Developmental Origins of Neural Tumors Using a Novel Genetic Inducible Analysis

使用新型遗传诱导分析研究神经肿瘤的发育起源

• 批准号: 8516603
• 负责人: Praveen B. Raju
• 金额: $ 17.74万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516603
• 关键词: Address; Animal Model; Biology; Brain Neoplasms; Cause of Death; Cell Count; Cell Lineage; Cell Nucleus; Cells; Cerebellum; Characteristics; Child; Classification; Clinical; Collagen; Cytoplasmic Granules; Dependence; Desmoplastic; Development; Diagnostic Neoplasm Staging; Dorsal; Erinaceidae; Faculty; Fostering; Future; Gene Expression Profile; Genes; Genetic; Genetic Techniques; Genomics; Glial Fibrillary Acidic Protein; Goals; Golgi Apparatus; Human; Inherited; Interneurons; K-Series Research Career Programs; Knockout Mice; Laboratories; Lip structure; Malignant Neoplasms; Malignant neoplasm of brain; Maps; Mentors; Mentorship; Methodology; Modality; Molecular; Molecular Profiling; Mus; Mutate; Mutation; Neuroepithelial, Perineurial, and Schwann Cell Neoplasm; Neurons; Oncogenic; Outcome; Pathway interactions; Play; Positioning Attribute; Proliferating; Proteins; Purkinje Cells; Radiation; Research; Research Personnel; Resistance; Role; Scientist; Secondary to; Signal Pathway; Sonic Hedgehog Pathway; Staging; Syndrome; System; Techniques; Testing; Therapeutic; Time; Toxic effect; Treatment outcome; Tumor Biology; Tumor stage; Ventricular; age group; base; career development; cell type; granule cell; improved; in vivo; loss of function mutation; medulloblastoma; mortality; mouse model; mutant; neoplastic cell; nestin protein; neural precursor cell; neurodevelopment; novel; postnatal; precursor cell; programs; research study; smoothened signaling pathway; success; tumor; tumor progression

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.

髓母细胞瘤是死亡率明显且结果差的儿童的恶性脑肿瘤 继发于Cun-tent疗法的毒性。证据指向髓母细胞瘤起源于神经 位于小脑内的前体细胞以及声音刺猬和Wnt信号通路的角色 该脑肿瘤也已被牵涉。这个项目的长期目标是更好地了解 通过研究零星髓母细胞瘤的发育起源和分子特征 遗传学和病理生理学相关的小鼠模型的特征，以改善治疗 选项。我假设每个特定的髓母细胞瘤亚型来自 小脑和结果具有独特的分子特征和对信号的依赖性 途径与它们的原始肿瘤细胞有关。我将使用一种新颖的遗传技术来产生镶嵌小鼠 基因在内源性基因座有条件突变，并同时用GFP标记。 在时间和细胞类型特异性控制下的细胞。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，例如肿瘤原产细胞，微环境在 促进或限制肿瘤形成，明确确定GFP+标记的分子谱 肿瘤天花板在不同的肿瘤阶段，并表征了耐药的GFP+肿瘤细胞。 这些研究将在神经专家亚历山德拉·乔伊纳（Alexandra Joyner）的指导下进行 发育和小鼠遗传学，以及脑肿瘤专家埃里克·霍兰德（Eric Holland）博士的同学 生物学。导师及其实验室都为发展专业知识提供了最佳的环境 过渡到独立的技术和方法学所需的技术和方法 该K奖期间的教师职位。威尔·康奈尔（Weill Cornell）杰出的机构承诺 通过将临床责任和行政职责限制为促进我的职业发展 至少允许致力于研究并提供独立的研究空间和终身制的努力 我过渡到独立研究科学家时的教师职位。 相关性（请参阅Instnjctions）： 髓母细胞瘤是儿童中最常见的脑肿瘤，也是死亡的主要原因之一 年龄段。这种应用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，目的是识别新目标进行治疗 破坏性癌症。