The Molecular Basis of Cadherin-Mediated Cell Adhesion

在这个项目中，PI将研究细胞-细胞粘附的分子机制。该项目本质上是多尺度和跨学科的，正在开发的策略可以作为在现代生物学前沿领域整合计算和实验方法的其他此类努力的模型。这项研究的一个特别重要的因素是培训具有计算和实验工作专业知识的科学家，包括由背景非常不同的高级研究人员联合指导。培训妇女和少数民族科学家是这项研究计划的一个组成部分。许多从事美国国家科学基金会资助项目的女性博士后已经走上了成功的独立研究事业，这一传统将继续保持下去。此外，每年夏天，实验室都会接待少数民族本科生，并接受高中生作为实习生。在实验室接受训练的本科生和研究生都成为了非常成功的研究科学家。该项目的成果将对纳米生物技术产业的劳动力发展和预测工具的发展产生重大影响。本研究项目的目的是阐明钙粘蛋白介导的细胞-细胞粘附的分子机制。钙粘蛋白是细胞表面分子，也具有跨膜区域和细胞质结构域，可与肌动蛋白细胞骨架相互作用。经典的钙粘蛋白由五个细胞外钙粘蛋白（EC）结构域组成，这些结构域由连接子区域连接。当两个细胞初次相遇时，对立膜表面上的钙粘蛋白相互结合并启动一系列事件，从形成大的有序组装开始，最终导致细胞-细胞粘附。该项目包括对经典钙粘蛋白的结构、动力学性质和功能进行综合实验和计算研究。现有三维结构的分析、位点定向突变体的设计、结合亲和力测量和电子顺磁共振（EPR）光谱将用于阐明使钙粘蛋白以高度特异性的方式相互结合的因素，尽管它们在序列和结构上彼此相似。EPR还将用于研究细胞间接触和反式（不同细胞）粘合键形成的钙粘蛋白柔韧性的变化。粗粒度的分子模拟将用于理解这些灵活性的变化如何导致顺式（相同细胞）相互作用的形成，从而驱动细胞表面钙粘蛋白的横向聚集。该项目将导致对这类重要分子的更深层次的理解，也将揭示有关其他粘附分子家族介导细胞-细胞识别的机制的一般原理。该项目由生物科学理事会分子与细胞生物科学部的分子生物物理学和数学与物理科学理事会物理部的计算物理项目共同支持。

In this project the PI will study the molecular mechanisms that underlie cell-cell adhesion. The project is multi-scale and interdisciplinary in nature and the strategy that is being developed can serve as a model for other such efforts that integrate computational and experimental methods in cutting edge areas of modern biology. A particularly important element of this research is the training of scientists with expertise in both computational and experimental work including joint mentoring from senior researchers with very different backgrounds. The training of women and minority scientists is an integral component of this research program. A number of women postdocs working on previous NSF funded projects have gone on to successful independent research careers and this tradition will be maintained. In addition, each summer the lab hosts minority undergraduate students and accepts high school students as interns. Both undergraduate and graduate minority students trained in the lab have become highly successful research scientists. The outcomes of this project will have substantial impacts on the workforce development and on the development of predictive tools in nanobiotechnology industry.The objective of this research project is to elucidate the molecular mechanisms that underlie cadherin-mediated cell-cell adhesion. Cadherins are cell surface molecules that also have a trans-membrane region and a cytoplasmic domain that interacts with the actin cytoskeleton. Classical cadherins consist of five extracellular cadherin (EC) domains connected by linker regions. Upon initial encounter of two cells, cadherins on opposing membrane surfaces bind to one another and initiate a series of events, beginning with the formation of large ordered assemblies, that ultimately lead to cell-cell adhesion. The project involves integrated experimental and computational studies on the structure, dynamical properties and function of classical cadherins. Analysis of existing three-dimensional structures, the design of site directed mutants, binding affinity measurements and Electron Paramagnetic Resonance (EPR) spectroscopy will be used to elucidate the factors that enable cadherins to bind to one another in a highly specific fashion, despite being similar to one another in sequence and structure. EPR will also be used to study changes in cadherin flexibility resulting from cell-cell contact and the formation of trans (different cell) adhesive bonds. Coarse-grained molecular simulations will be used to understand how these changes in flexibility lead to the formation of cis (same cell) interactions that drive the lateral clustering of cadherins on cell surfaces. The project will lead to a deeper understanding of this important class of molecules and will also reveal general principles regarding the mechanisms employed by other families of adhesion molecules to mediate cell-cell recognition. This project is jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and the Computational Physics Program in the Division of Physics in the Mathematical and Physical Sciences Directorate.