TGF-Beta, Neural Stem Cella and Gliomagenesis

TGF-β、神经干细胞和胶质瘤发生

• 批准号: 8127820
• 负责人: Ty William Abel
• 金额: $ 16.58万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127820
• 关键词: Accounting; Anterior; Area; Astrocytes; Behavior; Biological; Biological Assay; Brain; Brain Neoplasms; Cell Culture Techniques; Cells; Characteristics; Clinical; Complex; Cultured Cells; Data; Development; Development Plans; Diagnosis; Differentiation and Growth; Disease; Educational process of instructing; Experimental Designs; Genetic Markers; Glial Fibrillary Acidic Protein; Glioma; Gliomagenesis; Growth; Growth Factor; Histology; Human; Immunohistochemistry; In Vitro; K-Series Research Career Programs; Knowledge; Lead; Maintenance; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Mentors; Methodology; Methods; Modeling; Molecular; Mus; Mutation; Nature; Neoplasm Metastasis; Neoplasms; Newborn Infant; Normal tissue morphology; Oncogenic; Pathogenesis; Pathway interactions; Patients; Pattern; Physicians; Principal Investigator; Process; Property; Published Comment; Readability; Recurrence; Regulation; Research; Research Personnel; Role; Scientist; Serum; Signal Pathway; Signal Transduction; Staging; Stem cells; Study Section; Testing; Text; Training; Transforming Growth Factor beta; Transgenic Mice; Transplantation; Tumor Stem Cells; Work; anticancer research; base; carcinogenesis; career development; clinically relevant; conventional therapy; effective therapy; flasks; genetic manipulation; human TGFBR2 protein; improved; in vivo; insight; interest; member; migration; mouse model; neoplastic cell; nerve stem cell; neuropathology; new therapeutic target; novel; relating to nervous system; research study; response; self-renewal; skills; stem; subventricular zone; tumor; tumor growth; tumorigenic

DESCRIPTION (provided by applicant): Malignant gliomas are among the most deadly of human cancers, with most patients succumbing to the disease within a year of diagnosis. Recently, tumor cells with properties of stem cells have been identified in malignant gliomas. These cells share properties with normal neural stem cells, including multipotency and the capacity for self-renewal. Experimental evidence suggests that this relatively small and quiescent component of the overall tumor is responsible for tumor growth and maintenance and may account for tumor recurrence despite conventional therapies. The identification of these cells has spurred intense interest in understanding their relationship to normal CMS stem cells and the molecular mechanisms that regulate their biological behavior. Such knowledge promises to open entirely new avenues of treatment for glioma patients by targeting these cells and the signaling pathways that regulate their survival, growth and differentiation. Emerging data indicate that members of the transforming growth factor-beta (TGF-beta) superfamily regulate thetumorigenic properties of brain tumor stem cells, and TGF-beta has been implicated in the pathogenesis and progression of human gliomas. TGF-beta signaling has also recently been shown to regulate normal neural stem cells. By conditional activation of oncogenic k-ras and deletion of the TGF-(beta type II receptor in the mouse brain, we have developed a novel model that provides insight into the role of Ras and TGF-beta signaling in gliomagenesis and the regulation of neural stem cells. In the experiments proposed in Specific Aim 1 of this Mentored Career Development Award application, the role of TGF-beta in the pathogenesis of glioma will be investigated in clinically relevant mouse models of human glioma. In Specific Aim 2, the mechanisms by which the Ras and TGF-beta signaling pathways regulate the proliferation, differentiation and migration of normal and transformed neural stem cells will be examined. In Specific Aim 3, we will test, in orthotopic transplant experiments, whether stem cells with genetic alterations that are common in human glioma are capable of tumor formation and whether TGF-beta signaling modulates this process. A comprehensive career development plan for the principal investigator, Dr. Ty Abel, a physician-scientist with clinical neuropathology training, is described. The pursuit of the specific aims will teach Dr. Abel new investigative skills, including glioma modeling and stem cell culture, and will facilitate his transition to independent investigator in brain cancer research. Relevance: Malignant gliomas are aggressive, nearly uniformly fatal cancers. A better understanding of the molecular pathways, including the role of stem cells, regulating the development and progression of glioma may lead to novel and more effective treatments.

描述（由申请人提供）：恶性神经胶质瘤是人类癌症中最致命的胶质瘤之一，大多数患者在诊断的一年内屈服于该疾病。最近，在恶性神经胶质瘤中已经鉴定出具有干细胞特性的肿瘤细胞。这些细胞与正常的神经干细胞共享特性，包括多能力和自我更新的能力。实验证据表明，整体肿瘤的这种相对较小且静止的成分负责肿瘤的生长和维持，并且尽管有常规的疗法，但仍可能解释肿瘤复发。这些细胞的鉴定引起了人们对理解其与正常CMS干细胞的关系以及调节其生物学行为的分子机制的强烈兴趣。这些知识有望通过针对这些细胞以及调节其生存，生长和分化的信号传导途径来为神经胶质瘤患者提供全新的治疗途径。新兴数据表明，转化生长因子-Beta（TGF-BETA）的成员可以调节脑肿瘤干细胞的苏省特性，而TGF-β已与人胶质瘤的发病机理和进展有关。最近还显示，TGF-β信号传导调节正常的神经干细胞。通过有条件地激活致癌k-ras和TGF-（小鼠大脑中的II型受体II受体的缺失，我们开发了一个新型模型，可以深入了解RAS和TGF-BETA信号在神经胶质作用中的作用，并在神经干细胞的调节中调节神经干细胞的调节。在临床上相关的人胶质瘤模型中，在特定目标2中进行了研究，RAS和TGF-BETA信号通路可以调节正常和转化的神经细胞的增殖，分化和迁移，我们将在特定的AIM中进行特定的动力。 TGF-BETA信令调节了这一过程。对特定目标的追求将教授亚伯博士的新调查技能，包括神经胶质瘤建模和干细胞培养，并促进他在脑癌研究领域向独立研究者的过渡。相关性：恶性神经胶质瘤是侵略性的，几乎统一致命的癌症。更好地理解分子途径，包括干细胞的作用，调节神经胶质瘤的发展和进展可能会导致新颖和更有效的治疗方法。