Function of HSPs in mouse models for human diseases

热休克蛋白在人类疾病小鼠模型中的功能

• 批准号: 7268225
• 负责人: Dimitrios Moskofidis
• 金额: $ 25.81万
• 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 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7268225
• 关键词: Ablation; Address; Advanced Development; Affect; Aging; Animal Model; Aorta; Apoptosis; Biochemical Genetics; Blood Vessels; Bone Marrow; Breast Cancer Model; Cancer Biology; Cardiovascular Diseases; Cell Differentiation process; Cell Survival; Cell physiology; Cells; Cessation of life; Clinical; Comparative Study; Condition; Cytoplasm; Data; Development; Disease; Disruption; Dissection; Embryonic Development; Endoplasmic Reticulum; Endothelial Cells; Ensure; Epithelial; Experimental Designs; Gene Targeting; Goals; Grant; Growth; Heat shock proteins; Human; Human Pathology; Inhibition of Apoptosis; Literature; Lymphoma; Maintenance; Malignant Neoplasms; Mediating; Mitochondria; Molecular; Molecular Chaperones; Molecular Weight; Mus; Mutant Strains Mice; Neoplasm Transplantation; Neoplasms in Vascular Tissue; Nerve Degeneration; Numbers; Pathway interactions; Physiological; Play; Process; Proteins; Relative (related person); Research Personnel; Role; Signal Pathway; Signal Transduction; Stem cells; Stimulus; Stress; System; TP53 gene; Technology; Testing; Therapeutic; Transgenic Mice; Tumor Angiogenesis; Whole Organism; angiogenesis; base; biological adaptation to stress; c-myc Genes; cell growth; cell transformation; chaperone machinery; heat shock transcription factor; human disease; in vivo; interest; knockout gene; mouse model; mutant mouse model; neoplastic cell; prevent; programs; protein folding; protein misfolding; repaired; research study; response; tumor; tumor growth; tumor progression; tumorigenesis; vasculogenesis

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.

描述（由申请人提供）：应激反应是一种进化上保守的细胞反应机制，其特征在于热休克蛋白（Hsps）的合成和积累增强。这些蛋白质充当分子伴侣并防止错误折叠蛋白质的聚集;它们还协助蛋白质在细胞质、线粒体和内质网中的重折叠、运输和组装。在许多人类病理学中，包括癌症、神经退行性疾病、衰老和心血管疾病，Hsp分子伴侣的功能受到广泛的临床关注。突变小鼠模型的发展使我们对病理状态下热休克蛋白功能的理解有了很大的进展。在这项研究中，主要目标是确定三种主要热休克蛋白之间的相互作用框架，即组成型HscVO、其诱导型对应物HspVO 1和小分子量Hsp 27（小鼠Hsp 25），它们通过调节内皮细胞分化和新生血管生成以及影响细胞存活/死亡的分子途径在肿瘤发展中发挥密切作用。通过常规或条件性基因靶向策略产生的这些热休克蛋白缺陷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HspVO 1、HscVO或Hsp 25在肿瘤血管发生和/或血管生成中的功能贡献。(2)为了表征Hsp 70 i、Hsc 70和Hsp 25在调节应激反应中的生理作用，并确定它们在体内肿瘤发展中的贡献。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来调节特定的伴侣依赖性宿主途径，作为对抗人类癌症和其他相关疾病的治疗方法。