REGULATION AND FUNCTION OF MAST CELL SECRETED PROTEINASES

肥大细胞分泌的蛋白酶的调节和功能

• 批准号: 7381490
• 负责人: Helen C Turner
• 金额: $ 26.81万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381490
• 关键词: REGULATION; FUNCTION; MAST; CELL; SECRETED

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mast cells are orchestrators of tissue immune responses to innate and adaptive challenge. Stimulation of mast cells results in the release of diverse pro-inflammatory mediators, including a class of secreted proteinases. These proteinases are central to the tissue remodeling that is a feature of physiological, and pathological, inflammatroy responses. The long-term objective of the current proposal is to understand the signaling pathways that control pro-inflammatory responses in mast cells. From this understanding, we hope to identify novel targets for intervention in the progression of inflammatory diseases. We will address three specific aims. As described above, mast cells respond to various pro-inflammatory stimuli, including IgE-mediated and innate immunological challenges, as well as to secretagogues and neurotransmitters. These diverse activation mechanisms for mast cells have one key commonality; all involve the sustained elevation of intracellular free-calcium levels. In fact, calcium mobilization using ionophore compounds is sufficient to induce mast cell activation in the absence of other stimuli. The calcium channels that permit this sustained calcium influx are important targets for therapeutic modulation of mast cell responses, but remain undefined at the molecular level. Immunological stimuli appear to induce a highly selective, store-operated calcium conductance. However, several other activating stimuli for mast cells cause the activation of NSCC, which may be encoded by members of the TRP family. The PI¿s laboratory has screened rodent and human mast cells for the representation of TRP channel mRNA and protein. Mast cells contain TRPV2 protein, which as not been described to respond to lipid ligands. TRPV4 message, but not protein, has been detected in mast cells, and the diverse activation mechanisms for this channel may encompass cannabinoids. The mast cells that we have examined do not contain TRPV1, but do express the cannabinoid-sensitive TRPA1 channel. The experiments that we now propose will aim to dissect the regulation, and function, of TRPA1 in mast cells.

该主题是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构是针对该中心的，这不是调查人员的机构。肥大细胞是组织免疫反应对先天和适应性挑战的编排。肥大细胞的刺激导致潜水促炎性介质的释放，包括一类分泌的蛋白酶。这些蛋白酶是组织重塑的核心，这是生理和病理，炎症反应的特征。当前建议的长期目标是了解控制肥大细胞中促炎反应的信号传导途径。从这种理解中，我们希望确定炎症性疾病进展的新颖目标。我们将解决三个具体目标。如上所述，肥大细胞对各种促炎性刺激有反应，包括IgE介导的和先天的免疫学挑战，以及促分泌物和神经递质。这些针对肥大细胞的发散激活机制具有一个关键的共性。所有这些都涉及细胞内自由钙升高的持续升高。实际上，使用离子载体化合物动员钙动员足以在没有其他刺激的情况下诱导肥大细胞活化。允许这种持续钙影响的钙通道是肥大细胞反应热调节的重要目标，但在分子水平上保持不确定。免疫学刺激似乎会诱导高度选择性的储存钙电导。但是，肥大细胞的其他几种激活刺激会导致NSCC的激活，这可能由TRP家族的成员编码。 Pi s实验室已经筛选了啮齿动物和人类肥大细胞，以表示TRP通道mRNA和蛋白质。肥大细胞含有TRPV2蛋白，该蛋白没有被描述为对脂质配体有反应。在肥大细胞中已经检测到TRPV4消息，但没有蛋白质，该通道的发散激活机制可能包含大麻素。我们检查的肥大细胞不含TRPV1，而是表达对大麻素敏感的TRPA1通道。我们现在建议的实验将旨在剖析肥大细胞中TRPA1的调节和功能。