Heat Shock Factor-1 and Death Ligand Expression

热休克因子 1 和死亡配体表达

• 批准号: 7087688
• 负责人: HELEN MARY BEERE
• 金额: $ 25.31万
• 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/7087688
• 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）：激活应力途径和凋亡程序的参与代表了两个对损害的基本细胞反应。细胞应力反应的配位是由热休克因子1（HSF-1）的转录活性（热休克蛋白表达的主要调节剂）的转录活性。压力诱导的死亡配体表达的调节代表了凋亡的转录调节范式，对免疫系统的体内稳态调节有影响。该提案研究了热休克因子1（HSF-1）在免疫调节中的作用，这是由于其对死亡配体表达的影响。我们将确定（a）HSF-1是否调节体内FASL表达的诱导和后果。在（i）激活诱导的细胞死亡（AICD）和（ii）T淋巴细胞中FASL升高的升高中，最好用（i）激活诱导细胞死亡（AICD）和（ii）T淋巴细胞中的FASL升高的生理后果。 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 （c）HSF-1介导的FASL表达转录调控的精确机制，重点是其与NFAT的相互作用。为此，此目标将确定HSF-1的非热冲击靶标，以及NFAT和HSF-1之间的新型合作相互作用。最终，如果HSF-1的转录活性代表了通过调节死亡配体的表达来调节细胞对损伤的敏感性，则该目标将解决。总而言之，我们想提出，HSF-1对多种应激源的无处不在激活代表了协调调节各种非热冲击靶基因的基本机制，包括密切涉及细胞凋亡的基因。 HSF-1与其他转录因子的合作相互作用（其中之一可能是NFAT）可以根据应力的性质和持续时间来差异地调节基因表达，并可能以细胞类型的特定方式来调节基因表达。概述的研究将剖析因T细胞受体激活而产生的那些信号，这些信号会影响HSF-1活性以调节死亡配体表达和对凋亡的敏感性，并且通过这样做将定义一种与T细胞功能和维持免疫稳态有关的新型调节途径。