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？

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.