PROGRAM PROJECT: RED CELL MEMBRANE STUDIES

描述(由申请人提供)： 该计划的总体目标是详细了解红细胞的发生和组装的分子和结构基础，重点是膜骨架；并改进对红细胞生成的机制的理解，目的是确定贫血的病理生理机制，贫血是影响全球超过10亿人的主要健康问题。拟议的研究计划的范围还包括描绘细胞骨架在调节造血细胞分化中的作用。为实现这些广泛的目标，提出了四种补充方法：1)详细了解红系细胞中一个重要的细胞骨架蛋白家族的功能和结构基础；2)从机制上了解疟疾寄生虫的蛋白质与红细胞之间相互作用的功能和生物学后果；3)描述红系终末分化过程中去核和膜生物发生的机制；4)从机制上了解骨髓基质僵硬在造血方面的作用，特别是红细胞生成。为了实现这些目标，一群在血液学、生物化学、细胞生物学、生物物理学、遗传学、寄生虫学和分子生物学方面具有专长的研究人员以及对红细胞膜生理学长期感兴趣的人聚集在一起，共同努力。预计在这些研究中获得的信息将有助于更深入地了解骨骼蛋白在膜组装、稳态和结构-功能关系中的作用，特别是在红系细胞和一般体细胞中，这将对我们理解重要人类疾病的病理生理学产生重大影响。

DESCRIPTION (provided by applicant): 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.