Analysis of Mammalian Hematological Diseases in a Mouse Atpif1 Deficient Models

描述(由申请人提供)：分析控制红细胞发育的新基因和机制对开发先天性和获得性贫血的治疗方法很重要。本应用的目的是分析小鼠ATPIF1在哺乳动物血液病中的作用。我们最近克隆了ATPIF1基因，并对其在血红蛋白合成和红细胞发育中的作用进行了研究。我们在红系细胞中建立了ATPIF1、线粒体pH、Fech酶和血红素合成之间的功能联系。我们在斑马鱼、小鼠和人类的造血模型中证明了ATPIF1基因的缺失会导致贫血。因此，我们假设有条件的小鼠ATPIF1基因敲除将模拟人类血液疾病，如先天性贫血和线粒体疾病。具体地说，我们将：(1)分析来源于小鼠胚胎干细胞分化的原始和确定的红细胞。(2)用条件性小鼠ATPIF1基因敲除模型分析哺乳动物血液病。我们期望ATPIF1缺陷小鼠模型能够复制人类低色素性、铁粒母细胞和/或小细胞性贫血。从长远来看，我们将检查患有类似血液病的人类患者的部分或完全ATPIF1突变，并研究他们新的有效治疗方案。该项目是我的K01基金特殊目标1的直接延伸，它的完成将促进我们对红细胞发育调控机制的理解，并为我的独立研究项目后续的R01申请提供初步数据。

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.