Function of HSPs in mouse models for human diseases

应激反应是进化上保守的细胞反应机制，其特征在于： 增强热休克蛋白（Hsps）的合成和积累。这些蛋白质作为分子 分子伴侣和防止聚集的错误折叠的蛋白质;他们也有助于重折叠，运输， 蛋白质在细胞质、线粒体和内质网中的组装。人们普遍 Hsp分子伴侣在包括癌症在内的许多人类病理学中的功能的临床意义， 神经退行性疾病、衰老和心血管疾病。我们对热休克蛋白功能的理解 通过突变小鼠模型的开发，病理状况得到了极大的改善。在这 格兰特的主要目标是确定三种主要热休克蛋白之间相互作用的框架， 组成型HscVO、其诱导型对应物HspVO 1和小分子量Hsp 27（小鼠 Hsp 25），其通过调节内皮细胞分化在肿瘤发展中发挥密切作用， 从而通过影响细胞存活/死亡的分子途径而导致新血管生成。突变缺陷小鼠 在这些由常规或条件性基因靶向策略产生的热休克蛋白中， 在整个生物体水平上解决癌症生物学中这些重要问题的机会。期间 下一个项目周期我们计划遵循两个目标：（1）定义HspVOi的功能贡献， HscVO或Hsp 25在肿瘤血管生成和/或血管生成中的作用(2)来描述 Hsp 70 i、Hsc 70和Hsp 25在调节应激反应中的作用及其对肿瘤的作用 体内发育拟议的研究将有助于更好地了解 这些分子伴侣参与促进肿瘤生长的细胞过程， 开发调节特异性伴侣依赖性宿主途径的策略，作为治疗方法， 防治人类癌症和其他相关疾病。

The stress response is an evolutionarily conserved cellular response mechanism characterized by the enhanced synthesis and accumulation of heat shock proteins (Hsps). These proteins act as molecular chaperones and prevent aggregation of misfolded proteins; they also assist in the refolding, transport, and assembly of proteins in the cytoplasm, mitochondria and endoplasmic reticulum. There is widespread clinical interest in Hsp chaperone function in a number of human pathologies including cancer, neurodegenerative conditions, aging, and cardiovascular diseases. Our understanding of Hsp function in pathological situations has been greatly advanced by the development of mutant mouse models. In this grant the major goal is to define a framework of interactions between three major heat shock proteins, constitutive HscVO, its inducible counterpart HspVOi and the small molecular weight Hsp27 (mouse Hsp25), which play intimate roles in tumor development by modulating endothelial cell differentiation and thus neoangiogenesis, and by affecting molecular pathways for cell survival/death. Mutant mice deficient in these heat shock proteins generated by conventional or conditional gene targeting strategies offer unique opportunities to address these important issues in the cancer biology at the whole organism level. During the next project period we plan to follow two aims: (1) To define the functional contribution of HspVOi, HscVO or Hsp25 in tumor vasculogenesis and/angiogenesis. (2) To characterize the physiological roles of Hsp70i, Hsc70, and Hsp25 in regulating the stress response and define their contribution to tumor development in vivo. The proposed studies will help to achieve a better understanding of the fundamental cellular processes in which these molecular chaperones engage to promote tumor growth, and may help to develop strategies to modulate specific chaperone-dependent host pathways as a therapeutic approach to combat human cancers and other relevant diseases.