Heat Shock Factor-1 and Death Ligand Expression

热休克因子 1 和死亡配体表达

• 批准号: 7935078
• 负责人: HELEN MARY BEERE
• 金额: $ 11.47万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7935078
• 关键词: Address; Animals; Apoptosis; Apoptotic; Calcium; Cell Death; Cell physiology; Cells; Cellular Stress Response; Cessation of life; Event; Fibrinogen; Gene Expression; Gene Targeting; Generations; Genetic Transcription; Harvest; Heat shock proteins; Heat-Shock Response; Homeostasis; Immune; Immune system; Lead; Ligands; Ligation; Maintenance; Mediating; Nature; Nuclear Translocation; Pathway interactions; Pattern; Peripheral; Phosphorylation; Phosphotransferases; Physiological; Play; Post-Translational Protein Processing; Reactive Oxygen Species; Receptor Activation; Regulation; Regulatory Pathway; Role; Shock; Signal Pathway; Signal Transduction; Stress; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Transcriptional Regulation; Tumor Necrosis Factor Ligand Superfamily Member 6; Up-Regulation; base; biological adaptation to stress; cell type; heat-shock factor 1; immune function; in vivo; mouse HSF1 protein; novel; programs; protein expression; response; stressor; transcription factor

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）：应激途径的激活和细胞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，HSF-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调节代表了细胞凋亡转录调节的范例，对免疫系统的稳态调节具有影响。该提案探讨了热休克因子 1 (HSF-1) 在免疫调节中的作用，以及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。死亡配体表达改变的生理后果最好的例证是 (i) 激活诱导细胞死亡 (AICD) 和 (ii) T 淋巴细胞外周缺失中 FasL 的升高。我们建议利用 HSF-1-/- 小鼠和从这些动物中收获的细胞来确定 HSF-1 在 FasL 表达上调和细胞对 Fas 介导的细胞凋亡（与 AICD 和外周缺失相关）敏感中的作用 (b) T 细胞受体激活导致哪些信号通路激活直接影响 HSF-1 的转录活性以调节死亡配体表达 (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，该目标将确定 HSF-1 的非热休克靶标，并且重要的是确定 NFAT 和 HSF-1 之间的新型合作相互作用。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，通过调节死亡配体的表达来调节细胞对损伤的敏感性。总之，我们想提出，HSF-1响应多种应激源的普遍激活代表了协调调节多种非热休克靶基因（包括那些密切参与细胞凋亡调节的靶基因）的基本机制。 HSF-1 与其他转录因子（其中之一可能是 NFAT）的协同相互作用，可以根据应激的性质和持续时间，并可能以细胞类型特异性的方式，差异性地调节基因表达。概述的研究将剖析 T 细胞受体激活产生的信号，这些信号影响 HSF-1 活性，以调节死亡配体表达和细胞凋亡敏感性，并通过这样做将定义涉及 T 细胞功能和免疫稳态维持的新调节途径。