Function of inducible HSP70 genes in mouse model

诱导型 HSP70 基因在小鼠模型中的功能

• 批准号: 6321415
• 负责人: Dimitrios Moskofidis
• 金额: $ 26.49万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6321415
• 关键词: apoptosis; developmental genetics; embryogenesis; environmental stressor; gene expression; gene targeting; genetic promoter element; genetic regulation; genetic transcription; genetically modified animals; heat shock proteins; immunocytochemistry; in situ hybridization; inflammation; laboratory mouse; mutant; myocardial ischemia /hypoxia; neoplastic cell; protein structure function; reporter genes; skin neoplasms; thermodynamics; tissue /cell culture; transcription factor; ultraviolet radiation

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.

描述：许多遗传性和获得性人类疾病的结果，从生产 由于突变或极端压力条件导致的错误折叠蛋白质， 破坏许多细胞代谢过程并最终导致细胞死亡。作为 防御策略，细胞通过快速合成热量来应对这些压力 休克或应激蛋白（hsps），修复或降解受损蛋白。的 诱导型hsp 70亚家族，其包含两个在遗传上保守的 在小鼠中，hsp70.1和hsp70.3的功能是独特的。这些 蛋白质作为分子伴侣，防止错误折叠的 蛋白质;它们还有助于重折叠，运输和组装 细胞质、线粒体和内质网中的蛋白质。有 hsp 7 O分子伴侣在许多人类中的功能引起了广泛的临床兴趣 病理学，包括癌症、神经退行性疾病、衰老和 心血管疾病然而，努力了解的职能作用， 体内应激诱导的hsp 70由于缺乏实验性的 模型为了达到这个效果，我们通过替换hsp 70， hsp70.1或hsp70.3基因的整个编码区， β-半乳糖苷酶基因序列。这些突变小鼠提供了一个独特的机会， 在动物模型中研究诱导型hsp 70的调节，并允许 研究它在临床上重要的状态，如癌症， 缺血、高热、炎症、血管肥大和氧化 应力本研究的具体目的是：（1）研究转录 hsp70.1或hsp70.3基因在发育和成年期的调控 正常和环境应力条件下的组织。(2)分析 HSP 70的功能。1或hsp70.3基因在体内耐受维持中的作用 并确定它们对炎症、保护 和肿瘤细胞存活的影响。(3)为了检查是否功能 诱导型热休克蛋白70在获得性热耐受和胁迫保护中作用 在发育期间和成年期， 不可或缺且不能由HSP的其他相关成员补偿 家人这里提出了对完全缺乏诱导因子的突变小鼠进行研究 hsp 70表达（两种hsp 70. 1和hsp70.3基因）。拟议 这些研究将帮助我们更好地理解细胞的基本功能， 热休克蛋白70分子伴侣参与的过程， 环境压力，以及确定其在临床上的作用， 人类的相关病理学。