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，生长锥体导航取决于两者的调节变化 F-肌动蛋白和微管(MT)对外部引导线索的响应。然而， 这些线索导致生长锥MT动态发生特定变化的机制 是该领域一个根本性的悬而未决的问题。家长的研究经费就是针对这一点的 通过研究两个相互作用的微管‘正端跟踪蛋白’的功能 (+TIPS)、TACC3和XMAP215及其调控机制。这两个+提示是独一无二的 结合到MT的末端，它们与MT的结合被认为是受 磷酸化。我们的数据支持这样一个模型，即TACC3和XMAP215在 引导提示信号下游的MT动力学。我们目前的资金是为了测试中央 机制假说，主要的指导信号通路汇聚在TACC3和TACC3上 XMAP215控制MT加端动态并控制增长锥体。这份副刊将 资助具有高度干劲和热情的第一人的研究、培训和职业指导- 一代西班牙裔女本科生，对以下领域有浓厚兴趣和潜力 最终参加了生物学的研究生课程。本科生将接受培训 不仅在许多不同的板凳技术，而且她将在如何成为一个密集的指导 成功的生物医学科学家，并成功攻读生物学博士研究生课程。有了这个 作为补充，她将与一个支持团队合作，对机械原理提出新的见解 使用一系列互补方法，在神经发育过程中对TACC3的调节 在接下来的三年里。首先，她将确定四个关键的磷酸化氨基酸 酸在TACC3与XMAP215的生化相互作用中是重要的。然后，她会决定 这些氨基酸是否影响TACC3结合和调节微管的能力 神经元生长锥体。最后，她将研究这些氨基酸是否对 TACC3促进非洲爪哇蝌蚪正常游泳行为的脑读数 发展。这位本科生将与她的导师以及 其他接受父母资助的人(包括一名资深科学家、在校博士生和资深学生 本科生)。在她的本科学习过程中，她将有很多 在多个论坛上讨论和展示她的研究的机会，发展她的技能不是 只是作为一名生物医学研究人员，而是作为一名科学传播者。她将收到 从她的导师那里得到了密集的指导，并将参加许多额外的培训 有机会让她为严苛的研究生课程做好充分准备。

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.