Developmental Origins of Neural Tumors Using a Novel Genetic Inducible Analysis

描述(申请人提供)：项目摘要：髓母细胞瘤是一种儿童恶性脑肿瘤，由于目前治疗的毒性，死亡率高，预后差。有证据表明髓母细胞瘤起源于小脑内的神经前体细胞，Sonic hedgehog和Wnt信号通路在这种脑瘤中的作用也被牵连。该项目的长期目标是通过研究散发性髓母细胞瘤在遗传学和病理生理学相关的小鼠模型中的特征，更好地了解散发性髓母细胞瘤的发育起源和分子特征，以改进治疗方案。我假设每一种特定的髓母细胞瘤亚型都来自小脑不同的生发区，因此具有不同的分子特征，并依赖于与其起源的肿瘤细胞相关的信号通路。我将使用一种新的遗传技术来产生镶嵌小鼠，在这种小鼠中，基因在内源性基因座上有条件地突变，同时在时间和细胞类型特定的控制下的单个细胞中用GFP标记。这一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，微环境在促进或限制肿瘤形成中的作用，明确确定不同肿瘤阶段GFP+标记的肿瘤细胞的分子图谱，以及表征耐药的GFP+肿瘤细胞。这些研究将在神经发育和小鼠遗传学专家亚历山德拉·乔伊纳博士的指导下进行，并由脑瘤生物学专家埃里克·霍兰德博士共同指导。导师和他们的实验室都为发展技术和方法方面的专业知识提供了最佳的环境，这些专业知识是我在K奖期间过渡到独立教员职位后在这一领域取得成功所需的。威尔·康奈尔在促进我的职业发展方面的杰出机构承诺表现在：限制临床责任和行政职责，允许至少75%的努力致力于研究，并在我过渡到独立研究科学家时提供独立研究空间和终身教职。 公共卫生相关性：髓母细胞瘤是儿童最常见的脑肿瘤，也是该年龄段的主要死亡原因之一。这项应用的目的是利用基因相关的小鼠模型更好地了解髓母细胞瘤的分子基础，目的是确定治疗这种毁灭性癌症的新靶点(S)。

DESCRIPTION (provided by applicant): Project Summary: 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. Public Health Relevance: 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.