Novel Calcium Release Mechanism Regulates Dendritic Cell Function

新型钙释放机制调节树突状细胞功能

基本信息

批准号：
8670693
负责人：
Santiago Partida-Sanchez
金额：
$ 36.2万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8670693
关键词：
Adenosine Diphosphate Ribose Affect Antigen Presentation Antigen-Presenting Cells Binding Proteins Biological Calcium Calcium/calmodulin-dependent protein kinase Calpain Cell Maturation Cell membrane Cell physiology Cells Cellular biology Chemotaxis Chronic Clinical Communicable Diseases Crohn&apos s disease Data Dendritic Cells Development Disease Endoplasmic Reticulum Escherichia coli Exhibits Goals Grant Homeostasis Immune Immune response Immune system Immunity Immunization Infection Infiltration Inflammation Inflammatory Knowledge Life Lymphocyte Lysosomes Mediating Mitogen-Activated Protein Kinase Kinases Molecular Mucous Membrane Mus Pathway interactions Phagocytes Phagocytosis Phagosomes Play Process Production Protein Tyrosine Kinase Psoriasis Regulation Relative (related person)Research Rest Role Shapes Signal Pathway Signal Transduction Signal Transduction Pathway Skin Testing Urinary tract Urinary tract infection Vesicle Work adaptive immunity antigen processing base cell motility cell type chemokine chemokine receptor cytokine design extracellular in vivo insight macrophage migration mouse model neutrophil new therapeutic target novel novel therapeutics receptor research study response sulfated glycoprotein 2 trafficking

项目摘要

DESCRIPTION (provided by applicant): Dendritic cells (DCs) are multi-potent regulators of the immune system. Many critical DC functions involve calcium (Ca2+) signaling. Ca2+ is the most versatile eukaryotic intracellular messenger that mediates regulation of many processes important to cell life. Ca2+ levels in DCs and many other immune cell types are tightly regulated through multiple mechanisms during the resting state as well as during activation. Chemokine receptor stimulation increases intracellular Ca2+ concentration ([Ca2+]i) and chemotaxis in DCs. Despite important advances in our understanding of Ca2+ signaling in lymphocytes, the molecular players involved in shaping intracellular Ca2+ in DCs remain to be characterized. The current paradigm states that increases in DC cytosolic Ca2+ levels are caused by release from endoplasmic reticulum (ER) Ca2+ stores and/or via influx of extracellular Ca2+ by opening of store-operated Ca2+ channels at the plasma membrane. We propose a novel Ca2+ release mechanism in DCs, which operates via a Ca2+ channel expressed on lysosomal compartments and, we postulate this pathway is essential for Ca2+-dependent DC functions. Preliminary data that support our proposal show: i) Exclusive localization of functional Ca2+-permeant melastatin-related transient receptor potential channel (TRPM2) in endolysosomal compartments of DCs. ii) Both adenosine diphosphoribose (ADPR) and chemokines induce TRPM2 mediated Ca2+ signals in DCs, iii) TRPM2 channel acts as a Ca2+ release channel in DCs. iv) TRPM2-deficient DCs exhibit impaired chemotactic responses to chemokines. v) TRPM2-deficient mice elicit reduced inflammatory recruitment upon infection. Based upon these data, we hypothesize that: TRPM2 functions as an intracellular lysosome- associated calcium release channel that regulates Ca2+-dependent processes in DCs. To critically test our hypothesis, we propose the following specific aims: Aim 1. Identify mechanisms of activation of Ca2+ release via TRPM2 channel, and elucidate how this pathway impacts on DC Ca2+-dependent functions. Aim 2. Define the specific roles for TRPM2-mediated Ca2+ signaling in DCs during inflammation, immunization and cellular inflammatory infiltration to the mucosa using a mouse model of urinary tract infection. The findings from this proposal will provide insights into how the intracellular function of TRPM2 channel affects Ca2+-mediated signal transduction pathways that play a central regulatory role during DC responses. The completion of these studies will unveil the utility of new pharmacological targets (ADPR and/or TRPM2) for manipulation of DCs' Ca2+responses and functions, and will further facilitate the design of new therapeutic strategies for chronic inflammatory or infectious diseases, where DCs may play important pathogenic roles.

