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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：
7858332
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 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7858332
关键词：
Accounting Actins Adherence Adhesions Adhesives Behavior Biochemical Biological Biophysics Carrier Proteins Cations Cell Adhesion Cell Membrane Alteration Cell Membrane Proteins 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 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 Spectrin Staging Sulfoglycosphingolipids Techniques Testing Therapeutic Tissues Transgenic Organisms Vascular Endothelial Cell base cellular engineering cohesion defined contribution density design dimer human disease improved in vivo innovation insight intravital microscopy membrane skeleton novel protective effect receptor sickling skeletal

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(申请人提供)：本申请的研究目标是对循环中镰状红细胞的流变性和粘附性的异质性进行详细的分子和机理了解，并确定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)确定不同亚群的循环镰状红细胞的异质性流变性的结构基础，并研究这些亚群的体内流动行为和存活率。2)确定K-CI共转运体和Gardos通道在神学上受损的致密镰状细胞的产生中的作用。3)评价特异性黏附受体、配体和血浆蛋白在介导镰状红细胞与血管内皮细胞黏附中的作用。4)通过使用编码特定黏附配体或受体的基因失活的镰刀鼠细胞进行黏附研究，验证各种黏附配体和受体对镰刀细胞黏附的贡献。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个临床特征的镰状小鼠是拟议的实验策略的关键组成部分。我们新的实验策略的应用和对创新生物学概念的探索为阐明痛苦的血管闭塞和慢性器官损伤的原因提供了希望。我们预计，我们的发现将导致确定有效的治疗策略，以有效地临床管理这种令人衰弱的人类疾病。

项目成果

期刊论文数量（55）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hypoxia-induced in vivo sickling of transgenic mouse red cells.

缺氧诱导转基因小鼠红细胞体内镰状化。

DOI：
10.1172/jci115041
发表时间：
1991
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
Rubin,EM;Witkowska,HE;Spangler,E;Curtin,P;Lubin,BH;Mohandas,N;Clift,SM
通讯作者：
Clift,SM

Hypoxia-induced acute lung injury in murine models of sickle cell disease.

DOI：
10.1152/ajplung.00288.2002
发表时间：
2004-04
期刊：
American journal of physiology. Lung cellular and molecular physiology
影响因子：
0
作者：
K. Pritchard;J. Ou;Zhi‐jun Ou;Yang Shi;J. Franciosi;Paul R Signorino;Sushma Kaul;C. Ackland-Berglund-C.-Ackland
通讯作者：
K. Pritchard;J. Ou;Zhi‐jun Ou;Yang Shi;J. Franciosi;Paul R Signorino;Sushma Kaul;C. Ackland-Berglund-C.-Ackland

Thrombospondin mediates adherence of CD36+ sickle reticulocytes to endothelial cells.

血小板反应蛋白介导 CD36 镰状网织红细胞与内皮细胞的粘附。

DOI：
发表时间：
1992
期刊：
Blood
影响因子：
20.3
作者：
Sugihara,K;Sugihara,T;Mohandas,N;Hebbel,RP
通讯作者：
Hebbel,RP

The unusual pathobiology of hemoglobin constant spring red blood cells.

DOI：
10.1182/blood.v89.5.1762
发表时间：
1997-03
期刊：
Blood
影响因子：
20.3
作者：
S. L. Schrier;A. Bunyaratvej;A. Khuhapinant;S. Fucharoen;M. Aljurf;LM Snyder;C. Keifer;Lisa Ma;Narla Mohandas
通讯作者：
S. L. Schrier;A. Bunyaratvej;A. Khuhapinant;S. Fucharoen;M. Aljurf;LM Snyder;C. Keifer;Lisa Ma;Narla Mohandas

Characterization of cellular determinants and plasma factors responsible for increased adherence of sickle cells to vascular endothelium.

负责镰状细胞与血管内皮细胞粘附增加的细胞决定因素和血浆因子的表征。