The long-term objective of this application is to develop a detailed understanding of the molecular and structural basis for red cell membrane function in health and disease.
The aim of this application is to define the origins of red cell membrane material behavior at the molecular level by combining structural and functional information on individual proteins with detailed biophysical characterization of red cells. To achieve our stated objective we have designed a series of studies with the following specific aims: 1) Explore the hypothesis that distinct macromolecular complexes of membrane proteins are assembled in the red cell membrane and linkage of these complexes to the membrane skeleton regulates several membrane functions. 2) Explore the hypothesis that dynamic regulations of lateral linkages between skeletal proteins play a key role in modulating membrane mechanical stability. In particular, we will explore the dynamic regulation of linkage between spectrin dimers and between junctional complex proteins, spectrin, 4.1R, actin and adducin. 3) Explore the hypothesis that interaction of lipids with skeleton modulates membrane function. 4) Explore the hypothesis that significant structural reorganization of integral and skeletal proteins is responsible for the documented changes in membrane material properties during maturation of reticulocytes into mature red cells. For the proposed studies we will employ a variety of biophysical strategies including fluorescence-imaged micropipet aspiration, the technique of magnetic tweezers and ektacytometry. Human red cells with defined protein defects and red cells from knockout and knockin mice will be used to critically evaluate the contribution of various proteins to membrane function. We anticipate that successful execution of our proposed studies will enable us to critically test the various hypotheses for the origins of membrane material behavior at the molecular level and offer significant insights into functional consequences of altered membrane organization in pathologic red cells. We anticipate that findings from these studies will lead to development of better clinical management strategies for inherited and acquired red cell disorders which affect over a billion humans around the world. Project Narrative: Inherited and acquired red cell disorders including hereditary spherocytosis, hereditary elliptocytosis, hereditary ovalocytosis, thalassemias, sickle cell disease, enzymopathies, malarial anemia and iron deficiency anemia affect over billion humans. A feature of all these disorders is altered membrane function which in turn contributes to clinical manifestations. The research project will explore the molecular and structural basis for red cell membrane material behavior in health and disease. It is anticipated that the findings from the proposed studies will contribute to better clinical management of red cell disorders and for developing new therapeutic approaches for management of hemolytic anemias.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Erythrocyte and Leukocyte Biology Study Section (ELB)
Program Officer
Bishop, Terry Rogers
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
New York Blood Center
New York
United States
Zip Code
Blanc, Lionel; Papoin, Julien; Debnath, Gargi et al. (2015) Abnormal erythroid maturation leads to microcytic anemia in the TSAP6/Steap3 null mouse model. Am J Hematol 90:235-41
Pimentel, Harold; Parra, Marilyn; Gee, Sherry et al. (2014) A dynamic alternative splicing program regulates gene expression during terminal erythropoiesis. Nucleic Acids Res 42:4031-42
Wang, Jie; Song, Jinlei; An, Chao et al. (2014) A 130-kDa protein 4.1B regulates cell adhesion, spreading, and migration of mouse embryo fibroblasts by influencing actin cytoskeleton organization. J Biol Chem 289:5925-37
Liu, Dun; Zhang, Xinhua; Yu, Lihua et al. (2014) KLF1 mutations are relatively more common in a thalassemia endemic region and ameliorate the severity of ?-thalassemia. Blood 124:803-11
An, Xiuli; Schulz, Vincent P; Li, Jie et al. (2014) Global transcriptome analyses of human and murine terminal erythroid differentiation. Blood 123:3466-77
Franco, Sara Santos; De Falco, Luigia; Ghaffari, Saghi et al. (2014) Resveratrol accelerates erythroid maturation by activation of FoxO3 and ameliorates anemia in beta-thalassemic mice. Haematologica 99:267-75
Weng, Haibo; Guo, Xinhua; Papoin, Julien et al. (2014) Interaction of Plasmodium falciparum knob-associated histidine-rich protein (KAHRP) with erythrocyte ankyrin R is required for its attachment to the erythrocyte membrane. Biochim Biophys Acta 1838:185-92
Sui, Zhenhua; Nowak, Roberta B; Bacconi, Andrea et al. (2014) Tropomodulin3-null mice are embryonic lethal with anemia due to impaired erythroid terminal differentiation in the fetal liver. Blood 123:758-67
Liu, Congrong; Weng, Haibao; Chen, Lixiang et al. (2013) Impaired intestinal calcium absorption in protein 4.1R-deficient mice due to altered expression of plasma membrane calcium ATPase 1b (PMCA1b). J Biol Chem 288:11407-15
Arashiki, Nobuto; Kimata, Naoki; Manno, Sumie et al. (2013) Membrane peroxidation and methemoglobin formation are both necessary for band 3 clustering: mechanistic insights into human erythrocyte senescence. Biochemistry 52:5760-9

Showing the most recent 10 out of 119 publications