Mechanisms of Hedgehog Signal Transduction

项目摘要 进化上保守的Hedgehog（Hh）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Hh途径活性的机制。我的实验室的长期目标是确定 在发展过程中控制Hh途径活动的过程，并利用这些知识来识别机会 针对疾病中不适当的Hh信号传导。未来5年，我们将继续为此努力。 通过询问和定义控制Hh关键调节步骤的分子机制， 信号转导级联我们的重点是阐明1）Hh配体的释放和运输是如何 控制以建立形态发生梯度，2）Smo激活、信号偏置和效应器接合是如何 控制在发展过程中和损坏的疾病，以及3）如何Gli转录激活诱导和 去稳定化被协调以确保适当的转录应答。

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.