BOOKCHIN

书钦

• 批准号: 7375452
• 负责人: ROBERT M BOOKCHIN
• 金额: $ 0.34万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7375452
• 关键词: BOOKCHIN

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The main long-term goal is a thorough understanding of the molecular and cellular pathophysiology of sickle cell (SS) disease. One project focuses on the mechanisms by which Hb S interacts with the RBC membranes to alter cell functions, contributing to clinical hemolytic anemia and widespread microvascular occlusion. Our immediate aims are: I. To characterize the functional properties and possible molecular nature of the sickling-induced ion permeability pathway(s), "Psickle";II. To investigate the mechanism(s) of generation of the high-Na+, low-K+, low-density, cation-leaky SS and normal RBCs we discovered; Ill. To pursue our hypothesis that the marked heterogeneity of volume and density (or cell Hb concentration) among circulating SS and variant RBCs results from heterogeneity of transport systems in the reticulocytes, with the direct and indirect effects of Hb membrane interactions. IV. To characterize the Hb-polymerization properties and RBC ion-transport; functions of a variety of transgenic sickle mouse models to identify those most suitable to test various pathophysiological mechanisms and therapeutic maneuvers in sickle cell disease. Once characterized, these will serve investigations within the above three aims. In the second project, we will: V. Continue to characterize the molecular interaction sites of the deoxy-Hb S polymers, fibers and gels, focusing on potentially important sites susceptible to specific modification, by semisynthetic approaches or direct chemical modification; on the cis or trans role of specific residues at different structural levels of the polymer; and on the way non-S Hbs participate in or alter the polymerization process; VI. develop further our new micro- excluded volume assay of the equilibrium solubility of the polymer, the dextran-Csat; VII. Test the constancy or variability of Cp, the Hb concentration in the polymer; VIII. Examine the partitioning in the PWC, sol and membrane of 2,3-DPG, ATP, RBC enzymes and small molecules; IX. Assess the role of normal or abnormal (sickle cell) components of the RBC membrane on the kinetics and assembly of intracellular polymer; and X. Study by direct observation the formation of deoxy-Hb S fibers in RBCs.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中出现。列出的机构是中心的机构，不一定是研究者的机构。主要的长期目标是彻底了解镰状细胞（SS）疾病的分子和细胞病理生理学。其中一个项目重点研究 Hb S 与红细胞膜相互作用以改变细胞功能，从而导致临床溶血性贫血和广泛的微血管闭塞的机制。我们的近期目标是： I. 表征镰状化诱导的离子渗透途径“Psickle”的功能特性和可能的​​分子性质；II。为了研究我们发现的高Na+、低K+、低密度、阳离子泄漏SS和正常红细胞的生成机制； III. 为了追求我们的假设，即循环 SS 和变异红细胞之间体积和密度（或细胞 Hb 浓度）的显着异质性是由网织红细胞中运输系统的异质性造成的，以及 Hb 膜相互作用的直接和间接影响。四．表征 Hb 聚合特性和红细胞离子传输；各种转基因镰状小鼠模型的功能，以确定最适合测试镰状细胞病的各种病理生理机制和治疗策略的模型。一旦表征，这些将服务于上述三个目标的研究。在第二个项目中，我们将： V. 继续表征脱氧 Hb S 聚合物、纤维和凝胶的分子相互作用位点，重点关注易于通过半合成方法或直接化学修饰进行特定修饰的潜在重要位点；关于聚合物不同结构水平上特定残基的顺式或反式作用；以及非 S Hb 参与或改变聚合过程的方式；六．进一步开发我们新的微排除体积测定法来测定聚合物右旋糖酐-Csat的平衡溶解度；七．测试聚合物中Cp、Hb浓度的恒定性或变化性；八．检查2,3-DPG、ATP、RBC酶和小分子在PWC、溶胶和膜中的分配；九．评估红细胞膜正常或异常（镰状细胞）成分对细胞内聚合物动力学和组装的作用； X.通过直接观察研究红细胞中脱氧-Hb S纤维的形成。