Calcium Signaling in Dendritic Cell Function

超出提供的空间。树突状细胞(DC)是一种由稀有的白细胞组成的异质性群体，具有高度的免疫监视、诱导和调节原发免疫反应的功能。这种独特的能力反映了它们持续采样微环境并摄取外来和自身抗原的能力。在遇到微生物、炎症分子或过敏原形式的“危险”刺激后，DC转化为强大的刺激细胞，并迁移到次级淋巴组织，在那里它们触发抗原特异性效应器T细胞的激活。这些过程背后的信号通路无疑是复杂的，但细胞内钙似乎扮演着关键角色。我们最近在DC中描述了两个新的钙信号通路。首先，我们鉴定了DC中的骨骼肌型ryanodine受体(RyR1)。RyR1是一个巨大的细胞内通道，可以放大细胞内的微小钙瞬变，从而产生更大、更持续的钙升高。第二，我们已经证明了钙离子通量触发了DC的快速分泌。这些途径使DC能够对外界刺激做出快速反应，并释放自分泌和旁分泌信号因子，包括外体和无引导性分泌蛋白。本研究的目的是确定DC中RyRl-钙调节通路。我们假设RyR1整合了不同的细胞刺激，并介导了驱动DC功能的钙通路。我们概述了一种跨学科的方法来研究这些钙信号机制的性质，并了解它们如何参与DC生物学。我们将通过追求以下具体目标来实现本提案的目标：目标1.旨在确定RyR1在DC发展和功能中的作用。目的2检测RyR1内源性激活剂和药理激活剂对DC的影响。在目标3中，我们将阐明钙触发的分泌在DC中的作用。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. Dendritic cells (DC) are a heterogeneous population of rare leukocytes highly specialized for immune- surveillance, and the induction and regulation of primary immune responses. This unique capacity reflects their ability to continuously sample the microenvironment and ingest foreign and self antigens. After encountering a "danger" stimulus in the form of microbes, inflammatory molecules or allergens, DC transform into potent stimulatory cells and migrate to secondary lymphoid tissues, where they trigger the activation of antigen-specific effector T cells. The signaling pathways that underlie these processes are undoubtedly complex, but intracellular calcium appears to play a crucial role. We have recently characterized two novel calcium signaling pathways in DC. First, we have identified the skeletal muscle-type ryanodine receptor (RyR1) in DC. RyR1 is a massive intracellular channel that can amplify small calcium transients within a cell to produce much larger, sustained calcium rises. Second, we have demonstrated that calcium fluxes trigger rapid secretion by DC. Such pathways enable DC to respond rapidly to external stimuli, and release autocrine and paracrine signaling factors including exosomes and leaderless secretory proteins. The goal of this proposal is to determine the RyRl-calcium regulated pathways in DC. We hypothesize that RyR1 integrates diverse cellular stimuli, and mediates the calcium pathways that drive DC function. An inter-disciplinary approach is outlined to investigate the properties of these calcium signaling mechanisms and understand how they participate in DC biology. We will accomplish the objectives of this proposal by pursuing the following specific aims: Aim 1. is designed to determine the role of RyR1 during DC development and fucntion. Aim 2 tests the impact of endogenous and pharmacologic activators of RyR1 on DC. In Aim 3, we will elucidate the role of calcium triggered secretion in DC. PERFORMANCE SITE ========================================Section End===========================================