Diamond-Blackfan Anemia and Ribosomal Protein S19

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DESCRIPTION (provided by applicant): The long-term objective of this new application is to develop a detailed mechanistic understanding of the pathophysiology of Diamond-Blackfan anemia (DBA). Specifically, the role of the ribosomal protein S19 (RPS19) in normal erythropoiesis and in disordered erythropoiesis in DBA will be explored. The rationale for the proposed studies is that although 25% of DBA subjects have been documented to harbor mutations in one allele of the RPS19 gene, there is currently no information on how this protein regulates erythropoiesis. In the present application, we propose to test several hypotheses regarding the pathophysiology of DBA and the role of RPS19 in erythropoiesis: i) altered trafficking and/or expression levels of RPS19 in erythroblasts leads to disordered erythropoiesis; ii) a signal transduction pathway involving a multiprotein complex of RPS19 and its binding partners regulates erythropoiesis; and iii) prolactin is a modulator of in vivo erythropoiesis and that the observed beneficial response to metoclopramide of some DBA affected individuals is through prolactin synthesis and release induced by this treatment. To achieve our stated objectives we have designed a series of studies with the following three specific aims. 1) Study subcellular localization and expression levels of normal and mutant proteins in erythroblasts and determine if conditional haploinsufficiency could account for the pleiotropic character of DBA. Obtain insights into role of RPS19 in erythropoiesis by defining alterations in erythroid differentiation of progenitors following specific inhibition of RPS19 by RNA mediated interference (RNAi). 2) Characterize the binding partners of RPS19 protein and determine if multiprotein complex of RPS19 and its binding partners regulate erythropoiesis. 3) Define the role of prolactin in regulating erythropoiesis and develop mechanistic understanding for the efficacy of metoclopramide in treatment of DBA. We anticipate that successful achievement of the proposed aims will provide fundamental insights into the DBA pathophysiology and the role of RPS19 in erythropoiesis. Furthermore, it is our hope that the new insights generated by our studies might lead to the development of new therapeutic strategies for the treatment of DBA patients presenting with RPS19 gene mutations.