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Rheological and Adherence Properties of Sickle Cells

镰状细胞的流变学和粘附特性

基本信息

批准号：
7251949
负责人：
Mohandas Narla
金额：
$ 35.5万
依托单位：
NEW YORK BLOOD CENTER
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-10-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7251949
关键词：
Accounting Actins Adherence Adhesions Adhesives Behavior Biochemical Biological Biophysics Carrier Proteins Cations Cell Adhesion Cell Membrane Alteration Cell Separation Cell Survival Cell membrane Cell surface Cells Cellular biology Chronic Clinical Clinical Management Dehydration Development Disease Documentation Elements Endothelial Cells Erythrocytes Event Exhibits Flow Cytometry Functional disorder Gene Targeting Generations Genes Genetic Heterogeneity Homeostasis Human In Vitro Integrins Knockout Mice Lateral Lead Ligands Lipids Measures Mechanics Mediating Membrane Membrane Proteins Molecular Molecular Biology Mus Muscle Rigidity Nature Numbers Organ Pain Pathologic Phosphatidylserines Physiological Physiology Plasma Plasma Proteins Play Population Property Protein Dynamics Protein Fragment Proteins Reagent Regulation Relative (related person)Research Rheology Role Series Sickle Cell Sickle Cell Anemia Sickle Hemoglobin Signal Transduction Skeletal system Skeleton Spectrin Staging Sulfoglycosphingolipids Techniques Testing Therapeutic Tissues Transgenic Organisms Vascular Endothelial Cell base cellular engineering cohesion concept defined contribution density design dimer human disease improved in vivo innovation insight intravital microscopy knockout gene novel protective effect receptor sickling

项目摘要

DESCRIPTION (provided by applicant): The research objective of this application is to develop a detailed molecular and mechanistic understanding of the heterogeneity in the rheological and adherence properties of circulating sickle red cells and define the in vivo pathologic sequelae of these cellular changes. To achieve our objective we propose the following series of studies: 1) Determine the structural basis for the heterogeneous rheological properties of distinct subpopulations of circulating sickle red cells and study the in vivo flow behavior and survival of these subpopulations. 2) Determine the contributions of the K-CI cotransporter and the Gardos channel to the generation of theologically compromised dense sickle cells. 3) Evaluate the contributions of specific adhesive receptors, ligands, and plasma proteins in mediating adhesion of sickle red cells to endothelial cells in vitro. 4) Validate the contribution of various adhesive ligands and receptors to sickle cell adhesion by performing adhesion studies using cells from sickle mice in which genes encoding specific adhesive ligands or receptors are inactivated. For the proposed studies, we will use multiple techniques in biophysics, molecular biology, cell biology, mouse genetics and circulatory physiology. The sickle mice that we developed expressing exclusively human sickle hemoglobin and exhibiting several clinical features of human disease are a key component of the proposed experimental strategy. Our application of novel experimental strategies and exploration of innovative biological concepts offers promise for elucidating the causes of painful vaso-occlusion and chronic organ damage. We anticipate that our findings will lead to the identification of useful therapeutic strategies for the effective clinical management of this debilitating human disease.

描述（由申请人提供）：本申请的研究目的是对循环镰状红细胞流变学和粘附特性的异质性进行详细的分子和机制理解，并确定这些细胞变化的体内病理学后遗症。为了实现我们的目标，我们提出了以下一系列的研究：1）确定循环镰状红细胞的不同亚群的异质流变学性质的结构基础，并研究这些亚群的体内流动行为和存活。2)确定K-CI协同转运蛋白和Gardos通道对产生流变学受损的致密镰状细胞的贡献。3)评价特异性粘附受体、配体和血浆蛋白在介导镰状红细胞与内皮细胞体外粘附中的作用。4)通过使用编码特异性粘附配体或受体的基因失活的镰状小鼠细胞进行粘附研究，证实各种粘附配体和受体对镰状细胞粘附的贡献。对于拟议的研究，我们将使用生物物理学，分子生物学，细胞生物学，小鼠遗传学和循环生理学的多种技术。我们开发的仅表达人类镰状血红蛋白并表现出人类疾病的几种临床特征的镰状小鼠是所提出的实验策略的关键组成部分。我们应用新的实验策略和探索创新的生物学概念，为阐明疼痛性血管闭塞和慢性器官损伤的原因提供了希望。我们预计，我们的研究结果将导致确定有用的治疗策略，有效的临床管理这种衰弱的人类疾病。