LENS PROTEIN ALPHA-CRYSTALLIN B CHAIN

α-B-晶状体蛋白是脊椎动物透镜的主要成分，也是 在晶状体外组织中表达。最近的研究表明，阿尔法- B-晶状体蛋白应被认为是一种“热休克”或“应激”蛋白。 首先，α-晶体蛋白与α-晶体蛋白家族共享同源序列。 低分子量热休克蛋白（hsps）。其次，虽然α-B-晶体蛋白是 在某些组织中组成型表达， 戏剧性地通过各种经典的“应激因子，包括热 休克、氧化应激和过渡金属。 一个奇异的例子 α-B-晶状体蛋白表达发生在儿童脑白质营养不良中， 亚历山大病，其中星形胶质细胞积聚大量蛋白质 被称为罗森塔尔纤维的内含物其中的主要组成部分 夹杂物是α-B-晶体蛋白和相关的小分子量热休克 蛋白质，hsp 27。在这项赠款的头两年里，我们发现， a）。α-B-晶状体蛋白和hsp 27的mRNA和蛋白质水平是 在亚历山大病CNS中显著升高，B）。星形胶质细胞上调 这两个基因既协调又独立地响应于 各种“应激”剂，和c）。α-B-晶体蛋白保护星形胶质细胞 细胞免受盐浓度增加的压力。我们建议 继续我们对亚历山大病的研究， 小分子量热休克蛋白在中枢神经系统， 遵循几条调查路线：一。其他的热休克蛋白是否在 亚历山大病，如果是这样，他们参与RP的形成？二.并 应激诱导星形胶质细胞α-B-晶状体蛋白和热休克蛋白27表达增加 发生在转录水平上三.我们能识别出 作为α-B-晶体蛋白和热休克蛋白27的转录调节因子？做这些 蛋白质在应激反应中的作用这些蛋白质是否在 亚历山大病以及它们是否在压力的积累中起作用 亚历山大中枢神经系统中的蛋白质四.α-B-晶状体蛋白是否保护细胞 从特定的“压力”或它是否有一般的保护性能 面对诸多“压力”？

Alpha-B-crystallin, a major element of the vertebrate lens, is also expressed in extralenticular tissues. Recent findings indicate that alpha- B-crystallin should be considered a "heat shock" or "stress" protein. First, the alpha-crystallins share homologous sequences with the family of low MW heat shock proteins (hsps). Second, although alpha-B-crystallin is constitutively expressed in some tissues, it can be upregulated dramatically by a variety of classical "stress agents, including heat shock, oxidative stress, and transitional metals. A singular example of alpha-B-crystallin expression occurs in the childhood leukodystrophy, Alexander disease, in which astrocytes accumulate large, proteinaceous inclusions known as Rosenthal fibers. The major components of these inclusions are alpha-B-crystallin and the related small MW heat shock protein, hsp27. Over the first two years of this grant we have found that a). levels of mRNA and protein for alpha-B-crystallin and hsp 27 are markedly elevated in Alexander disease CNS, b). astrocytes upregulate these two genes both coordinately and independently in response to a variety of "stress" agents, and c). alpha-B-crystallin protects astroglial cells from the stress of increased salt concentration. We propose to continue our studies on Alexander disease and to focus on the regulation of small MW heat shock proteins in the central nervous system and shall follow several lines of inquiry: I. Are other hsps overexpressed In Alexander disease and if so, are they involved in RP formation? II. Does the stress-induced increase in alpha-B-crystallin and hsp27 in astrocytes occur at a transcriptional level? III. Can we identify proteins that act as transcriptional regulators for alpha-B-crystallin and hsp27? Do these proteins function in stress responses? Are these proteins expressed in Alexander disease and might they play a role in the accumulation of stress proteins in the Alexander CNS? IV. Does alpha-B-crystallin protect cells from specific "stresses" or does it have general protective properties against many "stresses"?