CAREER: Molecular Mechanisms Regulating Neural Regeneration in Planarians

目前尚不清楚为什么有些生物(如扁虫)能够轻易地再生它们的大脑和神经系统，而另一些生物(如人类)则不能。扁虫可以令人印象深刻地再生新的头部和大脑，但控制它们的成体干细胞的信号，导致它们分裂并产生这些新组织的信号尚不清楚。这个项目试图了解这些信号的分子身份和功能--特别是新组织如何确定其再生何时完成，以及重建神经回路的再生细胞的个体身份是如何建立的。这些目标将在扁虫身上使用复杂的遗传学、分子、细胞生物学、显微镜和成像技术的组合来实现。这些研究的结果将提供更多关于干细胞生长后新组织和器官是如何形成模式的知识，并可能为潜在的诱导神经再生的方法开辟新的研究途径。本科生将对这项研究做出重大贡献，该项目包括一套广泛的推广目标，通过与当地初中生、他们的家长和STEM教师联系，并增加他们的课堂研究经验，促进中学后STEM教育的多样性和兴趣。该项目是一个综合的研究、教育和推广倡议，重点关注平面细胞极性(PCP)作为组织水平组织机制的作用，将成人干细胞生物学与修复性神经发生和形态联系起来。本项目的目标是：1)通过研究PCP丢失对神经干细胞及其后代的影响，来表征PCP信号与神经干细胞增殖/分化之间的相互作用；2)利用标记分析和RNA干扰增强/抑制筛选，验证多种神经元亚型需要PCP建立适当的再生模式的假设；3)确定PCP蛋白在神经和/或非神经细胞类型中的定位；4)在高年级本科课程中纳入和发展一项新的教学计划，让本科生在课堂上进行研究；以及5)将社区外展试点计划扩展到其他地区的初中和高中，这些学校接触STEM实践经验的机会有限。这项拟议的工作将阐明PCP与神经干细胞及其后代协调以准确地再生大小、形状和方向正确的神经组织的机制。

It is not understood why some organisms (such as planarian flatworms) are easily able to regenerate their brain and nervous system, while others (such as humans) cannot. Planarian flatworms can impressively regenerate a new head and brain, yet the signals that control their adult stem cells, causing them to divide and produce these new tissues, are not known. This project seeks to understand the molecular identity and function of these signals - particularly, how new tissues determine when their regeneration is complete, and how the individual identity of the regenerated cells that rebuild neural circuits is established. These goals will be pursued in flatworms using a combination of sophisticated genetic, molecular, cell-biological, microscopy and imaging techniques. The results of these studies will provide increased knowledge about how new tissues and organs are patterned after stem cell growth, and could open novel research avenues into potential ways to induce neural regeneration. Undergraduate students will contribute substantially to this research, and this project includes an extensive set of outreach goals to promote diversity and interest in post-secondary STEM education by connecting with local middle and high students, their parents and STEM instructors, and increasing their classroom research experiences.This project is an integrated research, education, and outreach initiative focused on the role of planar cell polarity (PCP) as a tissue-level organizing mechanism that links adult stem cell biology to reparative neurogenesis and morphology. The objectives of this project are: 1) To characterize interactions between PCP signaling and neural stem cell proliferation/differentiation, by investigating the effects of PCP loss on neural stem cells and their progeny; 2) To test the hypothesis that multiple neuronal subtypes require PCP to establish proper regenerative patterning, using marker analyses and RNA interference enhancer/suppressor screens; 3) To identify PCP protein localization in neural and/or non-neural cell types; 4) To incorporate and develop a new teaching initiative in the upper-division undergraduate curriculum, involving undergraduates in research in the classroom; and 5) To expand a community outreach pilot program to other area middle and high schools where exposure to STEM practicum experiences is limited. The proposed work will elucidate the mechanisms by which PCP coordinates with neural stem cells and their progeny to regenerate nervous tissue of precisely the correct size, shape, and orientation.