Mechanisms of Hedgehog Signal Transduction

项目总结 进化上保守的Hedgehog(HH)信号通路调控组织形态发生 并有助于成人的组织动态平衡。途径活动驱动的改变 发育障碍包括全前脑畸形、Pallister-Hall综合征和基底细胞痣 综合症。发育后信号的不适当激活经常与癌症有关， 是基底细胞癌和髓母细胞瘤的病因，并作为一种生存因素在一系列 其他肿瘤类型。因此，有很大的兴趣和治疗潜力定义 HH途径活性的调控机制。我的实验室的长期目标是定义监管 在发育过程中控制HH途径活动的过程，并使用这些知识来识别机会 针对疾病中不适当的HH信号。在接下来的5年里，我们将继续为此而努力 通过询问和定义控制HH关键调控步骤的分子机制来实现目标 信号转导级联。我们专注于阐明1)HH配体是如何释放和转运的 控制以建立形态梯度，2)如何激活Smo、信号偏差和效应器接合 在发育过程中被控制，在疾病中被破坏，以及3)Gli转录激活子如何诱导和 失稳是协调的，以确保适当的转录反应。

PROJECT SUMMARY The evolutionarily conserved Hedgehog (Hh) 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 Hh pathway activity. My laboratory's long-term goal is to define the regulatory processes governing Hh pathway activity during development, and use this knowledge to identify opportunities for targeting inappropriate Hh 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 Hh signal transduction cascade. We are focused on elucidating 1) how Hh ligand release and transport are controlled to establish a morphogen gradient, 2) how Smo activation, signal bias and effector engagement are controlled during development and corrupted in disease, and 3) how Gli transcriptional activator induction and destabilization are coordinated to assure an appropriate transcriptional response.