Function of inducible HSP70 genes in mouse model

描述：许多遗传性和获得性人类疾病是由生产造成的。 由于突变或极端压力条件而错误折叠的蛋白质，这 扰乱许多细胞代谢过程，最终导致细胞死亡。作为一名 防御策略，细胞通过快速合成热量来响应这些压力 休克或应激蛋白(HSPs)，修复或降解受损的蛋白质。这个 可诱导的hsp7O亚家族，包含两个在系统发育上保守的 其成员(hsp7O.1和hsp70.3)在小鼠体内具有独特的功能。这些 蛋白质充当分子伴侣，防止错误折叠的聚集 蛋白质；它们还帮助重折叠、运输和组装 细胞质、线粒体和内质网中的蛋白质。的确有 一些人类对hsp70O伴侣功能的广泛临床兴趣 包括癌症、神经退行性疾病、衰老和 心血管疾病。然而，努力理解的功能作用 体内应激诱导的hsp7os由于缺乏实验研究而受到阻碍。 模特们。为此，我们通过替换HSP7O缺陷小鼠 Hsp7O.1或hsp70.3基因的整个编码区 β-半乳糖苷酶基因序列。这些突变的小鼠提供了一个独特的机会 在动物模型中研究诱导型HSP70的调节，并允许 对它在癌症等临床意义状态下的作用的研究， 缺血、高热、炎症、血管肥大和氧化 压力。这项建议的具体目的是：(1)研究转录 Hsp7O.1或hsp70.3基因在发育和成人中的调控 组织在正常和环境应激条件下。(2)分析 热休克蛋白70的功能。1或hsp70.3基因在体内维持耐受中的作用 并确定它们对炎症、保护作用的贡献 从缺血，到肿瘤细胞存活。(3)审查政府部门的职能是否 获得性耐热性与应激保护中的诱导型HSP70 在发育过程中和成人中，辐射和缺血等情况 HSP的其他相关成员是不可或缺的，无法弥补 一家人。这里提出了对完全没有诱导性的突变小鼠的研究。 HSP70表达(两种HSP70均缺乏)。1和hsp703基因)。建议数 研究将帮助我们更好地理解基本的细胞 HSP70分子伴侣参与应答的过程 环境应激，以及确定它们在临床上的作用 人类的相关病理。

DESCRIPTION: Many heritable and acquired human diseases result from production of misfolded proteins due to mutations or extreme stress conditions, which disrupt numerous cellular metabolic processes and culminate in cell death. As a defense strategy, cells respond to these stresses by rapidly synthesizing heat shock or stress proteins (hsps), which repair or degrade damaged proteins. The inducible hsp7O subfamily, which contains two phylogenetically conserved members (hsp7O.1 and hsp7O.3) in mice, is unique in its function. 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 hsp7O chaperone function in a number of human pathologies including cancer, neurodegenerative conditions, aging, and cardiovascular diseases. However, efforts to understand the functional roles of stress-inducible hsp7Os in vivo have been hampered by a lack of experimental models. To this effect, we have generated mice deficient in hsp7O by replacing the entire coding region of the hsp7O.1 or hsp70.3 gene with an in frame b-galactosidase gene sequence. These mutant mice offer an unique opportunity to study in an animal model the regulation of inducible hsp70, and allow for studies of it's function in clinically significant states such as cancer, ischemia, hyperthermia, inflammation, vascular hypertrophy, and oxidative stress. The specific aims of this proposal are: (1) To study transcriptional regulation of the hsp7O.1 or hsp70.3 genes during development and in adult tissues under normal and environmental stress conditions. (2) To analyze the function of the hsp70. 1 or hsp70.3 genes in maintenance of tolerance in vivo to thermal stress and to define their contribution to inflammation, protection from ischemia, and tumor cell survival. (3) To examine whether the function of inducible hsp70 in acquired thermotolerance and protection from stress situations such as radiation and ischemia, during development and in adult is indispensable and cannot be compensated by other related members of the hsp family. Here studies are proposed on mutant mice completely devoid of inducible hsp70 expression (deficient in both hsp70. 1 and hsp7o.3 genes). The proposed studies will help us achieve a better understanding of the fundamental cellular processes in which hsp70 molecular chaperones engage to respond to environmental stresses, as well as to determine their role in clinically relevant pathologies in humans.