Function of HSPs in mouse models for human diseases

应激反应是一种进化保守的细胞反应机制，其特征是 促进热休克蛋白(HSPs)的合成和积累。这些蛋白质作为分子发挥作用 伴侣和防止错误折叠的蛋白质聚集；它们还帮助重折叠、运输和 蛋白质在细胞质、线粒体和内质网中的组装。有一种广泛的 热休克蛋白伴侣功能在包括癌症在内的许多人类病理中的临床意义 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 突变小鼠模型的发展极大地改善了病理情况。在这 格兰特的主要目标是定义三种主要热休克蛋白之间相互作用的框架， 结构型HscVO及其诱导型HspVOi和小分子Hsp27(小鼠) HSP25)，它们通过调节内皮细胞分化和 因此，新的血管生成，并通过影响细胞生存/死亡的分子途径。缺乏突变的小鼠 在这些由常规或条件性基因打靶策略产生的热休克蛋白中提供了独特的 在整个生物体水平上解决癌症生物学中的这些重要问题的机会。在.期间 在下一个项目期，我们计划遵循两个目标：(1)确定HspVOi的功能贡献， HscVO或HSP25在肿瘤血管生成和/或血管生成中的作用(2)确定人的生理作用 HSP70i、Hsc70和HSP25在调节应激反应中的作用及其在肿瘤中的作用 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，并可能有助于 制定策略来调节特定的依赖于伴侣的宿主通路作为治疗方法 抗击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.