The overall objectives of this program are to develop a detailed understanding of the molecular and structural basis for the genesis and assembly of the red cell, with emphasis on the membrane skeleton;and to develop an improved mechanistic understanding of erythropoiesis, with the goal of defining pathophysiologic mechanisms of anemia, a major health problem affecting over billion individuals around the world. The scope of the proposed research program also includes delineating the role of cytoskeleton in regulating hematopoietic cell differentiation. To achieve these broad goals, four complementary approaches are proposed: 1) Develop a detailed understanding of the molecular and structural basis for the functions of an important family of cytoskeletal proteins in erythroid cells;2) Obtain detailed mechanistic understanding of the functional and biological consequences of interaction between proteins of the malarial parasite and the red cell;3) Delineate mechanisms involved in enucleation and membrane biogenesis during terminal erythroid differentiation;and 4) Obtain mechanistic understanding of the role of the bone marrow matrix stiffness on hematopoiesis, with particular emphasis on erythropoiesis. To achieve these objectives, a group of investigators with expertise in hematology, biochemistry, cell biology, biophysics, genetics, parasitology, and molecular biology, as well as a long standing interest in red cell membrane physiology, have come together to mount a concerted effort. It is anticipated that information garnered during these studies will contribute towards increased insights into the role of skeletal proteins in membrane assembly, homeostasis and structure-function relationships in erythroid cells in particular, and somatic cells in general, that will have significant impact on our understanding of the pathophysiology of important human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK032094-28
Application #
8298258
Study Section
Special Emphasis Panel (ZDK1-GRB-9 (M2))
Program Officer
Bishop, Terry Rogers
Project Start
1997-01-30
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
28
Fiscal Year
2012
Total Cost
$1,629,873
Indirect Cost
$325,500
Name
New York Blood Center
Department
Type
DUNS #
073271827
City
New York
State
NY
Country
United States
Zip Code
10065
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Shin, Jae-Won; Buxboim, Amnon; Spinler, Kyle R et al. (2014) Contractile forces sustain and polarize hematopoiesis from stem and progenitor cells. Cell Stem Cell 14:81-93
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Oltra, NĂºria Sancho; Nair, Praful; Discher, Dennis E (2014) From stealthy polymersomes and filomicelles to "self" Peptide-nanoparticles for cancer therapy. Annu Rev Chem Biomol Eng 5:281-99
An, Xiuli; Schulz, Vincent P; Li, Jie et al. (2014) Global transcriptome analyses of human and murine terminal erythroid differentiation. Blood 123:3466-77
Harada, Takamasa; Swift, Joe; Irianto, Jerome et al. (2014) Nuclear lamin stiffness is a barrier to 3D migration, but softness can limit survival. J Cell Biol 204:669-82
Buxboim, Amnon; Swift, Joe; Irianto, Jerome et al. (2014) Matrix elasticity regulates lamin-A,C phosphorylation and turnover with feedback to actomyosin. Curr Biol 24:1909-17
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

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