MOLECULAR PATHOLOGY OF HBC AND SICKLE CELL DISEASE

(改编自申请者摘要)本项目建议回答 关于HBC和HBC发病的分子基础的质疑 其对HBC和HBS双杂合子的影响。第一项基本原则 问题是：氧合Hb倾向于 结晶？目前的数据表明， β-6赖氨酸突变和β-A中央空腔的改变 螺旋远离亚铁血红素是最好的候选者。有最新的- ART光谱学和X射线结晶学研究人员建议 证明或反驳这一假设。下一个基本问题是： 这些在红细胞中有利于或抑制结晶的调节剂，但 问题仍然是胞浆的其他成分是否 参与者。要回答这个问题，调查人员需要知道更多 关于晶体生长，以及更多关于是否有核的问题 这些水晶。调查人员已经与罗森伯格和 维基洛夫大学微重力与材料研究中心 阿拉巴马州)回答这个问题，使用砍伐年龄定制 用于跟踪晶体生长和取芯的仪器(取芯是 存在“加速或延缓晶体生长的杂质”。 最后，另一个基本问题是分子基础。 均一的小红细胞增多症，在含有HBC的不同证型中不同。一 这种影响可能与HBC的异常相互作用有关。 该膜特别影响体积调节转运体。 因此，调查人员需要测试K：C1的异常关闭是否与 该小组在C细胞中发现的运输是罪魁祸首。为了这个 目的：研究人员正在培育转基因小鼠。 表达HBc和表达人K：C1共刺激基因的转基因小鼠 转运体(因为小鼠K：C1共转运体具有现象学 与人类运输者的区别)。潜在的答案是 上述问题具有实际应用价值：由于SC病是由 HBC诱导的红细胞内Hb浓度升高 这些调查只包含哈佛商学院50%的股份，可以解决这个问题 通过纠正运输异常来治疗疾病。此外，由于 结晶的HBC在SC细胞中发生聚合，严重程度 综合征候群将显著减少。

(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.