The Molecular Basis of Cadherin-Mediated Cell Adhesion

本项目的主要目的是了解钙粘蛋白介导的细胞-细胞粘附的分子基础。钙粘蛋白是位于许多细胞表面的一类分子。当相似的细胞接触时，它们会粘在一起，而不同类型的细胞则倾向于分离。这种关键的特性使得体内不同的组织能够形成并相互分离，这可以追溯到单个钙粘蛋白分子的分子特性。但是不同的钙粘蛋白家族成员都是相似的。什么机制允许小分子差异介导高度特异性的细胞行为？为了解决这些问题，将对野生型和设计突变型钙粘蛋白的结合亲和力进行研究，目的是以可控的方式改变它们的行为。实验工作将基于理论方法的使用，这将阐明钙粘蛋白结合的分子基础。该项目的第二阶段将集中于将分子与细胞特性联系起来。一旦含有钙粘蛋白的细胞开始粘附，每个细胞上的钙粘蛋白就倾向于聚集在一起形成连接。将进行模拟以阐明这是如何发生的，并根据所获得的结果，将开发新的理论方法来模拟细胞过程。该研究项目是理论与实验相结合的综合研究成果，涵盖了分子建模与模拟、结构生物学、溶液生物物理学和细胞生物学等多个学科。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将计算方法整合到现代生物学前沿领域的其他此类努力的模型。该项目的一个特别重要的因素是培养具有计算和实验工作专长的科学家，包括来自不同背景的高级研究人员的联合指导。培训妇女和少数民族科学家是这项研究的一个组成部分。该实验室参加了由HHMI组织的EXROP（特殊研究机会）计划，并在此背景下，每年夏天接待少数民族本科生。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。该项目由分子和细胞生物科学部的生物分子系统和细胞系统集群共同支持。

The main objective of this project is to understand the molecular basis of cadherin-mediated cell-cell adhesion. Cadherins are a family of molecules that are located on the surfaces of many cells. When like cells come in contact they adhere to one another whereas cells of different types tend to separate. This crucial property, which allows different tissues in the body to form and to separate from one another, can be traced to the molecular properties of individual cadherin molecules. But different cadherin family members are all similar to one another. What mechanisms allow small molecular differences to mediate highly specific cellular behavior? To address these questions, binding affinities of wild type and designed mutant cadherins will be carried out with the goal of modifying their behavior in controlled ways. The experimental work will be based on the use of theoretical methods that will elucidate the molecular basis of cadherin binding. The second stage of the project will focus on relating molecular to cellular properties. Once cells containing cadherins begin to adhere, the cadherins on each cell tend to cluster together to form junctions. Simulations will be carried out to clarify how this occurs and, based on the results that are obtained, new theoretical methods to simulate cellular processes will be developed. This research project represents an integrated research effort involving both theory and experiment and spans quite diverse disciplines including molecular modeling and simulation, structural biology, solution biophysics, and cell biology.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 methods in cutting edge areas of modern biology. A particularly important element of the project is the development 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 the research. The lab participates in the EXROP (Exceptional Research Opportunities) program organized by HHMI and, in this context, hosts minority undergraduate students each summer. Both undergraduate and graduate minority students trained in the lab have become highly successful research scientists.This project is jointly supported by the Biomolecular Systems and Cellular Systems Clusters in the Division of Molecular and Cellular Biosciences.