Role of Sec7 Domain Guanine Nucleotide Exchange Factors in Membrane Traffic

所有的细胞生命都需要膜交通。在多细胞生物体中，细胞外基质的沉积和细胞黏附、生长因子和营养物质的释放和吸收以及表面信号和刺激接收都需要膜运输，这些过程整合了组织和器官的发育和生理反应。了解控制膜流动的调节机制为理解疾病中的细胞功能障碍提供了重要的框架。一个称为ADP-核糖化因子(ARF)的小GTP酶家族通过在运输小泡形成过程中成核涂层复合体来控制膜运输的关键方面。ARF在膜运输中的正常功能需要它们的激活。ARF被一系列鸟嘌呤核苷酸交换因子(GEF)激活。这些GEF作用于ARF的上游，拦截内部和外部线索，然后将其转化为ARF激活。因此，了解全球环境基金的功能对于了解ARF是如何被激活以及如何调节膜交通是至关重要的。研究人员旨在描述全球环境基金调控的三个方面。首先，他们将定义GEF如何定位于亚细胞隔室。全球环境基金的细胞内定位是至关重要的，因为它定义了ARF激活的位置，并在空间上限制了随后的效应器级联。其次，他们将定义全球环境基金的领域结构如何与其功能相关联。第三，他们将确定影响全球环境基金活动的外部和内部信号。该项目对教育、科学公平、跨学科协同作用和科学基础设施产生广泛影响。这些研究将促进对本科生和研究生以及博士后研究员的培训，重点是培训代表性不足群体的成员。该项目与物理和数学相结合，以开发生物过程的模型。该项目将促进专业教育，增加少数群体在科学领域的代表性，促进跨学科研究，并开发对膜贩运领域重要的试剂和资源。

All cellular life requires membrane traffic. In multicellular organisms, membrane traffic is required for the deposition of the extracellular matrix and cell adhesion, the release and uptake of growth factors and nutrients, and surface signaling and stimulus reception, processes that integrate the developmental and physiological responses of tissues and organs. Understanding the regulatory mechanisms that govern membrane flow provides an essential framework for understanding cellular dysfunction in disease.A family of small GTPases called the ADP-ribosylation factors (ARFs) controls key aspects of membrane traffic by nucleating coating complexes during formation of transport vesicles. The proper function of ARFs in membrane traffic requires their activation. The ARFs are activated by a family of guanine nucleotide exchange factors (GEFs). These GEFs act upstream of ARFs to intercept and then translate internal and external cues into ARF activation. Therefore, understanding GEF function is essential for understanding how ARFs are activated and how membrane traffic is regulated.The investigators aim to characterize three aspects of GEF regulation. First, they will define how GEFs target to subcellular compartments. The intracellular localization of a GEF is critical since it defines the site of ARF activation and spatially restricts the ensuing effector cascade. Second, they will define how the domain structure of GEFs correlates with their function. Third, they will identify external and internal signals that modulate GEF activity. This project impacts broadly on education, scientific equity, inter-disciplinary synergy and scientific infrastructure. These studies will promote the training of undergraduate and graduate students and post-doctoral fellows, with emphasis on training members of underrepresented groups. The project interfaces with physics and mathematics to develop models of biological processes. The project will contribute to professional education, increase representation of minorities in sciences, promote inter-disciplinary research, and develop reagents and resources important to the membrane trafficking field.