IL-1R1 promoter complex in the neuroendocrine, nervous, and immune systems

描述（由申请人提供）：I型白介素-1受体（IL-1R1）是IL-1的功能性受体。IL-1介导神经内分泌、神经和免疫系统的许多活动。IL-1R1的转录调控尚不清楚。我们实验室目前的工作已经确定了三种控制小鼠IL-1R1转录的启动子。这些IL-1R1启动子的活性具有组织特异性、细胞类型特异性和发育阶段依赖性。此外，这些启动子被发现受到外源和内源遗传调控元件的调控。在体内，三种小鼠IL-1R1启动子的活性表现出不同的分布模式。此外，这些IL-1R1启动子受到信号分子（如糖皮质激素）的差异调节。我们进行了鼠与人IL-1R1结构的物种比较研究。比对得到的人和小鼠IL-1R1启动子区域揭示了一个保守的框架，这两个物种的IL-1R1基因可能受到保守的调控序列的调控。这些初步发现使我们确定了一个称为IL-1R1启动子复合物的遗传区域。该应用的中心假设是：1)在给定细胞中表达的IL-1R1 mrna的水平和类型由IL-1R1启动子复合物调节；2) IL-1R1启动子复合体的转录调控机制决定了IL-1R1的组织和细胞特异性表达；3) IL-1R1启动子复合物有助于IL-1R1承载细胞在受到信号分子刺激时的精确响应特性。我们将追求以下具体目标：1)确定启动子特异性IL-1R1表达的分布模式；2)阐明IL-1R1启动子复合物的转录调控机制；3)研究不同信号分子刺激细胞后IL-1R1基因启动子活性。这些结果将揭示IL-1R1的组织特异性和细胞类型特异性表达和调控的转录机制，这可能是多种系统中IL-1R1功能多样性的关键。本研究将对IL-1R1的生物学研究做出重要贡献，并为我们了解IL-1R1转录如何参与发病机制提供新的基础。本研究探讨了控制1型白介素-1受体表达的转录机制。这种受体对神经、神经内分泌和免疫系统的许多功能都很重要。该结果将为理解1型白细胞介素-1受体表达失调如何参与多系统疾病的发病机制提供基础。

DESCRIPTION (provided by applicant): Type I interleukin-1 receptor (IL-1R1) is the functional receptor for IL-1. IL-1 mediates numerous activities in the neuroendocrine, nervous, and immune systems. The transcriptional regulation of IL-1R1 is poorly understood. Current work in our lab has identified three promoters that control the transcription of IL-1R1 in mouse. The activities of these IL-1R1 promoters are tissue-specific, cell type-specific and dependent on developmental stages. In addition, these promoters are found to be regulated by exogenous as well as endogenous genetic regulatory elements. In vivo, the activities of the three murine IL-1R1 promoters showed distinct distribution patterns. Further, these IL-1R1 promoters are differentially regulated by signaling molecules, such as glucocorticoids. A species comparison study between murine and human IL-1R1 structures has been conducted. Aligning the resulting human and murine IL-1R1 promoter regions revealed a conserved framework by which IL-1R1 gene in both species are likely to be regulated by conserved regulatory sequences. These preliminary discoveries lead us to define a genetic region termed IL-1R1 promoter complex. The central hypotheses of this application are: 1) the level and type of IL-1R1 mRNAs expressed in a given cell are regulated by the IL-1R1 promoter complex; 2) the transcriptional control mechanisms in the IL-1R1 promoter complex determine the tissue- and cell type-specific expression of IL-1R1; and 3) IL-1R1 promoter complex contributes to the precise response characteristics of IL-1R1-bearing cells when they are stimulated by signaling molecules. We will pursue the following specific aims: 1) Determine the pattern of distribution of the promoter-specific IL-1R1 expression; 2) Elucidate transcriptional control mechanisms of the IL-1R1 promoter complex; and 3) Investigate promoter activity of IL-1R1 gene in selected cell types after the cells are stimulated by different signaling molecules. The results will reveal the transcriptional mechanisms that allow tissue-specific and cell type-specific expression and regulation of IL-1R1 that may be critical for the vast diversity of IL-1R1 function in multiple systems. This study will contribute significantly to IL-1R1 biology and provide a new foundation for our understanding of how IL-1R1 transcription might be involved in pathogenesis. for "IL-1R1 promoter complex in the neuroendocrine, nervous, and immune system" This study investigates the transcriptional mechanisms that control the expression of the type 1 interleukin-1 receptor. This receptor is important for many functions in the nervous, neuroendocrine, and immune systems. The results will provide a foundation for the understanding of how dysregulation of the expression of type 1 interleukin-1 receptor may be involved in the pathogenesis of diseases in multiple systems.