CAREER: Integrated Models of Neural Axon Guidance

1055990，中枢神经系统的正常功能依赖于神经细胞之间的准确连接。在发育和修复期间，神经通过对来自微环境的大量物理和分子信号做出反应，导航到预定的目标。例如，研究表明，视网膜的神经细胞被一种名为netrin-1的化学物质吸引到视束，这种化学物质在组织中扩散，形成浓度梯度。这些神经细胞后来会受到另一种化学物质的排斥力的影响，沿着一条通往大脑一侧或另一侧的路径前进，这种化学物质与特定位置的组织结合在一起。细胞整合多种信号的确切机制仍不清楚，部分原因是测试这种机制的实验方法严重依赖于困难的细胞准备。合成生物材料有望成为更容易和更定量地控制物理和分子引导线索的空间分布的手段。这项建议的目的是利用新的光反应生物材料和计算机模拟来开发一个集成的神经生长模型，以响应微环境中的结构和分子线索。开发的模型将实现对多个指导线索的前所未有的控制，使进一步调查它们如何影响轴突指导。这项申请中提出的研究可能会使定量的、更容易实现的技术受益于社会，这些技术可能有助于发现对胚胎发育、神经障碍和再生过程至关重要的生物机制。此外，开发的新型生物材料可能会在许多意想不到的应用中找到用途。这项提议也将实现教育方面的影响。大量的研究生和本科生将在调查员S实验室接受教育，所开发的技术将被引入研究生和本科生的课程。该研究实验室还将作为一个枢纽，向路易斯安那州少数族裔服务学校的学生和教师推广科学、工程、技术和数学方面的职业机会。这将通过向代表人数不足的群体的本科生以及新奥尔良地区少数族裔服务高中的高中教师提供暑期研究经验来实现。

1055990, MooreProper functioning of the central nervous system is dependent on accurate connections between nerve cells. During both development and repair, nerves navigate toward intended targets by responding to numerous physical and molecular signals from their microenvironment. For example, it has been shown that nerve cells from the retina are attracted toward the optic tract by a chemical called netrin-1 that diffuses through the tissue forming a concentration gradient. These same nerve cells are later influenced to follow a path toward one side of the brain or the other by repulsion from another chemical called ephrin-B2 that is bound to the tissue in a specific location. The precise mechanisms by which cells integrate multiple signals remain unclear, partly because the experimental methods to test such mechanisms have relied heavily upon difficult cell preparations. Synthetic biomaterials are poised as means to more easily and quantitatively control the spatial distribution of physical and molecular guidance cues. The purpose of this proposal is to make use of new photoreactive biomaterials along with computer simulation to develop an integrated model of nerve growth in response to structural and molecular cues in the microenvironment. The models developed will enable unprecedented control of multiple guidance cues, enabling further investigation into how they influence axon guidance. The research proposed in this application may benefit society by enabling quantitative, more readily-implementable techniques that may aid discovery of biological mechanisms important for embryonic development, neurological disorders, and regeneration processes. Further, the novel biomaterials developed may find use in many unforeseen applications. Educational impacts will also be realized by this proposal. Numerous graduate and undergraduate students will be educated in the investigator?s laboratory, and the techniques developed will be introduced into a course taken by graduate and undergraduate students. The research lab will also serve as a hub for promoting career opportunities in science, engineering, technology, and mathematics to students and teachers in underrepresented minority-serving schools in Louisiana. This will be accomplished through summer research experiences provided to undergraduate students in underrepresented groups as well as to high school teachers in minority-serving high schools in the New Orleans area.