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.

Public Health Relevance

The success of this application will help us model human congenital anemias using the Atpif1- deficient mouse model. 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
1R03DK100672-01
Application #
8619052
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Bishop, Terry Rogers
Project Start
2013-12-12
Project End
2015-11-30
Budget Start
2013-12-12
Budget End
2014-11-30
Support Year
1
Fiscal Year
2014
Total Cost
$88,291
Indirect Cost
$38,291
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115