii) to evaluate the protective effects of HO-1's enzymatic products, carbon monoxide and bilirubin, on hypoxic PHTN. The experimental design employs both in vivo studies in transgenic mice and in vitro studies using adenoviral-mediated gene transfer of HO-1 in hypoxic cells. These studies will increase our understanding of hypoxia-induced inflammation, the pathogenesis of hypoxic PHTN, and the protective actions of HO-1 in both processes.

描述（由申请人提供）：我的长期职业目标是将临床实践与儿科强化主义者，实验室调查相结合，旨在回答有关疾病细胞和分子机制的床边提出的问题，以及在临床和研究领域的教育和指导，以长期的教育和指导，以使学术医学中的职业成熟。在接下来的五年中，我希望能够增强作为儿科浓缩主义者的技能，但我也致力于将大部分时间用于获得必要的技能和知识，以便成为独立的医师科学家。具体来说，我打算在实验室中发展我的技术和实验设计技能，通过课程工作来提高我对基本分子和细胞生物学的了解，并通过文献综述以及在实验室，部门，医院和国际会议上对数据的介绍以及对数据的介绍来增强我的分析和沟通技巧。实现这些目标的环境将是波士顿儿童医院的肺和血管生物学家斯特拉·库里姆巴纳斯（Stella Kourembanas）博士的实验室，他研究了缺氧对血管系统的影响，以便了解缺氧诱发的肺部高血压（PHTN）的发病机理。暴露于慢性缺氧会导致肺部炎症细胞浸润和细胞因子/趋化因子表达，这可能在许多疾病过程中起作用。血红素氧酶-1（HO-1）是一种可诱导的低氧酶，可防止低氧炎症和PHTN。我的长期研究目标是了解缺氧导致PHTN和HO-1预防PHTN的机制。我假设在缺氧炎症期间释放的细胞因子和趋化因子会触发导致PHTN的肺脉管系统的变化，并且HO-1会干扰低氧诱导这种炎性细胞因子和趋化因子释放的信号传导机制。拟议项目的具体目的是（i）确定炎症在低氧PHTN的发展中是否起因作用，（ii）研究HO-1抑制缺氧诱导的炎症基因表达的机制，以及（III）评估HO-1的酶促产物的保护作用，碳氧化碳一氧化氧化物和bilirirubirubirubirubic phttn of Ho-1的保护作用。实验设计使用腺病毒介导的HO-1在低氧细胞中的基因转移基因转移，在转基因小鼠和体外研究中采用体内研究。这些研究将增加我们对缺氧引起的炎症，低氧PHTN的发病机理以及HO-1在这两个过程中的保护作用的理解。