The hbd mutation in double gene dose in mice is associated with hypochromic, microcytic anemia. The anemia is due to a defect in the iron procurement mechanism of erythroid cells leading in turn to elevated free erythrocyte protoporphyrin levels and diminished hemoglobin synthesis. The overall objectives of the project are to characterize the effects of the hbd mutation and to determine the pathogenetic mechanisms underlying hemoglobin deficit. This information will lead to an understanding of the role of the normal allele for the hbd locus in iron procurement and hemoglobin synthesis and provide insight into human iron metabolism and its disorders.
Specific aims for this proposal are: 1. To elucidate the basic pathogenetic mechanism of hbd by a) establishing that the transferrin molecule from hbd mice is normal, but that the transferrin cycle is defective; b) determining the number and affinity of total transferrin receptors by Scatchard analysis using 125I-transferrin; c) examining one transferrin cycle using 59 Fe- and 125I-transferrin, i.e., binding internalization and release of iron-transferrin and, in particular, what form of transferrin (diferric, monoferric or apo) is released by hbd reticulocytes; d) measuring the rate constants of the transferrin cycle; e) examining the time dependent distribution of iron among cellular compartments; and f) measuring the pH of the acid compartment. 2. To determine whether another tissue and another receptor are affected by the hbd mutation. 3. To examine the effect of the hbd mutation on globin synthesis and mRNA levels in hbd reticulocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK033039-06
Application #
3231429
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1983-12-01
Project End
1991-11-30
Budget Start
1989-12-01
Budget End
1991-11-30
Support Year
6
Fiscal Year
1990
Total Cost
Indirect Cost
Name
State University of New York at Buffalo
Department
Type
Schools of Medicine
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260