Analysis of Mammalian Hematological Diseases in a Mouse Atpif1 Deficient Models

描述（由申请人提供）：分析调节红细胞发育的新基因和机制对于开发先天性和获得性贫血的治愈性疗法非常重要。本申请的目的是分析小鼠Atpif 1在哺乳动物血液病中的作用。我们最近克隆和特点的Atpif 1基因的血红蛋白合成和红细胞发育。我们建立了Atpif 1，线粒体pH值，费希酶和血红素合成在红系细胞之间的功能联系。我们证明了Atpif 1的缺失在斑马鱼、小鼠和人类造血模型中产生贫血。因此，我们假设条件性小鼠Atpif 1基因敲除将模拟人类血液学疾病，如先天性贫血和先天性肾病。具体而言，我们将：（1）分析小鼠胚胎干（ES）细胞分化的原始和定形成红细胞。(2)在条件性小鼠Atpif 1敲除模型中分析哺乳动物血液病。我们希望Atpif 1缺陷小鼠模型复制人类低色素，铁粒幼细胞和/或小红细胞贫血。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ATPIF 1突变，并研究他们新的有效治疗选择。该项目是我的K 01资助具体目标1的直接延伸，它的完成将促进我们对调节红细胞发育机制的理解，并提供初步数据，以支持我的独立研究项目的后续R 01申请。

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.