Analysis of Mammalian Hematological Diseases in a Mouse Atpif1 Deficient Models

小鼠 Atpif1 缺陷模型中哺乳动物血液疾病的分析

• 批准号: 8785680
• 负责人: DHVANIT INDRAVADAN SHAH
• 金额: $ 8.85万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-12 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8785680
• 关键词: Alleles; Aminolevulinic Acid; Anemia; CD34 gene; Cell Maturation; Cells; Congenital Anemia; Data; Defect; Development; Disease; Enzymes; Erythroblasts; Erythrocytes; Erythroid; Erythroid Cells; Erythropoiesis; Erythropoietic Protoporphyria; Fetal Liver; Genes; Genetic; Genetic Screening; Genetic Transcription; Grant; Health; Hematological Disease; Hematopoietic; Heme; Hemochromatosis; Hemoglobin; Hepatocyte; Homeostasis; Human; Hypochromic anemia; Intervention; Iron; Iron deficiency anemia; Knock-out; Knockout Mice; Knowledge; Link; Mitochondria; Mitochondrial Diseases; Modeling; Mus; Mutagenesis; Mutation; Nature; Oxidation-Reduction; Patients; Proton-Translocating ATPases; Randomized; Research; Role; Site; Therapeutic; Tissues; Variant; Zebrafish; embryonic stem cell; ferrochelatase; heme biosynthesis; iron metabolism; leukemia; metal transporting protein 1; microcytic anemia; mouse model; mutant; novel; programs; stem cell differentiation; success

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.

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开发先天性和获得性贫血的根治性治疗非常重要。本应用程序的目的是分析小鼠Atpif1在哺乳动物血液病中的作用。我们最近克隆并鉴定了血红蛋白合成和红细胞发育中的Atpif1基因。我们在红细胞中建立了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、小鼠和人类造血模型中证明了Atpif1的缺失会产生贫血。因此，我们假设条件小鼠Atpif1敲除将模拟人类血液系统疾病，如先天性贫血和线粒体病。具体来说，我们将：(1)分析来源于小鼠胚胎干细胞（ES）分化的原始和最终红母细胞。(2)在条件小鼠Atpif1敲除模型中分析哺乳动物血液病。我们希望atpif1缺陷小鼠模型能够复制人类低色素、铁母细胞和/或小细胞贫血。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ATPIF1突变，并研究他们的新的有效治疗方案。该项目是我的K01基金Specific Aim 1的直接延伸，它的完成将促进我们对红细胞发育调节机制的理解，并为我随后的独立研究项目的R01申请提供初步数据。