描述（由申请人提供）：树突状细胞（DC）是免疫系统的多能调节剂。许多关键的 DC 功能都涉及钙 (Ca2+) 信号传导。 Ca2+ 是最通用的真核生物细胞内信使，介导对细胞生命重要的许多过程的调节。 DC 和许多其他免疫细胞类型中的 Ca2+ 水平在静息状态和激活期间通过多种机制受到严格调节。趋化因子受体刺激可增加 DC 细胞内 Ca2+ 浓度 ([Ca2+]i) 和趋化性。尽管我们对淋巴细胞中 Ca2+ 信号传导的理解取得了重要进展，但参与形成 DC 细胞内 Ca2+ 的分子参与者仍有待表征。目前的范式指出，DC 胞质 Ca2+ 水平的增加是由内质网 (ER) Ca2+ 储存的释放和/或通过在质膜处打开储存操作的 Ca2+ 通道而流入细胞外 Ca2+ 引起的。我们提出了 DC 中一种新型的 Ca2+ 释放机制，该机制通过溶酶体区室上表达的 Ca2+ 通道发挥作用，并且我们假设该途径对于 Ca2+ 依赖性 DC 功能至关重要。支持我们建议的初步数据显示： i) 功能性 Ca2+ 通透性褪黑素相关瞬时受体电位通道 (TRPM2) 在 DC 的内溶酶体区室中的独家定位。 ii) 腺苷二磷酸核糖 (ADPR) 和趋化因子均在 DC 中诱导 TRPM2 介导的 Ca2+ 信号，iii) TRPM2 通道在 DC 中充当 Ca2+ 释放通道。 iv) TRPM2缺陷的DC表现出对趋化因子的趋化反应受损。 v) TRPM2 缺陷小鼠在感染时引起炎症募集减少。基于这些数据，我们假设： TRPM2 作为细胞内溶酶体相关的钙释放通道发挥作用，调节 DC 中 Ca2+ 依赖性过程。为了严格检验我们的假设，我们提出以下具体目标：目标 1. 确定通过 TRPM2 通道激活 Ca2+ 释放的机制，并阐明该途径如何影响 DC Ca2+ 依赖性功能。目标 2. 使用尿路感染小鼠模型确定炎症、免疫和细胞炎症浸润粘膜期间 DC 中 TRPM2 介导的 Ca2+ 信号传导的具体作用。该提案的结果将深入了解 TRPM2 通道的细胞内功能如何影响 Ca2+ 介导的信号转导途径，这些信号转导途径在 DC 反应过程中发挥核心调节作用。这些研究的完成将揭示新的药理学靶点（ADPR和/或TRPM2）在操纵DC的Ca2+反应和功能方面的实用性，并将进一步促进针对慢性炎症或传染病的新治疗策略的设计，其中DC可能发挥重要的致病作用。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CXCL10 induces the recruitment of monocyte-derived macrophages into kidney, which aggravate puromycin aminonucleoside nephrosis.

CXCL10诱导单核细胞源性巨噬细胞募集至肾脏，从而加重嘌呤霉素氨基核苷肾病。

DOI：
发表时间：
2015-05
期刊：
影响因子：
4.6
作者：
Petrovic;Popovic, M;Chittiprol, S;Cortado, H;Ransom, R F;Partida
通讯作者：
Partida

MIF Promotes Classical Activation and Conversion of Inflammatory Ly6C(high) Monocytes into TipDCs during Murine Toxoplasmosis.

MIF 促进鼠弓形虫病期间炎症性 Ly6C(高) 单核细胞经典激活和转化为 TipDC。

DOI：
发表时间：
2016
期刊：
影响因子：
4.6
作者：
Ruiz;Olguín, Jonadab E;Juárez;Saavedra, Rafael;Terrazas, Luis I;Robledo;Vazquez;Fernández, Jacquelina;Satoskar, Abhay R;Partida;Rodriguez
通讯作者：
Rodriguez

Intrauterine growth restriction is a direct consequence of localized maternal uropathogenic Escherichia coli cystitis.

宫内生长受限是局部母体尿路致病性大肠杆菌膀胱炎的直接后果。