Dissecting the Signaling Mechanisms of Smoothened

剖析 Smoothened 的信号机制

• 批准号: 8272944
• 负责人: Stacey Kathryn Ogden
• 金额: $ 33.69万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8272944
• 关键词: Adverse effects; Basal cell carcinoma; Biochemical; Biological Models; Breast; Candidate Disease Gene; Cells; Child; Cysteine; Development; Dissection; Disulfides; Drosophila genus; Drosophila melanogaster; Erinaceidae; Event; Extracellular Domain; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genes; Genetic; Goals; Health; Heterotrimeric GTP-Binding Proteins; Human; Laboratories; Lead; Ligands; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of brain; Maps; Mediating; Methods; Molecular; Molecular Conformation; Mutation; Pathway interactions; Pattern; Phenotype; Physiological; Play; Prostate; Proteins; Regulation; Rhabdomyosarcoma; Role; Saint Jude Children' s Research Hospital; Scientist; Signal Transduction; Signal Transduction Pathway; Testing; Training; Transducers; Work; chemotherapy; cytotoxic; design; extracellular; hedgehog signal transduction; human SMO protein; improved; in vivo; insight; interest; man; medulloblastoma; member; new therapeutic target; novel; outcome forecast; pressure; research facility; skills; smoothened signaling pathway; therapeutic target; tool

DESCRIPTION (provided by applicant): The Hedgehog (Hh) signal transduction pathway plays an essential role in patterning fields of cells during development, and is frequently activated in cancer. Inappropriate Hh signaling is causative in basal cell carcinoma, the most common cancer in humans, medulloblastoma, the most common malignant brain tumor in children, and rhabdomyosarcoma, where pathway activation correlates with poor prognosis. Hh has also been implicated in sporadic tumors of the lung, breast and prostate. Consequently, the Hh pathway has emerged as an attractive therapeutic target; specific inhibition of Hh signaling will likely have efficacy against these cancers without triggering the undesirable side effects associated with conventional chemotherapy. To design and employ Hh-specific therapies, a clear understanding of the regulatory mechanisms and signaling components controlling physiological Hh signal transduction is of paramount importance. Accordingly, the goals of this proposal are to dissect mechanistic events governing Hh pathway induction and to identify novel effectors facilitating downstream signaling. We will achieve these goals through molecular and functional analysis of Hh signal transduction using the fruit fly Drosophila melanogaster as our model system. Our studies primarily focus on elucidating the signaling mechanisms and downstream effectors of Smoothened, the critical signal transducer of the Hh pathway. Smoothened is a member of the G-protein coupled receptor (GPCR) superfamily. As such, this study includes three Specific Aims designed to better characterize Smoothened GPCR signaling activity: 1) To characterize the extracellular GPCR structural features that facilitate Hh- regulated Smoothened signaling, 2) To identify GPCR functional domains in Smoothened that govern signaling and 3) To map the G-protein effector network functioning downstream of Smoothened. The proposed studies will enhance our understanding of how the Hh signal is initiated and transduced, and may reveal novel therapeutic targets through identifying "pressure points" on Smoothened and within the Hh cascade. PUBLIC HEALTH RELEVANCE: The Hedgehog (Hh) signal transduction pathway plays an essential role in patterning fields of cells during development, and is frequently activated in cancer. Inappropriate Hh signaling is causative in basal cell carcinoma, the most common cancer in humans, medulloblastoma, the most common malignant brain tumor in children, and rhabdomyosarcoma, where pathway activation correlates with poor prognosis. Hh has also been implicated in sporadic tumors of the lung, breast and prostate. Consequently, the Hh pathway has emerged as an attractive therapeutic target; specific inhibition of Hh signaling will likely have efficacy against these cancers without triggering the undesirable side effects associated with conventional chemotherapy. To design and employ Hh-specific therapies, a clear understanding of the regulatory mechanisms and signaling components controlling physiological Hh signal transduction is of paramount importance. Accordingly, the goals of this proposal are to dissect mechanistic events governing Hh pathway induction and to identify novel effectors facilitating downstream signaling. We will achieve these goals through molecular and functional analysis of Hh signal transduction using the fruit fly Drosophila melanogaster as our model system. The proposed studies will enhance our understanding of how the Hh signal is initiated and transduced, and may reveal novel therapeutic targets through identifying "pressure points" within the Hh cascade.

描述（由申请人提供）：Hedgehog（Hh）信号转导途径在细胞发育过程中的模式化领域中发挥重要作用，并且在癌症中经常被激活。不适当的 Hh 信号传导是基底细胞癌（人类最常见的癌症）、髓母细胞瘤（儿童最常见的恶性脑肿瘤）和横纹肌肉瘤的病因，其中通路激活与不良预后相关。 Hh 还与肺癌、乳腺癌和前列腺的散发性肿瘤有关。因此，Hh 通路已成为一个有吸引力的治疗靶点。 Hh 信号传导的特异性抑制可能对这些癌症有效，而不会引发与传统化疗相关的不良副作用。为了设计和使用 Hh 特异性疗法，清楚地了解控制生理性 Hh 信号转导的调节机制和信号成分至关重要。因此，本提案的目标是剖析控制 Hh 通路诱导的机制事件，并确定促进下游信号传导的新效应器。我们将使用果蝇果蝇作为我们的模型系统，通过 Hh 信号转导的分子和功能分析来实现这些目标。我们的研究主要集中于阐明 Hh 通路的关键信号转导器 Smoothened 的信号传导机制和下游效应器。 Smoothened 是 G 蛋白偶联受体 (GPCR) 超家族的成员。因此，本研究包括三个具体目标，旨在更好地表征 Smoothened GPCR 信号传导活性：1) 表征促进 Hh 调节的 Smoothened 信号传导的细胞外 GPCR 结构特征，2) 识别 Smoothened 中控制信号传导的 GPCR 功能域，3) 绘制在 Smoothened 下游发挥作用的 G 蛋白效应网络。拟议的研究将增强我们对 Hh 信号如何启动和转导的理解，并可能通过识别 Smoothened 上和 Hh 级联内的“压力点”来揭示新的治疗靶点。 公共健康相关性：Hedgehog (Hh) 信号转导通路在细胞发育过程中的模式化领域中发挥着重要作用，并且在癌症中经常被激活。不适当的 Hh 信号传导是基底细胞癌（人类最常见的癌症）、髓母细胞瘤（儿童最常见的恶性脑肿瘤）和横纹肌肉瘤的病因，其中通路激活与不良预后相关。 Hh 还与肺癌、乳腺癌和前列腺的散发性肿瘤有关。因此，Hh 通路已成为一个有吸引力的治疗靶点。 Hh 信号传导的特异性抑制可能对这些癌症有效，而不会引发与传统化疗相关的不良副作用。为了设计和使用 Hh 特异性疗法，清楚地了解控制生理性 Hh 信号转导的调节机制和信号成分至关重要。因此，本提案的目标是剖析控制 Hh 通路诱导的机制事件，并确定促进下游信号传导的新效应器。我们将使用果蝇果蝇作为我们的模型系统，通过 Hh 信号转导的分子和功能分析来实现这些目标。拟议的研究将增强我们对 Hh 信号如何启动和转导的理解，并可能通过识别 Hh 级联内的“压力点”来揭示新的治疗靶点。