Molecular mechanisms of hypoxia tolerance and susceptibility

本项目（PPG）再次提交给NIH，其中心目标是研究心脏、肺和大脑对短期（持续或间歇性）和长期缺氧的易感性或耐受性的分子机制。这个PPG有三个项目和两个科学核心，总部设在加州大学圣地亚哥分校（UCSD），包括来自姐妹机构（如伯纳姆研究所）的科学家。它旨在推进生物医学知识，并对我们对细胞和组织对缺氧耐受的基础的理解产生重大影响，目的是提高我们诊断和治疗疾病的能力。根据我们所有的初步数据，我们制定了一个具有双重目的的PPG: a)加强我们对特定细胞和组织对心肺系统中持续或间歇性低氧的易感性或耐受性的基本和基本机制的理解；b)使哺乳动物中的易感细胞对这些压力具有抵抗力，最终目的是将基本机制转化为临床有用的结果。由于本计划的每个项目都有证据表明Notch信号是缺氧的重要途径，因此每个项目都以Notch为中心，研究Notch如何与其他重要的Notch活性调节剂（无论是Toll、HIF1还是胰岛素受体）相互作用。这两个核心将对PPG至关重要，因为它们将执行特定的功能，提高科学和实验的质量，降低成本，促进项目之间的协同作用，并提供基因途径的综合生物学观点（系统生物学和动物缺氧核心）。PPG的总体目标是：a)在细胞和分子水平上研究心血管和呼吸系统对缺氧的适应机制；b)在果蝇模型中研究耐受的基本遗传机制；C)调节/操纵哺乳动物细胞/组织/动物的分子机制，使其在向耐氧生物（如苍蝇）学习后具有耐氧能力；d)鉴定可能具有临床预测性的低氧耐受性和易感性的分子特征。我们相信这种PPG将对我们理解各种疾病的细胞和分子机制产生重大影响，包括阻塞性睡眠呼吸暂停及其相应的心脏和神经组织损伤、心脏缺氧和心肌损伤、镰状细胞病和心血管、呼吸和神经损伤以及COPD和心肺后果。

This Program Project (PPG) is re-submitted to the NIH with the central objective of studying the molecular mechanisms of susceptibility or tolerance to short term (constant or intermittent) and long term hypoxia in heart, lung and brain. This PPG has three Projects and two scientific Cores, is based at the University of California San Diego (UCSD) and includes scientists from sister institutions (e.g., the Burnham Institute). It is designed to advance biomedical knowledge and make a high impact on our understanding of the basis of cell and tissue tolerance to hypoxia with the purpose to advance our ability to diagnose and treat disease. As a result of all of our preliminary data, we have formulated a PPG with a two-fold thrust: a) To enhance our understanding of the basic and fundamental mechanisms underlying susceptibility or tolerance of specific cells and tissues to constant or intermittently low O2 in the cardio-respiratory system and b) to render susceptible cells in mammals resistant to these stresses, with the ultimate aim to translate basic mechanisms into clinically useful outcomes. Since every Project in this Program has evidence for considering Notch signaling as a central important pathway in hypoxia, each Project centers on Notch and investigates how Notch interacts with other important modulators of Notch activity, whether it is Toll, HIF1, or insulin receptor. The two Cores will be essential to the PPG since they will carry out specific functions that enhance the quality of the science and experiments, cut costs, fosters synergy between Projects and provide an integrative biological view of gene pathways (Systems biology and Animal Hypoxia Cores). The overall Specific Aims of the PPG are: a) To study the adaptive mechanisms to hypoxia in cardiovascular and respiratory systems at both cellular and molecular levels; b) to study the fundamental genetic mechanisms of tolerance in a Drosophila model; c) to modulate/manipulate molecular mechanisms in mammalian cells/tissues/animals to render them hypoxia-tolerant after learning from a tolerant organism, e.g., the fly; and d) to identify molecular signatures of hypoxia tolerance and susceptibility that may be predictive clinically. We believe that this PPG will have a major impact on our understanding of the cellular and molecular mechanisms that underlie a variety of diseases including obstructive Sleep Apnea and its consequential cardiac and neurologic tissue injury, cardiac hypoxia and cardiac muscle injury, Sickle Cell Disease and cardiovascular, respiratory and neurologic injury as well as COPD and cardio-respiratory consequences.