Analysis of Mammalian Hematological Diseases in a Mouse Atpif1 Deficient Models

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DESCRIPTION (provided by applicant): Analysis of new genes and mechanisms regulating red cell development is important to develop curative therapy for congenital and acquired anemias. The objective of this application is to analyze the role of mouse Atpif1 in mammalian hematological diseases. We recently cloned and characterized the Atpif1 gene in hemoglobin synthesis and red blood cell development. We established a functional link between Atpif1, mitochondrial pH, Fech enzyme and heme synthesis in erythroid cells. We demonstrated that the loss of Atpif1 produces anemia in zebrafish, mouse and human hematopoietic models. We, therefore hypothesize that a conditional mouse Atpif1 knockout will model human hematological diseases, such as congenital anemias and mitochondriopathies. Specifically, we will: (1) Analyze primitive and definitive erythroblasts derived from mouse embryonic stem (ES) cell differentiation. (2) Analyze mammalian hematological diseases in a conditional mouse Atpif1 knockout model. We expect Atpif1-deficient mouse model to replicate human hypochromic, sideroblastic and/or microcytic anemias. In the long- term, we will examine human patients with similar hematological disease for partial or complete ATPIF1 mutation and investigate their new effective therapeutic options. This project is a direct extension of my K01 grant Specific Aim 1, and its completion would advance our understanding of the mechanisms regulating red blood cell development and provide preliminary data to support a subsequent R01 application for my independent research program.