Molecular Mechanisms in Adhesion Protein Mediated Neuron-Neuron Recognition

神经元如何相互作用以创建成熟脊椎动物大脑的复杂布线图是一个重大谜团。由此产生的许多问题之一是神经元如何“条形码”;也就是说，它们如何区分自我和非自我。这种能力是必不可少的，因为如果没有它，就没有什么可以阻止神经元与自己形成连接（突触），基本上在大脑中形成短路。这个项目的基本目标是了解神经元是如何被条形码化的。神经元-神经元识别由蛋白质-蛋白质相互作用介导。该项目的重点是蛋白质家族的成员，这些蛋白质家族为个体脊椎动物神经元建立了独特的身份，使它们能够区分“自我”和“非自我”。 该研究将涉及计算机模拟，生物物理测量和高分辨率显微镜实验，以实验验证和描述细胞中的条形码机制。 这项研究的一个特别重要的因素是培养在计算和实验工作方面都有专长的科学家。培训妇女和少数民族科学家是拟议研究方案的一个组成部分。本科生和研究生少数民族学生都经过培训，成为非常成功的研究科学家。 该项目的主要目标是促进对神经元-神经元识别的分子基础的理解。细胞与细胞之间的相互作用是由蛋白质与蛋白质之间的相互作用介导的，研究的长期目标是了解潜在的机制。具体而言，涉及细胞表面蛋白的蛋白质-蛋白质相互作用如何介导高度特异性的细胞-细胞相互作用。鉴于神经系统的复杂性，神经元与神经元的相互作用在这方面提出了独特的挑战。这项研究的重点是聚集的原钙粘蛋白（Pcdhs），它为个体脊椎动物神经元建立了一个独特的身份，使它们能够区分“自我”和“非自我”。这些是神经元条形码蛋白。该研究涉及计算研究，以确定如何在Pcdh-Pcdh界面上编码嗜同性特异性，突变体的设计以测试所产生的假设，以及它们的实验测试。研究的第二个重点是阐明神经元条形码的分子基础。一种新的链终止机制的基础上组装的结晶状的“分子拉链”在细胞-细胞界面已被提出，并与所有可用的实验数据是一致的。该模型将通过多尺度模拟以及体外和体内实验研究进行探索。值得注意的是，该模型在细胞-细胞识别的分子基础中引入了新概念。该项目由生物科学理事会分子和细胞生物科学部的分子生物物理学小组支持。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

How neurons interact with one another to create the complex wiring diagram of a mature vertebrate brain is a major mystery. One of the many problems that arises is how neurons are "barcoded"; that is, how they distinguish self from non-self. This ability is essential since, without it, there would be nothing to prevent neurons from forming connections (synapses) with themselves, essentially creating a short circuit within the brain. The fundamental goal of this project is to understand how neurons are barcoded. Neuron-neuron recognition is mediated by protein-protein interactions. This project focuses on members of the Clustered Protocadherins (Pcdh) protein family that establish a unique identity for individual vertebrate neurons allowing them to distinguish "self" from "non-self". The research will involve computer simulations, biophysical measurements, and high-resolution microscopy experiments to experimentally validate and describe the barcoding mechanism in cells. A particularly important element of the research is the development of scientists with expertise in both computational and experimental work. The training of women and minority scientists is an integral component of the proposed research program. Both undergraduate and graduate minority students trained to be on a trajectory to become highly successful research scientists. The main objective of the project is to advance understanding of the molecular basis of neuron-neuron recognition. Cell-cell interactions are mediated by protein-protein interactions and the long-range goal of the research is to understand the underlying mechanisms. Specifically, how do protein-protein interactions involving cell surface proteins mediate highly specific cell-cell interactions. Given the complexity of the nervous system, neuron-neuron interactions offer a unique challenge in this regard. The research focuses on the clustered Protocadherins (Pcdhs) that establish a unique identity for individual vertebrate neurons allowing them to distinguish "self" from "non-self". These are neuronal barcoding proteins. The research involves computational studies to determine how homophilic specificity is coded on Pcdh-Pcdh interfaces, the design of mutants to test the hypotheses that are generated, and their testing experimentally. A second focus of the research is to elucidate the molecular basis of neuronal barcoding. A novel chain termination mechanism based on the assembly of crystalline-like "molecular zippers" in cell-cell interfaces has been proposed and is consistent with all available experimental data. The model will now be explored with multi-scale simulations, and in vitro and in vivo experimental studies. Notably, the model introduces new concepts in the molecular basis of cell-cell recognition. This project is supported by the Molecular Biophysics Cluster of the Molecular and Cellular Biosciences Division in the Biological Sciences Directorate.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.