Hypoxic inflammation, pulmonary hypertension, and HO-1

缺氧性炎症、肺动脉高压和 HO-1

• 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
• 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

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结合儿科强化医师的临床实践、旨在回答床边提出的关于疾病细胞和分子机制的问题的实验室调查，以及在临床和研究领域对实习生进行教育和指导，进入长期的学术医学职业生涯。在接下来的五年里，我希望加强我作为一名儿科重症医生的技能，但我也致力于将我的大部分时间投入到获得必要的技能和知识上，以便成为一名独立的内科科学家。具体地说，我打算在实验室发展我的技术和实验设计技能，通过课程工作增加我对基本分子和细胞生物学以及动物生理学的知识，并通过查阅文献和在实验室、部门、医院和国际会议的论坛上展示我的数据来增强我的分析和沟通技能。为实现这些目标而工作的环境将在波士顿儿童医院的肺和血管生物学家斯特拉·库伦巴纳斯博士的实验室中进行，他研究缺氧对血管系统的影响，以了解缺氧性肺动脉高压(PHTN)的发病机制。慢性低氧暴露可导致肺部炎症细胞浸润和细胞因子/趋化因子的表达，这可能在许多疾病过程中发挥作用。血红素氧合酶-1(HO-1)是一种低氧诱导的酶，具有抗缺氧性炎症和PHTN的作用。我的长期研究目标是了解缺氧导致PHTN的机制，以及HO-1对PHTN的保护作用。我假设在缺氧性炎症过程中释放的细胞因子和趋化因子引发肺血管的变化，从而导致PHTN，HO-1干扰了缺氧诱导炎性细胞因子和趋化因子释放的信号机制。本研究的具体目的是：(1)确定炎症是否在缺氧性PHTN的发生发展中起作用；(2)探讨HO-1抑制缺氧性PHTN炎症基因表达的机制；(3)评价HO-1‘S酶产物一氧化碳和胆红素对缺氧性PHTN的保护作用。实验设计采用了转基因小鼠的体内研究和在腺病毒介导的低氧细胞中HO-1基因转移的体外研究。这些研究将增加我们对缺氧诱导的炎症、缺氧性PHTN的发病机制以及HO-1在这两个过程中的保护作用的了解。