Developmental Origins of Neural Tumors Using a Novel Genetic Inducible Analysis

髓母细胞瘤是一种儿童恶性脑肿瘤，死亡率高，预后差 继发于当前治疗的毒性。有证据表明髓母细胞瘤起源于 位于小脑内的前体细胞以及Sonic hedgehog和Wnt信号通路在 这个脑瘤也有牵连该项目的长期目标是更好地了解 通过研究散发性髓母细胞瘤的发育起源和分子特征， 遗传和病理生理学相关小鼠模型的特征，以改善治疗 选项.我假设每一种特定的髓母细胞瘤亚型都来自不同的生发区， 小脑和相应地具有独特的分子特征和对信号的依赖性 与其肿瘤细胞起源相关的途径。我会用一种新的基因技术来制造嵌合体小鼠 其中基因在内源基因座处条件性突变，并且同时用GFP标记， 在时间和细胞类型特定的控制下的细胞。这种复杂的方法将使我能够解决 髓母细胞瘤生物学中的基本问题，如肿瘤细胞的起源，微环境的作用， 促进或限制肿瘤形成，明确确定GFP+标记的分子谱 在不同肿瘤阶段的肿瘤细胞，以及表征治疗抗性GFP+肿瘤细胞。 这些研究将在神经科学专家亚历山德拉·乔伊纳博士的指导下进行。 开发和小鼠遗传学，以及脑肿瘤专家埃里克·霍兰德博士的共同指导 生物学导师和他们的实验室都提供了最佳的环境， 技术和方法所需的未来成功在这一领域后，我的过渡到一个独立的 在这段时间里，K奖。威尔康奈尔大学的杰出机构承诺， 通过限制临床职责和行政职责来促进我的职业发展， 允许至少75%的精力用于研究，并提供独立的研究空间和终身教职 在我向独立研究科学家过渡的时候，我担任教职。 相关性（参见说明）： 髓母细胞瘤是儿童最常见的脑肿瘤，也是儿童死亡的主要原因之一 年龄段本申请的目的是更好地了解髓母细胞瘤的分子基础 使用遗传相关的小鼠模型，目的是鉴定用于治疗这种疾病的新靶点， 毁灭性的癌症

Medulloblastoma is a malignant brain tumor in children with significant mortality and poor outcomes secondary to toxicity of cun-ent therapy. Evidence points to medulloblastoma originating from neural precursor cells located within the cerebelluni and roles for Sonic hedgehog and Wnt signaling pathways in this brain tumor have also been implicated. The long-term goals ofthis project are to better understand the developmental origins and molecular signatures of sporadic medulloblastomas by studying their characteristics in genetically and pathophysiologically relevant mouse models in order to improve treatment options. I hypothesize that each particular medulloblastoma subtype arises from distinct germinal zones of the cerebellum and consequentially have distinctive molecular signatures and dependence on signaling pathways related to their tumor cell of origin. I will use a novel genetic technique to generate mosaic mice where genes are conditionally mutated at endogenous loci and simultaneously marked with GFP in single cells under both temporal and cell type-specific control. This sophisticated approach will allow me to address fundamental questions in medulloblastoma biology such as tumor cell of origin, role of microenvironment in promoting or restricting tumor formation, unambiguously determine the molecular profiles of GFP+ marked tumor ceils during different tumor stages, as well as characterize treatment-resistant GFP+ tumor cells. These studies will be performed under the mentorship of Dr. Alexandra Joyner, an expert in neural development and mouse genetics, and the co-mentorship of Dr. Eric Holland, an expert in brain tumor biology. Both mentors and their laboratories provide the optimal setting for developing expertise in the techniques and methodologies required for future success in this field after my transition to an independent faculty position during the period of this K award. Weill Cornell's outstanding institutional commitment to fostering my career development is shown by limiting clinical responsibilities and administrative duties to allow at least 75% effort devoted to research, and providing independent research space and a tenure-track faculty position at the time of my transition to an independent research scientist. RELEVANCE (See instnjctions): Medulloblastoma is the most common brain tumor in children and one of the leading causes of death in this age group. The goal ofthis application is to better understand the molecular basis of medulloblastoma using genetically relevant mouse models with the aim of identifying new target(s) for therapy for this devastating cancer.