RECIPROCAL SONIC HEDGEHOG AND CXCR4 INTERACTIONS IN MEDULLOBLASTOMA

Sonic Hedgehog 和 CXCR4 在髓母细胞瘤中的相互作用

• 批准号: 8201513
• 负责人: Stacey Ward
• 金额: $ 7.07万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8201513
• 关键词: ADRBK1 gene; ADRBK2 gene; Address; Adenylate Cyclase; Adverse effects; Arrestins; Basic Science; Binding; Brain Neoplasms; CXCL12 gene; CXCR4 gene; Caring; Cell Proliferation; Cell membrane; Cell surface; Cells; Child; Chronic; Cilia; Clinical; Cyclic AMP; Cytoplasmic Granules; Data; Development; Disease; Drug resistance; Erinaceidae; Event; Failure; Fellowship; Ferritin; G-Protein-Coupled Receptors; GRK6 gene; GTP-Binding Proteins; Goals; Growth; Health; Human; Immunofluorescence Immunologic; Life; Ligands; Light; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of central nervous system; Mediator of activation protein; Medical; Membrane; Mission; Modeling; Molecular; Mus; Mutate; Mutation; National Cancer Institute; Oncogenic; Pathway interactions; Patients; Phosphotransferases; Process; Proliferating; Proteins; Psychological reinforcement; Publishing; Research; Signal Transduction; Signal Transduction Pathway; Sonic Hedgehog Pathway; Staining method; Stains; Surface; Survivors; System; Tissues; Transgenic Mice; Translating; Xenograft procedure; base; brain cell; cancer cell; design; driving force; improved; medulloblastoma; mouse model; neuro-oncology; novel; novel strategies; precursor cell; protein expression; protein transport; receptor; receptor internalization; smoothened signaling pathway; success; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Medulloblastoma is the most common malignant central nervous system cancer in children. Decades of research have shed light on various molecular differences between cancer cells and nontransformed brain cells, but treatments to target only the tumor are lacking. The Sonic hedgehog (Shh) pathway is frequently mutated in these cancers and primary research indicates this pathway is a driving force in oncogenesis. Treatments that target the Shh pathway have been compromised by new mutations and drug resistance. The central hypothesis of this proposal is that growth-promoting pathways, such as Shh and CXCR4, act in concert to promote tumorigenesis and cell proliferation and that defining the mechanisms of their interaction will yield novel approaches to therapy. The mechanism of Shh-induced CXCR4 surface localization will be deciphered using primary mouse cerebellar granule precursor cells and primary murine medulloblastoma cells. Second, the impact of primary cilia on Shh modulation of CXCR4 function will be investigated. Completion of these aims will address the cross-talk between signal transduction pathways within cancer cells and move the field toward novel treatments which target the multiple dysregulations involved in tumorigenesis. This fellowship application addresses the mission statement of the National Cancer Institute by studying the molecular pathways that must be specifically targeted to better treat medulloblastoma, and possibly, other Shh-regulated tumors. PUBLIC HEALTH RELEVANCE: Medulloblastoma is the most common malignant brain cancer in children. While long-term survival is high, current treatments cause significant and chronic side effects, necessitating life-long medical care for survivors. The ultimate goal of this research is to improve the treatment for medulloblastoma by defining how two targetable pathways, the sonic hedgehog and CXCR4 pathways, converge to promote medulloblastoma genesis and growth.

描述（由申请人提供）：髓母细胞瘤是儿童中最常见的恶性中枢神经系统癌。数十年的研究揭示了癌细胞和未转化的脑细胞之间的各种分子差异，但缺乏针对肿瘤的治疗方法。在这些癌症中经常突变声音刺猬（SHH）途径，主要研究表明该途径是肿瘤发生的驱动力。针对SHH途径的治疗已被新的突变和耐药性所损害。该提议的中心假设是，促进生长的途径（例如SHH和CXCR4）共同起作用促进肿瘤发生和细胞增殖，并且定义相互作用的机制将产生新的治疗方法。 SHH诱导的CXCR4表面定位的机制将使用原代小鼠小脑颗粒前体细胞和原代鼠髓母细胞瘤细胞解密。其次，将研究原发性纤毛对CXCR4功能的SHH调制的影响。这些目的的完成将解决癌细胞内信号转导途径之间的串扰，并将领域转向针对涉及肿瘤发生的多种失调的新型治疗方法。该奖学金申请通过研究必须专门针对的分子途径来更好地治疗髓母细胞瘤以及其他SHH调节的肿瘤，以解决国家癌症研究所的任务陈述。 公共卫生相关性：髓母细胞瘤是儿童最常见的恶性脑癌。虽然长期生存较高，但目前的治疗会引起重大且慢性的副作用，因此需要为幸存者提供终身的医疗服务。这项研究的最终目的是通过定义两个可靶向途径，声音刺猬和CXCR4途径来改善髓母细胞瘤的治疗方法，从而促进髓母细胞瘤的创世纪和生长。