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

描述（申请人提供）：I型白细胞介素-1受体（IL-1 R1）是IL-1的功能性受体。IL-1介导神经内分泌、神经和免疫系统中的许多活动。IL-1 R1的转录调控知之甚少。本实验室目前的工作已经确定了三个控制小鼠IL-1 R1转录的启动子。这些IL-1 R1启动子的活性是组织特异性的、细胞类型特异性的并且依赖于发育阶段。此外，发现这些启动子受外源性以及内源性遗传调控元件的调控。在体内，三种小鼠IL-1 R1启动子的活性显示出不同的分布模式。此外，这些IL-1 R1启动子受信号分子如糖皮质激素的差异调节。已经进行了鼠和人IL-1 R1结构之间的种属比较研究。比对所得的人和鼠IL-1 R1启动子区域揭示了一个保守的框架，两个物种中的IL-1 R1基因可能通过该框架受到保守调节序列的调节。这些初步发现使我们确定了一个称为IL-1 R1启动子复合物的基因区域。本申请的中心假设是：1）在给定细胞中表达的IL-1 R1 mRNA的水平和类型由IL-1 R1启动子复合物调节; 2）IL-1 R1启动子复合物中的转录控制机制决定IL-1 R1的组织和细胞类型特异性表达; 3）IL-1 R1启动子复合物有助于携带IL-1 R1的细胞在受到信号分子刺激时的精确反应特性。我们将追求以下具体目标：1）确定启动子特异性IL-1 R1表达的分布模式; 2）阐明IL-1 R1启动子复合物的转录控制机制; 3）研究IL-1 R1基因在所选细胞类型中受不同信号分子刺激后的启动子活性。这些结果将揭示允许组织特异性和细胞类型特异性表达和调节IL-1 R1的转录机制，这可能对多种系统中IL-1 R1功能的巨大多样性至关重要。这项研究将大大有助于IL-1 R1的生物学，并为我们了解IL-1 R1的转录可能参与发病机制提供了新的基础。为“神经内分泌、神经和免疫系统中的IL-1 R1启动子复合物”而作本研究探讨了控制1型白细胞介素-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中的许多功能都很重要。本研究结果将为了解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.