Elucidating the role of Ybx1 in cerebellar development and medulloblastoma

项目摘要 小脑是哺乳动物后脑的一部分，在运动控制和一些 认知功能，如语言和空间记忆。尽管这些函数很复杂，但继续 出生后的发育和小脑的简单结构使其成为独特的理解模型 基因表达、增殖和分化的后天调节。有趣的是，同样的信号 在正常小脑发育中起作用的通路通常在癌症中被劫持和改变，如 如髓母细胞瘤(MB)--最常见的儿童恶性脑瘤。MB分为四个部分 亚组，其中这些信号通路的突变已知发生在SHH和WNT亚组中， 第3组和第4组肿瘤的复发改变很少。然而，最近的研究已经确定了一些 过度表达的发育调节基因是有吸引力的治疗靶点。Y-box结合蛋白 1，YBX1，最近被发现控制发育中的胚胎大脑的增殖/分化，具有高度的 在增殖期和分化期的小脑均有表达。此外，YBX1的水平很高 在髓母细胞瘤的所有亚组中，MYC高表达的MBS表达最高(组3- G3)。因此，了解YBX1在小脑发育和脑内的功能作用 髓母细胞瘤是高度相关的。我们的初步研究表明，YBX1是适当规格所必需的 而YBX1的缺失会减少体内G3MB的生长。这项建议的三个目的 目的是：1)确定YBX1在调节小脑增殖/分化中的作用和功能 祖细胞，2)评估YBX1在髓母细胞瘤发生和发展中的需求 人类和小鼠模型，以及3)确定YBX1下游的目标基因和表观遗传变化。最后， 我将评估YBX1的直接拮抗是否能抑制肿瘤生长。这项研究将发现新的基因调控机制 小脑发育网络以及那些调节MB启动和发展的网络，导致 识别新的目标。神经发育、干细胞生物学、生物化学和 癌症生物学使这成为一项创新的研究建议，这将对增加对 YBX1的正常功能及其作为药理靶点在G3MB中的固化。这项建议建立了 凭借我在表观遗传学、干细胞生物学和癌症生物学方面的深厚背景，我在毕业前和毕业后都是如此 博士奖学金。我的短期职业目标是在一家顶尖机构获得一个研究教员的职位。 在那里，我将重点了解正常发育和肿瘤发生中的表观遗传机制。使用 来自圣犹大这里的核心设施和我未来的机构的帮助，以及旧的和 新的，这个奖项将允许在CRISPR/Cas9基因编辑和生物信息学分析方面的进一步培训。 这项提议的完成将使我处于一个完美的位置，可以继续朝着我的长期目标努力 履行NCI的使命“促进科学知识，帮助所有人活得更健康、更长寿”。

Project Summary The cerebellum is part of the mammalian hindbrain which plays important roles in motor control and some cognitive functions, such as language and spatial memory. Although these functions are complex, the continued development after birth and simple structure of the cerebellum make it unique model for understanding postnatal regulation of gene expression, proliferation, and differentiation. Interestingly, the same signaling pathways that play a role in normal cerebellar development are commonly hijacked and altered in cancers, such as medulloblastoma (MB) – the most common malignant pediatric brain tumor. MB is divided into four subgroups, where mutations in these signaling pathways are known to occur in the SHH and WNT subgroups, with very few recurrent alterations in Group3 and 4 tumors. Recent studies, however, have identified a number of overexpressed developmentally regulated genes that are attractive therapeutic targets. Y-box binding protein 1, YBX1, recently identified to control proliferation/differentiation in the developing embryonic brain, is highly expressed in the cerebellum during both proliferative and differentiation phases. Further, YBX1 levels are high in all subgroups of medulloblastoma with the highest expression seen in high-MYC expressing MBs (Group3- G3). Therefore, understanding the functional role of YBX1 in both cerebellar development and in medulloblastoma is highly relevant. Our preliminary studies show that YBX1 is required for proper specification of the cerebellum and that loss of Ybx1 diminishes the growth of G3 MB in vivo. The three aims of this proposal are to: 1) determine the role and function of YBX1 in regulating proliferation/differentiation of cerebellar progenitors, 2) assess the requirement of YBX1 in initiation and progression of medulloblastoma using both human and mouse models, and 3) identify target genes and epigenetic alterations downstream of YBX1. Finally, I will assess if direct antagonism of YBX1 can inhibit tumor growth. This study will uncover new gene regulatory networks of cerebellar development as well as those which regulate MB initiation and progression, leading to the identification of novel targets. The integration of neurodevelopment, stem cell biology, biochemistry, and cancer biology make this an innovative research proposal that will be significant for increasing knowledge about the normal functions of YBX1 as well as solidifying it as a pharmacological target in G3 MB. This proposal builds upon my strong background in epigenetics, stem cell biology, and cancer biology from both my pre- and post- doctoral fellowships. My short-term career goal is to obtain a research faculty position at a leading institution where I will focus on understanding epigenetic mechanisms in normal development and tumorigenesis. With assistance from core facilities here at St. Jude and my future institution as well as collaborations both old and new, this award will allow for further training in CRISPR/Cas9 gene editing and bioinformatics analysis. Completion of this proposal will put me in a perfect position to continue work towards my long-term goal of fulfilling the NCI mission “to advance scientific knowledge and help all people live healthier, longer lives.”