Elucidating the role of Ybx1 in cerebellar development and medulloblastoma

阐明 Ybx1 在小脑发育和髓母细胞瘤中的作用

• 批准号: 10573136
• 负责人: Myron K Evans
• 金额: $ 18.71万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-21 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573136
• 关键词: Affect; Age; Award; Binding; Biochemical; Biochemistry; Bioinformatics; Biological Assay; Biology; Birth; Brain; CRISPR/Cas technology; Cancer Biology; Cells; Central Nervous System; Cerebellum; Child; Childhood Malignant Brain Tumor; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Complex; Core Facility; DNA; DNA binding protein B; Development; Disease; Disease Progression; Embryo; Epigenetic Process; Equilibrium; Fellowship; Functional disorder; Future; Gene Expression; Gene Expression Regulation; Generations; Genes; Genomics; Goals; Growth; Institution; Knowledge; Language; MYC gene; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Mission; Modeling; Molecular; Mus; Mutation; Neurodevelopmental Disorder; Normal Cell; Nuclear Translocation; Patients; Pediatric Neoplasm; Persons; Phase; Play; Polycomb; Positioning Attribute; Postdoctoral Fellow; Process; Prognosis; Proliferating; RNA Interference; RNA-Binding Proteins; Recurrence; Reporting; Research; Research Proposals; Role; SHH gene; Saint Jude Children' s Research Hospital; Scientific Advances and Accomplishments; Scientist; Signal Pathway; Signal Transduction; Specific qualifier value; Speech; Structure; Subgroup; Technical Expertise; Techniques; Training; Translating; Tumor Biology; Work; Xenograft procedure; antagonist; career; clinically relevant; cognitive function; design; epigenetic regulation; experimental study; extracellular; gain of function; gene network; gene regulatory network; genome sequencing; hindbrain; histone modification; human disease; human model; in vivo; inhibitor; innovation; insight; loss of function; medulloblastoma; motor control; mouse model; nerve stem cell; nervous system disorder; neurodevelopment; novel; novel therapeutic intervention; novel therapeutics; overexpression; pharmacologic; postnatal; pre-doctoral; progenitor; programs; research faculty; self-renewal; spatial memory; stem cell biology; stem cell self renewal; stem cells; therapeutic target; tool; transcriptome sequencing; transcriptomics; tumor; tumor growth; tumorigenesis; whole genome

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.”

项目概要 小脑是哺乳动物后脑的一部分，在运动控制和某些方面发挥着重要作用 认知功能，例如语言和空间记忆。虽然这些功能很复杂，但持续的 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、增殖和分化的产后调节。有趣的是，同样的信号 在正常小脑发育中发挥作用的通路通常在癌症中被劫持和改变，例如 髓母细胞瘤（MB）——最常见的恶性儿童脑肿瘤。 MB分为四 亚组，已知这些信号通路的突变发生在 SHH 和 WNT 亚组中， 第 3 组和第 4 组肿瘤中很少有复发性改变。然而，最近的研究发现了一些 过度表达的发育调节基因是有吸引力的治疗靶点。 Y盒结合蛋白 1、YBX1 最近被鉴定为控制发育中胚胎大脑的增殖/分化，具有高度的 在增殖期和分化期在小脑中表达。此外，YBX1水平很高 在髓母细胞瘤的所有亚组中，在高 MYC 表达的 MB 中观察到最高表达（组 3- G3）。因此，了解 YBX1 在小脑发育和大脑发育中的功能作用 髓母细胞瘤高度相关。我们的初步研究表明，YBX1 是正确规格所必需的 小脑的损伤和 Ybx1 的缺失会减少体内 G3 MB 的生长。本提案的三个目标 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) 使用两者评估 YBX1 在髓母细胞瘤发生和进展中的需求 人类和小鼠模型，3) 识别 YBX1 下游的靶基因和表观遗传改变。最后， 我将评估 YBX1 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 小脑发育网络以及调节 MB 启动和进展的网络，导致 新目标的识别。神经发育、干细胞生物学、生物化学和 癌症生物学使这是一项创新的研究提案，对于增加关于癌症的了解具有重要意义 YBX1 的正常功能以及将其巩固为 G3 MB 中的药理学靶点。该提案构建 基于我在治疗前和治疗后在表观遗传学、干细胞生物学和癌症生物学方面的深厚背景 博士奖学金。我的短期职业目标是在领先机构获得研究教职 我将重点了解正常发育和肿瘤发生中的表观遗传机制。和 圣裘德和我未来的机构的核心设施的帮助以及旧和旧的合作 新的，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。 完成这项提案将使我处于一个完美的位置，可以继续努力实现我的长期目标 履行 NCI 的使命“推进科学知识并帮助所有人过上更健康、更长寿的生活”。