Variant Hemoglobin and Cardiorespiratory Regulation in Humans

人类变异血红蛋白和心肺调节

• 批准号: 10532798
• 负责人: MICHAEL J JOYNER
• 金额: $ 80.62万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-19 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532798
• 关键词: Acute; Address; Affect; Affinity; Air; Altitude; Binding; Blood; CCL4 gene; Chronic; Clinic; Clinical; Complex; Congestive Heart Failure; Defect; Disease; Dissociation; Educational process of instructing; Elements; Evolution; Hemoglobin; Human; Hypoxia; Left; Life; Lung; Measures; Mitochondria; Molecular; Molecular Medicine; Muscle Mitochondria; Nature; Oxygen; Patients; Pharmaceutical Preparations; Physiological; Physiology; Population; Process; Property; Pulmonary Diffusing Capacity; Qualifying; Regulation; Risk Taking; Sentinel; System; Tissues; Translating; Translations; Variant; Work of Breathing; design; drug repurposing; experience; experimental study; flexibility; follow-up; healthy volunteer; idiopathic pulmonary fibrosis; insight; oxygen transport; response; tissue oxygenation; translational potential

Abstract I am seeking an R35 to address the fundamental issue of how right and left shifts in the O2 hemoglobin dissociation curve influence oxygen transport in humans. I am also proposing to translate key findings to the treatment of diseases with specific defects in the O2 transport cascade like idiopathic pulmonary fibrosis and/or congestive heart failure. I am also proposing reverse translation from observations in patients to more basic studies on O2 delivery and mitochondrial function. Hemoglobin is one of the sentinel molecules responsible for the concept of “molecular medicine”. A central element of this paradigm is that when the properties of the foundational molecular components of a system are understood, then more complex systems phenomenon will be explained. However, “well-established” concepts about hemoglobin and whole body oxygen transport are contradictory and deserve further scrutiny. The standard teaching is that in response to hypoxia, there is an acute right shift in the O2 hemoglobin dissociation curve via the actions of 2,3-DPG. This right shift facilitates the off-loading of oxygen at the tissues and protects against tissue hypoxia. However, species adapted to high altitude via evolution have left shifted O2 hemoglobin dissociation curves. This suggests that during hypoxia, loading more oxygen at the lung and relying on low tissue PO2 to maintain oxygen transport is a better overall solution to the challenge of hypoxia. These divergent observations indicate there is a complex set of context-dependent physiological “trade-offs” associated with shifts in O2 hemoglobin dissociation curve and O2 delivery. In this application, I propose studying patients at the Mayo Clinic with rare right and left shifted hemoglobin variants as unique “experiments in nature” that will allow exploration of these trade-offs. Patient studies will be augmented with studies in healthy volunteers using repurposed drugs that cause right and left shifts of the O2 hemoglobin dissociation curve. Insight from these studies will then be translated to clinical populations. If tissue oxygenation is maintained in humans with left shifted curves, then drugs that cause a left shift might be useful in patients with pulmonary diffusion limitation. This would permit such patients to better oxygenate their blood at the lung with a lower FiO2 and reduced work of breathing. Likewise, there is chronic tissue hypoxia in congestive heart failure that might be reduced by drugs that cause a right shift in the O2 hemoglobin dissociation curve. These changes in O2 delivery might also evoke long term changes in muscle mitochondrial function that will suggest follow-up reverse translation mechanistic studies. Importantly, I am uniquely qualified to explore these ideas because of my: 1) access to unique patients, 2) experience in drug re-purposing, 3) expertise in cardiorespiratory physiology, and 4) technical ability to measure essentially every element of the O2 transport cascade in humans. Finally, because the R35 mechanism is designed to promote flexibility and risk taking by the PI, it is ideal to pursue this big issue and the bi-directional translational opportunities that will flow from the experimental approach I have proposed.

摘要我正在寻找一个R35来解决O2中的左右移动的基本问题 血红蛋白解离曲线对人体氧转运影响。我还建议把钥匙 治疗具有O2转运级联特异性缺陷的疾病的发现，如特发性肺动脉高压， 纤维化和/或充血性心力衰竭。我还建议从病人的观察中进行反向翻译 更多关于氧气输送和线粒体功能的基础研究。血红蛋白是一种前哨分子 提出了“分子医学”的概念。这种模式的一个核心要素是， 一个系统的基本分子成分的性质被理解，然后更复杂的系统 现象将得到解释。然而，关于血红蛋白和全身的“公认”概念 氧气输送是矛盾的，值得进一步研究。标准的教导是， 缺氧时，通过2，3-DPG的作用，O2血红蛋白解离曲线出现急性右移。这 右移促进组织处氧的卸载并防止组织缺氧。然而，在这方面， 通过进化适应高海拔的物种已经左移了O2血红蛋白解离曲线。这 表明在缺氧期间，在肺中加载更多的氧气并依赖于低组织PO 2来维持 氧气输送是应对缺氧挑战的更好的整体解决方案。这些不同的观察结果表明 有一组复杂的环境依赖性生理“权衡”与氧血红蛋白的变化有关 解离曲线和O2输送。在这个应用程序中，我建议研究马约诊所的患者， 右移和左移血红蛋白变体作为独特的“自然实验”， 权衡患者研究将通过在健康志愿者中使用重新用途药物的研究来增强， 导致O2血红蛋白解离曲线左右移动。从这些研究中得到的见解将是 转化为临床人群。如果组织氧合在人类中以左移曲线维持，则 引起左移的药物可能对肺弥散受限的患者有用。这将使 这类患者可以更好地将其肺部血液净化，降低FiO 2并减少呼吸功。 同样，充血性心力衰竭中存在慢性组织缺氧，这可能会通过导致心力衰竭的药物来减轻。 氧血红蛋白解离曲线右移。O2输送的这些变化也可能引起长期的 肌肉线粒体功能的变化，这将建议后续的反向翻译机制研究。 重要的是，我是唯一有资格探索这些想法的人，因为我：1）接触独特的病人，2） 药物再利用经验，3）心肺生理学专业知识，4） 基本上测量人体内氧气运输级联的每一个元素。因为R35 机制的目的是促进灵活性和风险承担的PI，这是理想的追求这一大问题和 双向转化的机会，这些机会将从我所提出的实验方法中产生。