Function of HSPs in mouse models for human diseases

描述(申请人提供)：应激反应是一种进化保守的细胞反应机制，其特征是热休克蛋白(HSPs)的合成和积累增强。这些蛋白质充当分子伴侣，防止错误折叠的蛋白质聚集；它们还帮助蛋白质在细胞质、线粒体和内质网中的重折叠、运输和组装。热休克蛋白的伴侣功能在包括癌症、神经退行性疾病、衰老和心血管疾病在内的许多人类病理中具有广泛的临床意义。随着突变小鼠模型的发展，我们对热休克蛋白在病理情况下的功能有了很大的了解。在这项授权中，主要目标是定义三种主要热休克蛋白之间的相互作用框架，结构性HscVO、其可诱导的对应物HspVOi和小分子量HSP27(小鼠HSP25)，它们通过调节内皮细胞分化和新血管生成，并通过影响细胞生存/死亡的分子途径，在肿瘤的发展中发挥密切作用。由常规或条件性基因打靶策略产生的缺乏这些热休克蛋白的突变小鼠为在整个生物体水平上解决癌症生物学中的这些重要问题提供了独特的机会。在下一个项目期间，我们计划遵循两个目标：(1)确定HspVOi、HscVO或HSP25在肿瘤血管生成和/或血管生成中的功能贡献。(2)研究HSP70i、Hsc70和HSP25在调节应激反应中的生理作用，明确它们在体内肿瘤发展中的作用。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基本细胞过程，并可能有助于制定策略，调节特定的伴侣依赖宿主途径，作为对抗人类癌症和其他相关疾病的治疗方法。

DESCRIPTION (provided by applicant): 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.