Biochemical and structural studies of gamma-secretase

知识价值。生物膜包围着所有活细胞，限制其内部细胞器，并参与各种重要的细胞功能，包括细胞外信号传导、电解质平衡和能量转换。这些膜在结构和化学上都是不均匀的，由许多类型的脂质组成，它们排列成一个连续的双层，其中膜蛋白要么是嵌入的，要么是表面相关的。本项目的目的是了解脂质双分子层对膜蛋白-分泌酶的结构和功能的影响。这种蛋白酶非常重要，因为它负责激活许多参与神经元功能调节的信号分子，其底物特异性被认为随双分子层组成而变化。本研究将采用新颖的检测方法研究双分子层的物理和化学参数对分泌酶活性的影响。为了使酶在膜中的结构可视化，它将在脂质双层中结晶并使用电子显微镜进行分析。该项目构成了膜蛋白研究的范式转变，因为它从常用的人工洗涤剂系统转移到研究膜蛋白的天然脂质双分子层环境。更广泛的影响。通过培养膜蛋白研究和现代结构生物学原理与应用方面的科学家，该项目将为培养生物物理学、生物化学和生物学交叉领域的下一代科学家提供一个平台。PI将继续在纽约市所有机构的学生中开设电子显微镜课程。此外，通过教学、指导和职业咨询促进和鼓励少数民族参与科学是该项目的一个关键目标。该项目将通过现有的项目，如学士学位后研究教育项目（PREP）、暑期本科生研究项目（SURP）以及卓越青年教育中心（CEYE）的大学预科和大学项目，招收不同背景、不同职业阶段的学生。重点将放在提高公众的科学素养上，办法是不断开展外联活动，并每年接待一名当地高中生。这名学生将通过与科学教师在大颈南HS正在进行的合作选择。

Intellectual Merit. Biological membranes surround all living cells, confine their internal organelles, and participate in an astounding variety of essential cellular functions, including extracellular signaling, electrolyte balance and energy conversion. These membranes are structurally and chemically heterogeneous environments composed of numerous types of lipids arranged as a continuous bilayer, in which membrane proteins are either embedded or surface-associated. The goal of this project is to understand the effect of the lipid bilayer on the structure and function of the membrane protein gamma-secretase. This protease is of great importance as it is responsible for activating numerous signaling molecules involved in the regulation of neuronal function, and its substrate specificity is thought to vary with the bilayer composition. Using novel assays the research will study the effect of physical and chemical parameters of the bilayer on secretase activity. To visualize the structure of the enzyme in a membrane it will be crystallized in lipid bilayers and analyzed using electron microscopy. This project constitutes a paradigm shift in membrane protein research as it moves away from commonly used artificial detergent systems to the study of membrane proteins in their natural lipid bilayer environment.Broader impacts. By training scientists in membrane protein research and in the principles and applications of modern structural biology, this project will provide a platform for educating the next generation of scientists at the interface of biophysics, biochemistry and biology. The PI will continue to teach electron microscopy in a course available to students from all New York City institutions. Additionally, facilitating and encouraging minority participation in the sciences through teaching, mentoring and career counseling is a key goal of this project. This project will recruit students from various backgrounds at different career stages, through existing programs such as Post Baccalaureate Research Education Program (PREP), the Summer Undergraduate Research Program (SURP), and the precollege and collegiate programs of the Center for Excellence in Youth Education (CEYE). Emphasis will be placed on raising the scientific literacy of the public by ongoing outreach activities and by hosting one local high school student every year. This student will be chosen through an ongoing collaboration with the science faculty at Great Neck South HS.