Biochemical and structural studies of gamma-secretase

智力上的功绩。生物膜包裹着所有活细胞，限制它们的内部细胞器，并参与各种令人震惊的基本细胞功能，包括细胞外信号、电解质平衡和能量转换。这些膜是由多种类型的脂类组成的结构和化学上不同的环境，这些脂类以连续的双层形式排列，膜蛋白要么嵌入其中，要么与表面相关。这个项目的目的是了解脂双层对膜蛋白伽马分泌酶结构和功能的影响。这种蛋白酶非常重要，因为它负责激活参与神经元功能调节的众多信号分子，其底物特异性被认为随着双层组成的不同而不同。利用新的分析方法，该研究将研究双层的物理和化学参数对分泌酶活性的影响。为了显示膜中酶的结构，它将在脂双层中结晶，并用电子显微镜进行分析。这个项目构成了膜蛋白研究的一个范式转变，因为它从常用的人工洗涤剂系统转向研究天然脂双层环境中的膜蛋白。通过培训膜蛋白研究和现代结构生物学原理和应用方面的科学家，该项目将为培养生物物理、生物化学和生物学领域的下一代科学家提供一个平台。PI将继续在一门课程中教授电子显微镜，这门课程对来自纽约市所有机构的学生开放。此外，通过教学、辅导和职业咨询促进和鼓励少数群体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，如毕业后研究教育项目(PREP)、夏季本科生研究项目(SURP)以及青年教育卓越中心(CEYE)的大学预科和大学项目，在不同的职业阶段招收不同背景的学生。将重点放在通过持续的外展活动和每年接待一名当地高中生来提高公众的科学素养。这名学生将通过与大颈南HS的科学教员的持续合作而被选中。

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.