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，在运动控制和某些神经功能方面起着重要作用。 认知功能，如语言和空间记忆。虽然这些功能很复杂，但 出生后的发育和小脑的简单结构使其成为理解的独特模型 基因表达、增殖和分化的出生后调节。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， 髓母细胞瘤（MB）-最常见的恶性小儿脑肿瘤。MB分为四个 亚组，其中已知这些信号传导途径中的突变发生在SHH和WNT亚组中， 组3和组4肿瘤中复发性改变很少。然而，最近的研究发现， 过度表达的发育调控基因是有吸引力的治疗靶点。Y盒结合蛋白 1，YBX 1，最近被鉴定为控制发育中的胚胎脑的增殖/分化， 在增殖期和分化期均在小脑中表达。此外，YBX 1水平很高， 在成神经管细胞瘤的所有亚组中，在高表达MYC的MB中观察到最高表达（组3- G3）。因此，了解YBX 1在小脑发育和脑发育中的功能作用， 成神经管细胞瘤是高度相关的。我们的初步研究表明，YBX 1是必要的适当规格 的小脑和Ybx 1的损失减少了体内G3 MB的生长。该提案的三个目标 目的：1）研究YBX 1在小脑分化中的作用， 2）评估YBX 1在髓母细胞瘤发生和发展中的需要， 人和小鼠模型，和3）鉴定YBX 1下游的靶基因和表观遗传学改变。最后， 我将评估YBX 1的直接拮抗作用是否可以抑制肿瘤生长。这项研究将揭示新的基因调控 小脑发育的网络以及调节MB起始和进展的网络，导致 新目标的识别。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个创新的研究建议，这将是重要的增加知识， YBX 1的正常功能以及巩固其作为G3 MB中的药理学靶点。这一建议建立 基于我在表观遗传学，干细胞生物学和癌症生物学方面的强大背景， 博士奖学金。我的短期职业目标是在一所一流的大学里获得一个研究员的职位 在那里，我将专注于了解正常发育和肿瘤发生的表观遗传机制。与 来自圣裘德和我未来的机构的核心设施的帮助，以及旧的和新的合作， 该奖项将允许在CRISPR/Cas9基因编辑和生物信息学分析方面进行进一步培训。 完成这一建议将使我处于一个完美的位置，继续努力实现我的长期目标， 履行NCI的使命“推进科学知识，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.”