homeostatic regulation of erythrocytes

红细胞的稳态调节

• 批准号: RGPIN-2018-05626
• 负责人: Simpson, Jeremy
• 金额: $ 2.11万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=683113
• 关键词: homeostatic; regulation; erythrocytes

The hematopoietic hormone erythropoietin (EPO) is the main regulator of erythropoiesis; it stimulates the proliferation and differentiation of erythroid precursor cells. For over half a century, the kidney has been regarded as the primary site for EPO production. In 1957, Jacobson et al. used classical organ ablation experiments to conclude that the kidney is the site of EPO production in response to extreme (non-survivable) hypoxia (reduction in inspired oxygen). Subsequent studies were generally confined to confirming that the kidney produces EPO rather than exploring whether other tissues do so. We have established the kidney is not the sole producer of EPO in response to hypoxia. Surprisingly, although erythropoiesis is necessary to correct for reductions in circulating erythrocytes, no studies have performed an unbiased examination of the form(s) and tissue site(s) of EPO production. While the kidney does produce EPO, we have exciting preliminary data that the major form of EPO produced by the kidney is a novel splice variant. Further, we have identified a new tissue site for EPO production in response to low circulating erythrocytes that also produce their own unique splice variant of EPO. This poses the questions as to why there are two novel splice variants of EPO and what is the physiological relevance of this built-in redundancy that is specific to perturbations in circulating erythrocytes?******Multiple isoforms of EPO are present in normoxic human blood, raising the possibility of different sites of production and/or differential affinities for the EPO receptor at target organs/tissues. While multiple charge variants of EPO have been observed, whether these variants arise as a result of splice variants remains to be investigated. Thus, the specific questions this application aims to address are whether the different forms of EPO are produced by and for specific target organs and/or to elicit specific fundamental physiological responses?******EPO is no longer recognized as just a hematopoietic cytokine. EPO is important for organogenesis, is an inotropic agent, induces cell proliferation and confers profound cytoprotection against cellular stress. Thus, different forms of EPO are very likely of physiological importance for receptor specificity and downstream pathway activation. The objective of our research program is to uncover fundamental knowledge about EPO forms that are produced in various tissues to correct for perturbations in circulating erythrocytes. Further, we will study the ability of novel splice variants on hematopoiesis, contractility, proliferation and cytoprotection as well as their tissue source. Our research program seeks to advance the field of the basic physiological mechanism regulating erythrocyte homeostasis and provide a better understanding of the role and the impact of these novel splice variants on these important responses.**

造血激素促红细胞生成素（EPO）是红细胞生成的主要调节剂;它刺激红系前体细胞的增殖和分化。超过半个世纪以来，肾脏一直被认为是EPO产生的主要部位。1957年，Jacobson等人使用经典的器官消融实验得出结论，肾脏是响应极端（不可存活）缺氧（吸入氧气减少）的EPO产生部位。随后的研究通常局限于确认肾脏产生EPO，而不是探索其他组织是否也产生EPO。我们已经确定肾脏不是缺氧时EPO的唯一产生者。 令人惊讶的是，尽管红细胞生成对于校正循环红细胞的减少是必要的，但是没有研究对EPO产生的形式和组织部位进行公正的检查。虽然肾脏确实产生EPO，但我们有令人兴奋的初步数据表明，肾脏产生的EPO的主要形式是一种新的剪接变体。此外，我们已经确定了一个新的组织部位的EPO生产的低循环红细胞，也产生自己独特的剪接变体的EPO。这就提出了这样的问题：为什么EPO有两种新型剪接变体，以及这种特定于循环红细胞扰动的内置冗余的生理相关性是什么？* EPO的多种同种型存在于含氧量正常的人血液中，提高了在靶器官/组织中EPO受体的不同产生位点和/或不同亲和力的可能性。 虽然已经观察到EPO的多个电荷变体，但这些变体是否是剪接变体的结果仍有待研究。因此，本申请旨在解决的具体问题是不同形式的EPO是否由特定靶器官产生并用于特定靶器官和/或引起特定的基本生理反应？EPO不再仅仅被认为是一种造血细胞因子。EPO对于器官形成是重要的，是一种正性肌力剂，诱导细胞增殖并赋予针对细胞应激的深刻的细胞保护。因此，不同形式的EPO很可能对受体特异性和下游途径活化具有生理重要性。 我们的研究计划的目的是揭示有关EPO形式的基本知识，这些EPO形式在各种组织中产生，以纠正循环红细胞中的扰动。此外，我们将研究新的剪接变体对造血、收缩、增殖和细胞保护的能力以及它们的组织来源。我们的研究计划旨在推进调节红细胞稳态的基本生理机制领域，并更好地了解这些新的剪接变体对这些重要反应的作用和影响。