homeostatic regulation of erythrocytes

造血激素促红细胞生成素（EPO）是红细胞生成的主要调节因子；它刺激红细胞前体细胞的增殖和分化。半个多世纪以来，肾脏一直被认为是促红细胞生成素（EPO）产生的主要部位。1957年，Jacobson等人通过经典的器官消融实验得出结论，肾脏是极端（无法生存的）缺氧（吸入氧减少）时EPO产生的部位。随后的研究通常局限于确认肾脏产生促生成素，而不是探索其他组织是否也会产生促生成素。我们已经确定肾脏并不是唯一的促红细胞生成素的生产者，以应对缺氧。令人惊讶的是，虽然红细胞生成是纠正循环红细胞减少所必需的，但没有研究对EPO产生的形式和组织部位进行了公正的检查。虽然肾脏确实产生促生成素，但我们有令人兴奋的初步数据表明，肾脏产生的促生成素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位点，在低循环红细胞的反应中产生EPO，红细胞也产生它们自己独特的EPO剪接变体。这就提出了这样的问题：为什么EPO有两种新的剪接变体，以及这种内在冗余的生理相关性是什么，这种冗余是循环红细胞中特定的扰动？******正常环境下的人血液中存在多种EPO亚型，这增加了EPO受体在靶器官/组织中产生不同位点和/或不同亲和力的可能性。虽然已经观察到EPO的多种电荷变异，但这些变异是否由剪接变异引起仍有待研究。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不再被认为仅仅是一种造血细胞因子。EPO是一种肌力剂，在器官发生中起重要作用，可诱导细胞增殖，并对细胞应激具有深刻的细胞保护作用。因此，不同形式的EPO很可能对受体特异性和下游通路激活具有重要的生理意义。我们的研究计划的目的是揭示EPO形式的基本知识，EPO是在各种组织中产生的，以纠正循环红细胞的扰动。进一步，我们将研究新的剪接变异对造血、收缩、增殖和细胞保护的能力及其组织来源。我们的研究计划旨在推进红细胞稳态调节的基本生理机制领域，并更好地了解这些新的剪接变异在这些重要反应中的作用和影响

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.**