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

基本信息

批准号：
8619052
负责人：
DHVANIT INDRAVADAN SHAH
金额：
$ 8.83万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-12 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8619052
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 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 public health relevance stem cell differentiation success

项目摘要

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.