Heat Shock Factor-1 and Death Ligand Expression

热休克因子 1 和死亡配体表达

• 批准号: 7157175
• 负责人: HELEN MARY BEERE
• 金额: $ 21.75万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7157175
• 关键词: CD95 molecule; NOD mouse; SCID mouse; T cell receptor; T lymphocyte; apoptosis; biological signal transduction; flow cytometry; gene induction /repression; genetic transcription; genetically modified animals; heat shock proteins; laboratory mouse; oxidative stress; protein kinase C; protein protein interaction; protein structure function; receptor expression

DESCRIPTION (provided by applicant): Activation of the stress pathway and engagement of the apoptotic program represent two fundamental cellular responses to damage. Coordination of the cellular stress response is mediated by the transcriptional activity of heat shock factor-1 (HSF-1), the primary regulator of heat shock protein expression. Stress-induced regulation of death ligand expression represents a paradigm for the transcriptional regulation of apoptosis with implications in the homeostatic regulation of the immune system. This proposal examines the role of heat shock factor-1 (HSF-1) in immune regulation as a consequence of its effects on the expression of death ligands. We will determine (a) if HSF-1 regulates the induction and consequences of FasL expression in vivo. The physiological consequences of altered death ligand expression are best exemplified by the elevation of FasL in (i) activation induced cell death (AICD) and (ii) peripheral deletion in T lymphocytes. We propose to utilize HSF-1-/- mice and cells harvested from these animals to determine the role of HSF-1 in the upregulation of FasL expression and sensitization of cells to Fas-mediated apoptosis that is associated with AICD and peripheral deletion (b) which of the signaling pathways activated as a consequence of T cell receptor activation impact directly on the transcriptional activity of HSF-1 to modulate death ligand expression and (c) the precise mechanism of HSF-1-mediated transcriptional regulation of FasL expression with emphasis on its interaction with NFAT. To that end, this aim will identify a non-heat shock target for HSF-1 and significantly, a novel cooperative interaction between NFAT and HSF-1. Ultimately, this aim will address if the transcriptional activity of HSF-1 represents a fundamental stress-responsive mechanism engaged to modulate cellular sensitivity to damage via regulation of the expression of the death ligands. In summary, we would like to propose that the ubiquitous activation of HSF-1 in response to multiple stressors represents a fundamental mechanism to coordinately regulate a variety of non-heat shock target genes including those intimately involved in the regulation of apoptosis. Co-operative interaction of HSF-1 with other transcription factors, one of which may be NFAT, could serve to differentially regulate gene expression according to the nature and duration of the stress and potentially in a cell type specific manner. The studies outlined will dissect those signals generated as a consequence of T cell receptor activation that impact on HSF-1 activity to regulate death ligand expression and sensitivity to apoptosis and by doing so will define a novel regulatory pathway involved in T cell function and maintenance of immune homeostasis.

描述(由申请人提供)：应激通路的激活和凋亡程序的参与代表了细胞对损伤的两种基本反应。细胞应激反应的协调是由热休克因子-1(HSF-1)的转录活性介导的，热休克因子-1是热休克蛋白表达的主要调节因子。应激诱导的死亡配体表达的调节代表了一种转录调节细胞凋亡的范例，在免疫系统的动态平衡调节中具有重要意义。这项建议研究了热休克因子-1(HSF-1)在免疫调节中的作用，作为其对死亡配体表达的影响的结果。我们将确定(A)HSF-1是否调节体内FasL表达的诱导和后果。死亡配体表达改变的生理后果最好的例证是T淋巴细胞中FasL的升高，包括(I)激活诱导的细胞死亡(AICD)和(Ii)外周血细胞缺失。我们建议利用HSF-1-/-小鼠和从这些动物获得的细胞来确定HSF-1在上调FasL表达和使细胞对Fas介导的与AICD和外周缺失相关的凋亡敏感中的作用：(B)T细胞受体激活所激活的信号通路中的哪一条直接影响HSF-1的转录活性以调节死亡配体的表达；以及(C)HSF-1介导的FasL表达转录调控的确切机制，重点是它与NFAT的相互作用。为此，这一目标将为HSF-1确定一个非热休克靶标，并显著地确定NFAT和HSF-1之间的一种新的合作相互作用。最终，这一目标将解决HSF-1的转录活性是否代表一种基本的应激反应机制，参与通过调节死亡配体的表达来调节细胞对损伤的敏感性。综上所述，我们认为，HSF-1在多种应激源作用下的普遍激活是协调调控多种非热休克靶基因的基本机制，包括那些与细胞凋亡调控密切相关的基因。HSF-1与其他转录因子的协同作用，其中之一可能是NFAT，可以根据应激的性质和持续时间，并可能以一种细胞类型特有的方式，差异地调节基因的表达。这些研究将剖析由于T细胞受体激活而产生的影响HSF-1活性的信号，从而调节死亡配体的表达和对凋亡的敏感性，从而定义一条参与T细胞功能和维持免疫稳态的新的调控途径。