CONTROL OF SECRETION BY SMALL GTP BINDING PROTEINS

肥大细胞在过敏性疾病，包括哮喘， 同时也在防御压倒性的 细菌感染主要的效应机制是分泌 含有多种 炎症介质。我们的长期目标是了解 肥大细胞胞吐器的组成，了解其功能， 并确定其在哺乳动物生理学中的作用。Rab 3蛋白小 调节不同细胞内吞和外吞功能的GTP酶 类型，但其分子功能仍然知之甚少。我们有 发现Rab 3D定位于肥大细胞颗粒上，并移位至 胞吐时的质膜。我们假设它的缺失是由于 基因切除会导致结构上的改变， 正常表达的细胞分泌室的组织 分泌和内吞作用的细胞生理学变化 导致过敏原和微生物防御功能的改变 肥大细胞的变化;其他生物化学相互作用的变化 胞外机器的组分，特别是融合蛋白 Syntaxin及其调节Sec 1;以及整个动物生理学的变化 在过敏或感染性攻击的条件下。我们将测试这些 我们正在产生的Rab 3D缺失小鼠的假设，在现有的 Rab 3A缺失小鼠由于Rab 3A存在于肥大细胞的细胞质中， 和在双缺失小鼠中。我们的生化和细胞生理 分析将集中在从缺失小鼠中收获的肥大细胞上， 形态学分析将集中在肥大细胞和胰腺上 也富含Rab 3D实现我们的目标将提供 Rab 3蛋白的分子功能及其研究进展 了解肥大细胞在保护和 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.