Mechanistic studies of membrane lateral organization in cell plasma membranes.

我提议的研究的目的是描述细胞质中脂质介导的侧向组织的特征 并破译产生这种结构的潜在物理机制。通过这样做， 我将通过发展新的实验来克服目前细胞膜研究面临的重大障碍 操纵和测试活细胞中脂质介导的组织的功能后果的工具。我的 过去在简单模型膜中破译液体不混溶的成功为我的 生物膜的研究现状和未来。在我早年在贝尔德实验室的博士后工作中 康奈尔大学，我从RBL分离的质膜囊泡中发现了强大的临界波动 肥大细胞。这一结果有力地支持了我的工作假设，即细胞中存在临界波动 生理温度下的质膜。在这个奖项的指导阶段，我已经实施了 定量和解释完整细胞上纳米级组织的实验和分析技术 表面(目标1)，我已经研究了质膜成分和 RBL肥大细胞中IgE介导的信号通路的结构(目标2)。通过这些研究，我 成功地将这种定量和生物物理激励的方法应用到与生物医学相关的 研究领域。作为一名独立研究人员，我将继续这两个目标的工作，最终破译 膜横向组织的物理基础(目标1)，并开发新的方法进行探索 脂质介导的横向异质性在抗原诱导的免疫细胞信号转导中的功能后果 进程(目标2)。我的长期目标是开发通用的方法来探索脂质在心脏疾病中的作用 广泛的过程和细胞类型，将使生物医学的新研究路线成为可能 细胞内脂质介导的质膜组织的后果。通向独立的道路 获奖给了我独立的机会，让我能够专注于我博士后时期的生物训练， 以及顺利过渡到我目前的独立教职的资源。

The goal of my proposecJ research is to characterize lipid-mediated lateral organization in cell plasma membranes and to decipher the underlying physical mechanisms that give rise to this structure. In so doing, I will surmount significant barriers currently facing cell membrane research by developing new experimental tools to manipulate and test the functional consequences of lipid-mediated organization in living cells. My past success in deciphering liquid immiscibility in simple model membranes forms the foundation for my current and future studies in biological membranes. In my early postdoctoral work with Baird Laboratory at Cornell University, I identified robust critical fluctuations in plasma membrane vesicles isolated from RBL mast cells. This result strongly supports my working hypothesis that critical fluctuations are present in cell plasma membranes at physiological temperatures. In the mentored stage of this award, I have implemented experimental and analytic techniques to quantify and interpret nanometer-size organization on the intact cell surface (Aim 1), and I have investigated the functional effects of plasma membrane composition and structure on the IgE-mediated signaling pathway in RBL mast cells (Aim 2). Through these studies, I successfully applied this quantitative and biophysically motivated approach to this biomedically relevant area of research. As an independent researcher, I will continue work on both aims, eventually deciphering the physical basis of membrane lateral organization (Aim 1), and developing novel methodologies to probe the functional consequences of lipid-mediated lateral heterogeneity in antigen induced immune cell signaling processes (Aim 2). My long term goal is develop general methods to probe the functional roles of lipids in a wide range of processes and cell types which will enable new lines of study into the biomedical consequences of lipid mediated plasma membrane organization in cells. The Pathway to Independence Award has given me the independence to focus deeply on my biological training in my postdoctoral years, and the resources to smoothly transition into my current independent faculty position.