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: 7910489
• 负责人: Praveen B. Raju
• 金额: $ 17.15万
• 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 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7910489
• 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; Signal Transduction; 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; public health relevance; research study; success; tumor; tumor progression

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.

项目简介：髓母细胞瘤是一种发生于儿童的恶性脑肿瘤，死亡率高，急性治疗毒性导致预后差。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信号通路在这种脑肿瘤中的作用也有牵连。该项目的长期目标是通过研究散发性成神经管细胞瘤的遗传和病理生理相关小鼠模型的特征，更好地了解散发性成神经管细胞瘤的发育起源和分子特征，从而改进治疗方案。我假设每种特定的髓母细胞瘤亚型起源于小脑不同的生发区，因此具有不同的分子特征和依赖与其肿瘤细胞起源相关的信号通路。我将使用一种新的遗传技术来产生马赛克小鼠，在时间和细胞类型特异性控制下，基因在内源性位点上有条件地突变，同时在单细胞中标记GFP。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谱，以及表征抗治疗GFP+肿瘤细胞。这些研究将在神经发育和小鼠遗传学专家Alexandra Joyner博士和脑肿瘤生物学专家Eric Holland博士的指导下进行。导师和他们的实验室都为我提供了最佳的环境，让我在获得K奖期间过渡到独立教师职位后，在这一领域取得未来成功所需的技术和方法方面发展专业知识。威尔康奈尔在促进我的职业发展方面做出了杰出的机构承诺，通过限制临床责任和行政职责，允许至少75%的精力用于研究，并在我向独立研究科学家过渡时提供独立研究空间和终身教职。