CAREER: Integrated Models of Neural Axon Guidance

[05:59 . 90]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。在发育和修复过程中，神经通过对来自微环境的大量物理和分子信号作出反应，导航到预定的目标。例如，研究表明，来自视网膜的神经细胞被一种叫做netrin-1的化学物质吸引到视神经束，这种化学物质在组织中扩散，形成浓度梯度。这些神经细胞随后受到另一种化学物质ephrin-B2的排斥力的影响，向大脑的一侧或另一侧移动，这种化学物质被绑定在特定位置的组织上。细胞整合多种信号的确切机制尚不清楚，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制备。合成生物材料是一种更容易和定量控制物理和分子引导线索的空间分布的手段。本提案的目的是利用新的光反应性生物材料以及计算机模拟来开发微环境中响应结构和分子线索的神经生长的综合模型。所开发的模型将能够前所未有地控制多个引导线索，从而进一步研究它们如何影响轴突引导。本申请中提出的研究可能会通过实现定量的、更容易实现的技术来造福社会，这些技术可能有助于发现对胚胎发育、神经系统疾病和再生过程重要的生物机制。此外，开发的新型生物材料可能会在许多不可预见的应用中找到用途。这一提议也将对教育产生影响。众多的研究生和本科生将在研究者中接受教育。所开发的技术将被引入研究生和本科生的课程中。该研究实验室还将作为一个中心，为路易斯安那州少数族裔学校的学生和教师提供科学、工程、技术和数学方面的就业机会。这将通过向未被充分代表的群体的本科生以及新奥尔良地区少数民族高中的高中教师提供暑期研究经验来完成。

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.