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：
7434446
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/7434446
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）：本应用的研究目标是对循环镰状红细胞的流变学和依从性特性中的异质性进行详细的分子和机械理解，并定义这些细胞变化的体内病理后遗症。为了实现我们的目标，我们提出了以下一系列研究：1）确定循环镰状红细胞不同亚群的异质流变特性的结构基础，并研究这些亚群的体内流动行为和存活。 2）确定K-CI共转运蛋白和Gardos通道对神学受损致密的镰状细胞的贡献。 3）评估特定粘合受体，配体和血浆蛋白在体外介导镰状细胞对内皮细胞的粘附方面的贡献。 4）通过使用来自镰状小鼠的细胞进行粘附研究，验证各种粘合配体和受体对镰状细胞粘附的贡献，其中编码特定的粘附配体或受体的基因被灭活。对于拟议的研究，我们将在生物物理学，分子生物学，细胞生物学，小鼠遗传学和循环生理学中使用多种技术。我们开发的镰状小鼠专门表达人类镰状血红蛋白并表现出人类疾病的几个临床特征，是拟议的实验策略的关键组成部分。我们对新颖的实验策略的应用和对创新生物学概念的探索为阐明疼痛的血管肠咬合和慢性器官损害的原因提供了希望。我们预计我们的发现将导致确定有效的治疗策略，以有效地对这种使人衰弱的人类疾病进行临床管理。