Regulation of Cell Signaling by Transition Metal Dynamics

描述(申请人提供)：过渡金属对所有形式的生命都至关重要，而金属离子在各种基本的生物过程中扮演着重要的角色。金属代谢紊乱是一系列人类疾病的中心特征，然而，如果没有对金属如何影响正常细胞功能的基本了解，阐明金属状态改变是疾病的原因还是后果是极其困难的。虽然有一些关于金属如何驱动细胞变化的众所周知的例子，但我们对金属状态的变化如何影响细胞生理的理解存在重大差距。这一差距在锌方面尤为明显。越来越多的证据表明，锌会随着细胞状态的改变而改变，并可能在信号转导和生物调节中发挥作用。例如，卵母细胞减数分裂成熟需要大量锌的积累，受精会产生锌火花；骨髓来源的肥大细胞的刺激会导致锌波。此外，我的实验室已经表明，神经元和上皮细胞中的钙信号事件导致锌的动员，这增加了锌作为新的第二信使发挥作用的有趣可能性。但在所有这些案例中，下游效应器，即感知锌含量变化以调节细胞过程的蛋白质，仍然是一个完全的谜。这个项目的核心假设是，细胞锌的调节决定了锌蛋白质组的占有率，在动态金属调节和广泛的细胞信号反应之间提供了一种新的联系。这一假设的含义是，锌状态的变化--无论是在生理信号传递期间的动态变化，还是作为疾病的结果的永久性变化--微调数百个(如果不是数千个)依赖锌的蛋白质的活性，从而确立锌作为细胞功能的主要调节因子。目前锌生物学的教条认为，组成锌蛋白质组的~2000蛋白与锌结合

DESCRIPTION (provided by applicant): Transition metals are critical to all forms of life, and metal ions play vital roles in a diverse array of fundamental biological processes. Metal dyshomeostasis is a central feature of a broad spectrum of human diseases, yet elucidating whether altered metal status is a cause or consequence of disease is exceedingly difficult without a basic understanding of how metals influence normal cellular functions. While there are some well-known examples of how metals can drive cellular change, there are major gaps in our understanding of how changes in metal status influence cell physiology. This gap is particularly notable for zinc. There is growing evidence that zinc changes in response to cell state, and may function in signal transduction and biological regulation. For example, massive accumulation of zinc is required for meiotic maturation of oocytes and fertilization leads to zinc sparks; stimulation of bone marrow derived mast cells leads to zinc waves. Furthermore, my lab has shown that calcium signaling events in neurons and epithelial cells lead to mobilization of zinc, raising the intriguing possibility that zinc functions as a novel second messenger. But in al of these cases, the downstream effectors, i.e. the proteins that sense changes in zinc in order to regulate cellular processes remain a complete mystery. The core hypothesis of this project is that the regulation of cellular zinc dictates occupancy of the zinc proteome, providing a novel link between dynamic metal regulation and a wide swath of cellular signaling responses. The implication of this hypothesis is that changes in zinc status - either dynamically during physiological signaling, or permanently as a consequence of disease - fine-tune the activity of hundreds, if not thousands of zinc-dependent proteins, establishing zinc as a master regulator of cellular function. Current dogma in zinc biology asserts that the ~ 2000 proteins that comprise the zinc proteome bind zinc cons