MOLECULAR PATHOLOGY OF HBC AND SICKLE CELL DISEASE

（摘自申请人摘要）本项目拟回答 关于HbC引起的病理学的分子基础的问题， 对HbC和HbS双杂合子影响。第一基本 问题是：oxyHb倾向于 结晶？目前的数据表明， Beta 6赖氨酸突变和BetaA中央腔的改变 螺旋远离血红素是最好的候选者。与国家的- 艺术光谱学和X射线晶体学，研究人员提出， 证明或反驳这一假设。下一个基本问题是： 红细胞中的这些调节剂有利于或抑制结晶，但 问题仍然是胞质溶胶的其他成分是否 参与者要回答这个问题，研究人员需要了解更多 关于晶体生长，更多的是关于核的存在或不存在， 这些水晶。调查人员与罗森伯格联手， Vekilov（微重力和材料研究中心，莫斯科大学） 亚拉巴马）回答这个问题，采用扦插年龄定制 仪器跟踪晶体生长和取芯（取芯是 存在“加速或阻碍晶体生长的杂质”）。 最后，另一个基本问题是， 均匀的小红细胞增多，其在含有HbC的综合征中变化。一 这种效应可能与HbC的异常相互作用有关 膜特异性地影响体积调节转运蛋白。 因此，研究人员需要测试K：C1的异常关闭是否与 研究小组在C细胞中发现的转运是罪魁祸首。为此 研究人员正在培育转基因小鼠 表达HbC的转基因小鼠和表达人K：C1共 转运蛋白（因为小鼠K：C1共转运蛋白具有现象学的 与人类运输工具的差异）。潜在的答案 上述问题具有实际应用：由于SC疾病是由 RBC中HbC诱导的细胞内HB浓度升高 只有50%的血红蛋白，研究可以解决这个问题。 疾病通过纠正运输异常。此外，由于 HbC的结晶在SC细胞中具有聚合， 综合症将大大减少。

(Adapted from Applicant's Abstract) This project proposes to answer question about the molecular basis of the pathology engendered by HbC and its effect on double heterozygotes for HbC and HbS. The first fundamental question is: what is the molecular basis of the tendency of oxyHb to crystallize? The present data points to the combination of the presence of the Beta6lysine mutation and alteration of the central cavity of the BetaA helix moving away from the heme as the best candidates. With state-of-the- art spectroscopy and X-ray crystallography the investigators propose to prove or disprove this hypothesis. The next fundamental question is: are these modulators in red cells that favor or inhibit crystallization, but the question remains whether or not other components of the cytosol are participants. To answer this question the investigators need to know more about crystal growth and more about the presence or absence of coring in these crystals. The investigators have joined forces with Rosenberger and Vekilov (Center for Microgravity and Materials Research, University of Alabama) to answer this question, using cutting-age custom made instrumentation to follow crystal growth and coring (coring is the presence of "impurities that accelerate or retard crystal growth). Finally, another fundamental question is the molecular basis of the uniform microcytosis which varies among the syndromes containing HbC. One possibility is that this effect is related to abnormal interaction of HbC with the membrane specifically affecting volume-regulating transporters. Hence, the investigators need to test if the abnormal turn-off of K:C1 co- transport, discover by the group in C cells, is the culprit. For this purpose the investigators are in the process of generating transgenic mice expressing HbC and transgenic mice expressing the human K:C1 co- transporter (since the mouse K:C1 co-transporter has phenomenological differences with the human transporter). The potential answers to the above questions have practical applications: since SC disease is caused by an increase in intracellular HB concentration induced by HbC in RBC containing only 50 percent of Hbs, the investigations could cure this disease by correcting the transport abnormality. Also, since crystallization of HbC has polymerization in SC cells, the severity of the syndrome will be reduced significantly.