homeostatic regulation of erythrocytes

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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.**