Physical Chemistry of the spatiotemporal regulation of protein function through phosphoinositide domains and gradients

化学部生命过程化学项目将资助伍斯特理工学院的Arne Gericke博士和齐文博士，以确定导致复杂脂质混合物中磷脂聚集的物理化学条件，并表征磷酸酶PTEN与这种横向非均相脂质双分子层的膜结合。脂类是细胞膜的主要组成部分，这些生物分子的一个亚类通过在特定时间将蛋白质吸引到不同的细胞位置来控制细胞功能。这种脂质介导的信号事件需要在空间和时间上高度组织，而偏离这些信号通路的正确执行会导致广泛的细胞功能障碍。细胞对信号脂的局部积累的需求才刚刚开始出现，导致这些脂类库的依赖于时间的控制的机制需要确定。根据这项提议资助的研究将描绘导致局部信号池和信号脂梯度的形成和维持的机制。研究生和本科生将接受许多现代研究技术的培训，包括单分子显微镜。首席调查员将继续开发基于探究的中学科学项目，他的研究小组将参与一系列STEM外联活动。这项研究的影响将是了解肌醇磷脂是如何提供对蛋白质功能的时空控制的。肌醇磷脂是血浆和细胞内膜的少数成分。已经在体内观察到了磷脂酰肌醇梯度，然而，目前还没有可用的实验平台来测试关于这些梯度是如何产生和维持的假说。这笔赠款支持开发一种微流控设备，该设备将用于系统地研究肌醇磷脂的梯度是如何通过肌醇磷脂特定的激酶和磷酸酶的作用产生的，并随后通过其他生物分子稳定下来的。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Arne Gericke and Dr. Qi Wen from Worcester Polytechnic Institute to identify the physicochemical conditions that lead to the clustering of phosphoinositide lipids in complex lipid mixtures and to characterize the membrane association of the phosphatase PTEN with such laterally heterogeneous lipid bilayers. Lipids are major building blocks of cellular membranes and a subclass of these biomolecules control cellular functions by attracting proteins to distinct cellular sites at specific times. Such lipid mediated signaling events require a high degree of organization in space and time, and deviations from the proper execution of these signaling pathways result in a wide array of cellular dysfunctions. The cellular requirements for the local accumulation of signaling lipids are only beginning to emerge and the mechanisms leading to the time dependent control of these lipid pools need to be determined. The research funded under this proposal will delineate the mechanisms that lead to the formation and maintenance of localized pools and gradients of signaling lipids. Graduate and undergraduate students will receive training in many modern research techniques, including single molecule microscopy. The principal investigator will continue to develop inquiry based middle school science projects and his research group will be involved in a range of STEM outreach activities. The impact of the research will be to understand how phosphoinositides, which are minority components of plasma and intracellular membranes, provide spatiotemporal control of protein function. Phosphoinositide gradients have been observed in vivo, however, currently there is no experimental platform available that enables the testing of hypotheses about how these gradients are created and maintained. This grant supports the development of a microfluidic device that will be used to systematically investigate how phosphoinositide gradients are created through the action of phosphoinositide specific kinases and phosphatases and subsequently stabilized by other biomolecules.