Elucidating mechanistic connections between guidance signaling, microtubule regulation, and growth cone steering: Diversity Supplement

项目摘要 长期以来，人们已经确定，生长锥导航依赖于两者的调节变化， F-肌动蛋白和微管（MT）动态响应外部指导线索。但 这些线索引起生长锥MT动态变化的机制 是这个领域一个根本性的未解决的问题。家长研究补助金的目标是 void，通过研究两种相互作用的微管“正末端跟踪蛋白”的功能， （+TIPs）、TACC 3和XMAP 215及其调控机制。这两个+提示独特 结合到MT的末端，并且它们与MT的结合被认为是由 磷酸化我们的数据支持一个模型，其中TACC 3和XMAP 215介导的变化， 引导提示信号下游的MT动态。我们目前得到资金来测试中央 主要的引导线索信号通路会聚在TACC 3上的机制假说， XMAP 215控制MT加端动力学和引导生长锥。该补充将 资助研究培训和职业导师的高度驱动和热情的第一- 一代西班牙裔女本科生，谁有强烈的兴趣和潜力， 最终进入了生物学研究生课程。本科生将接受培训 不仅在许多不同的板凳技术，但她将集中指导如何成为一个 成功的生物医学科学家，并成功地在生物学博士研究生课程。与此 作为补充，她将与一个支持团队合作，对机械化的 在神经发育过程中调节TACC 3，使用一系列互补方法 在接下来的三年里。首先，她将确定四个关键的磷酸化氨基是否 酸对于TACC 3与XMAP 215的生物化学相互作用是重要的。然后她会决定 这些氨基酸是否影响TACC 3结合和调节微管的能力， 神经生长锥最后，她将研究这些氨基酸是否对 TACC 3作为脑读出器促进爪蟾蝌蚪正常游泳行为 发展本科生将与她的导师进行广泛的接触， 其他人在父母补助金（包括资深科学家，目前的博士生，和高级 本科生）。在本科学习过程中，她会有很多 有机会在多个论坛讨论和展示她的研究，发展她的技能， 我只是一个生物医学研究者，我是一个科学传播者。她将获得 她的导师的密集指导，并将参加许多额外的培训 机会，以强有力的准备她的研究生课程的严格。

Project Abstract It has long been established that growth cone navigation depends on regulated changes in both F-actin and microtubule (MT) dynamics in response to external guidance cues. However, the mechanisms by which these cues bring about specific changes in growth cone MT dynamics are a fundamental unresolved issue in the field. The parent research grant takes aim at that void, by investigating the functions of two interacting microtubule `plus-end tracking proteins' (+TIPs), TACC3 and XMAP215, and their regulatory mechanisms. These two +TIPs uniquely bind to the extreme end of the MT and their binding to MTs is thought to be regulated by phosphorylation. Our data support a model in which TACC3 and XMAP215 mediate changes in MT dynamics downstream of guidance cue signaling. We are currently funded to test the central mechanistic hypothesis that major guidance cue signaling pathways converge on TACC3 and XMAP215 to control MT plus-end dynamics and steer the growth cone. This supplement will fund the research training and career mentorship of a highly driven and enthusiastic first- generation female Hispanic undergraduate student, who has a strong interest and potential in eventually attending a graduate program in Biology. The undergraduate student will be trained not only in many diverse bench techniques, but she will be intensively mentored in how to be a successful biomedical scientist and succeed in a graduate PhD program in biology. With this supplement, she will work with a supportive team to make new insights into the mechanistic regulation of TACC3 during neural development, using a series of complementary approaches over the next three years. First, she will determine whether four critical phosphorylated amino acids are important for TACC3 biochemical interaction with XMAP215. Then, she will determine whether these amino acids affect the ability of TACC3 to bind to and regulate microtubules in neuronal growth cones. Finally, she will investigate whether these amino acids are important for TACC3 to promote normal swimming behaviors in Xenopus tadpoles as a readout of brain development. The undergraduate student will have extensive contact with her advisor as well as others on the parent grant (including a senior scientist, current PhD student, and senior undergraduate students). In the course of her undergraduate studies, she will have many opportunities to discuss and present her research in multiple forums, developing her skills not only as a bench biomedical researcher but as a scientific communicator. She will receive intensive mentoring from her advisor, and will participate in numerous additional training opportunities to strongly prepare her for the rigors of a graduate program.