CONTROL OF SECRETION BY SMALL GTP BINDING PROTEINS

肥大细胞在包括哮喘在内的过敏性疾病中发挥着核心作用， 并在防御铺天盖地的战斗中发挥着至关重要的作用 细菌感染。主要的作用机制是分泌 所制备的颗粒剂中含有多种不同的 炎症介质。我们的长期目标是了解分子 肥大细胞排胞机的组成，了解其功能， 并确定其在哺乳动物生理学中的作用。Rab3蛋白很小 不同细胞中调节胞外和胞内功能的GTP酶 类型，但其分子功能仍知之甚少。我们有 发现Rab3D定位于肥大细胞颗粒上，并移位到 胞吐时的质膜。我们假设它的缺席是由于 基因消融会导致结构的改变。 正常表达的细胞的分泌室的组织 Rab3D；分泌和内吞作用的细胞生理学变化 导致致敏和微生物防御功能的改变 肥大细胞；其他生物化学相互作用的变化 胞外机的组件，特别是融合蛋白 Synaxin及其调节因子Sec1与整个动物生理学的变化 在过敏或感染的条件下挑战。我们将测试这些 我们在现有的Rab3D Deletant小鼠中产生的假说 Rab3A缺失小鼠由于Rab3A存在于肥大细胞的细胞质中， 在双重删除小鼠中也是如此。我们的生化和细胞生理学 分析将集中在从Deletant小鼠身上获取的肥大细胞，以及 形态分析将集中在肥大细胞和胰腺上。 它也富含Rab3D。我们目标的实现将提供 Rab3蛋白分子功能的研究进展 理解肥大细胞在保护和保护环境中的作用 病理生理免疫功能。

Mast cells play a central role in allergic diseases, including asthma, and also have an essential role in defense against overwhelming bacterial infection. The principal effector mechanism is secretion of the contents of performed granules which contain a variety of inflammatory mediators. Our long term goals are to know the molecular composition of the mast cell exocytic machine, understand its function, and determine its role in mammalian physiology. Rab3 proteins are small GTPases that modulate exocytic and endocytic function in diverse cell types, but whose molecular function remains poorly understood. We have found that Rab3D is localized on mast cell granules and translocates to the plasma membrane upon exocytosis. We hypothesize that its absence due to gene ablation will result in alterations in the structural organization of the secretory compartment of cells normally expressing Rab3D; changes in the cellular physiology of secretion and endocytosis leading to alterations in the allergenic and microbial defence functions of mast cells; changes in biochemical interactions among other components of the exocytic machine, particularly the fusion protein Syntaxin and its regulatory Sec1; and changes in whole animal physiology under conditions of allergic or infectious challenge. We will test these hypotheses in Rab3D deletant mice that we are generating, in existing Rab3A deletant mice since Rab3A is found in the cytoplasm of mast cells, and in double deletant mice. Our biochemical and cell physiological analyses will focus on mast cells harvested from deletant mice, and the morphologic analysis will focus both on mast cells and on the pancreas which is also rich in Rab3D. Accomplishment of our goals will provide insight into the molecular function of Rab3 proteins and advance understanding of the role of mast cells in protective and pathophysiologic immune function.