Hypoxic inflammation, pulmonary hypertension, and HO-1

描述（由申请人提供）： 我的长期职业目标是将联合收割机临床实践与儿科重症监护医师、实验室研究相结合，以回答在床边提出的有关疾病的细胞和分子机制的问题，并在临床和研究领域对受训者进行教育和指导，使其成为长期的、令人满意的学术医学职业。在接下来的五年里，我希望加强我作为儿科重症监护医师的技能，但我也致力于投入大部分时间来获得必要的技能和知识，以便作为一名独立的医生科学家取得成功。具体来说，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的基本分子和细胞生物学和动物生理学知识，并通过文献综述和在实验室，部门，医院和国际会议论坛上介绍我的数据来提高我的分析和沟通能力。实现这些目标的环境将在波士顿儿童医院的肺和血管生物学家Stella Kourembanas博士的实验室中进行，他研究缺氧对血管系统的影响，以了解缺氧诱导的肺动脉高压（PHTN）的发病机制。暴露于慢性缺氧导致肺中的炎性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。血红素氧合酶-1（HO-1）是一种缺氧诱导酶，具有保护缺氧炎症和PHTN的作用。我的长期研究目标是了解缺氧导致PHTN和HO-1保护PHTN的机制。我假设在缺氧炎症过程中释放的细胞因子和趋化因子触发了导致PHTN的肺血管系统的变化，并且HO-1干扰了缺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。该项目的具体目标是：（i）确定炎症是否在缺氧PHTN的发展中起致病作用，（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的酶产物一氧化碳和胆红素对缺氧PHTN的保护作用。实验设计采用转基因小鼠的体内研究和在缺氧细胞中使用腺病毒介导的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理解。

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.