Mechanisms of Sonic Hedgehog Signal Transduction

项目摘要 进化上保守的Sonic Hedgehog（SHH）信号通路在细胞周期中控制组织形态发生。 发育并有助于成年人的组织稳态。通路活动驱动的改变 发育障碍，包括前脑无裂畸形（HPE）、Pallister-Hall综合征和基底细胞痣 综合征发育后信号传导的不适当激活通常与癌症有关， 是基底细胞癌和髓母细胞瘤的病因，并在一系列肿瘤中作为一种生存因子。 其他肿瘤类型因此，在定义治疗中存在显著的兴趣和治疗潜力。 控制SHH通路活性的机制。我的实验室的长期目标是确定 在发育过程中控制SHH途径活性的过程，并使用这些知识来识别 针对疾病中不适当的SHH信号的机会。未来5年，我们将继续 通过询问和定义控制关键调节的分子机制， SHH信号转导级联的步骤。我们专注于阐明1）SHH配体如何释放， 控制运输以建立形态发生梯度，2）如何控制SMO活化以及它如何 协调其活动与其他G蛋白偶联受体在初级纤毛，和3）如何GLI 转录激活因子诱导和去稳定化是协调的，以确保适当的转录激活因子的表达。 反应

PROJECT SUMMARY The evolutionarily conserved Sonic Hedgehog (SHH) signaling pathway governs tissue morphogenesis during development and contributes to tissue homeostasis in adults. Alteration of pathway activity drives developmental disorders including Holoprosencephaly (HPE), Pallister-Hall Syndrome and Basal Cell Nevus syndrome. Inappropriate activation of signaling post-developmentally is frequently associated with cancer, being causative in basal cell carcinoma and medulloblastoma, and implicated as a survival factor in a range of additional tumor types. As such, there is significant interest and therapeutic potential in defining the mechanisms governing SHH pathway activity. My laboratory’s long-term goal is to define the regulatory processes governing SHH pathway activity during development and use this knowledge to identify opportunities for targeting inappropriate SHH signaling in disease. Over the next 5 years, we will continue to work toward this goal by interrogating and defining the molecular mechanisms controlling pivotal regulatory steps of the SHH signal transduction cascade. We are focused on elucidating 1) how SHH ligand release and transport are controlled to establish a morphogen gradient, 2) how SMO activation is controlled and how it coordinates its activity with other G protein coupled receptors at the primary cilium, and 3) how GLI transcriptional activator induction and destabilization are coordinated to assure an appropriate transcriptional response.