Hedgehog-mediated regulation of cell adhesion

描述（由申请人提供）：动物发育中的组织模式化需要促进和维持不同细胞群物理分离的粘附机制。 已经提出了许多旁分泌形态发生信号来指定细胞亲和力的差异以及尖锐和稳定边界的形成，这些边界反过来又用于在组织生长期间维持形态发生组织者的位置和形状。 该项目的长期目标是了解Hedgehog（Hh）信号定义特定细胞亲和力的细胞和分子机制，并导致Hh分泌（非应答）细胞和Hh应答（非分泌）细胞的分离。 越来越多的证据表明，某些人类癌细胞分泌的Hh可能向周围组织发出信号并促进肿瘤生长和转移。 此外，恶性侵袭可能被认为是细胞逆向分离的正常过程，其中癌细胞和组织细胞之间存在交叉粘附。 因此，这项研究不仅将有助于我们对组织模式的分子和细胞基础的了解，以及对Hh信号通路本身的进一步理解，而且还将揭示癌症进展的机制，可能导致发现新的癌症治疗靶点。 果蝇翅的成虫盘分为前室（A）和后室（P）。 P细胞分泌Hh，同时对Hh信号不敏感。 与此相反，A细胞可以接受并响应Hh，但自身不表达Hh。 两个隔室的细胞在发育过程中不混合。 然而，不能对Hh信号作出反应的A细胞不再与P细胞分离。 目前的观点是，对Hh信号的反应诱导了细胞周期的变化，这种差异导致了A细胞与P细胞的分离。 将该模型遗传系统与广泛的实验方法相结合，这些实验方法结合了强大的生物化学、分子和细胞技术，研究者提出：1）研究Hh信号如何通过调节Ihog家族蛋白的细胞表面水平直接改变分泌Hh的P细胞和响应Hh的A细胞之间的亲和力差异; 2）鉴定参与调节A/P细胞分离的另外的细胞粘附分子;和3）确定Shh信号是否和如何通过调节脊椎动物Ihog同源物的表达水平来改变细胞亲和力。 项目叙述：越来越多的证据表明，某些人类癌细胞分泌的Hedgehog（Hh）可以向周围组织发出信号，促进肿瘤的生长和转移。 此外，恶性侵袭可能被认为是细胞逆向分离的正常过程，其中癌细胞和组织细胞之间存在交叉粘附。 因此，这项研究，Hh信号定义特定细胞粘附的机制，不仅将大大有助于我们对组织模式的分子和细胞基础的了解，并进一步了解Hh信号通路，而且还将阐明癌症进展的机制，可能导致发现新的癌症治疗靶点。

DESCRIPTION (Provided by Applicant): Tissue patterning in animal development requires adhesive mechanisms that promote and maintain physical segregation of different cell populations. Many paracrine morphogen signals have been proposed to specify the differences in cell affinity and the formation of sharp and stable boundaries which, in turn, serve to maintain the position and shape of morphogen organizers during the growth of a tissue. The long-term goal of this project is to understand the cellular and molecular mechanisms by which the Hedgehog (Hh) signal defines specific cell affinities and lead to the segregation of Hh-secreting (non-responding) cells and Hh-responding (non-secreting) cells. Increasing evidence indicates that Hh secreted by certain human cancer cells may signal to surrounding tissue and promote tumor growth and metastasis. Furthermore, malignant invasion might be considered a normal process of cell segregation in reverse, in which there is cross-adhesion between cancer cells and tissue cells. Therefore, this study will not only contribute significantly to our knowledge of the molecular and cellular bases of tissue patterning as well as further understanding of the Hh signal pathway per se, but will also shed light on the mechanisms of cancer progression, perhaps leading to the discovery of new therapeutic targets in cancers. The Drosophila wing imaginal disc is subdivided into an anterior (A) and a posterior (P) compartment. P cells secrete Hh and, at the same time, are refractory to the Hh signal. In contrast, A cells can receive and respond to Hh, but do not express Hh by themselves. The cells of the two compartments do not intermingle during development. However, A cells unable to respond to the Hh signal no longer segregate from P cells. The current view is that the response to the Hh signal induces a change in the adhesiveness and that this difference leads to the segregation of A cells from P cell. Combining this model genetic system with broad experimental approaches that incorporate powerful biochemical, molecular, and cellular techniques, the investigator proposes: 1) to investigate how the Hh signal directly alters the affinity differences between Hh-secreting P cells and Hh- responding A cells by modulating cell surface levels of the Ihog family proteins; 2) to identify additional cell adhesion molecules involved in regulating A/P cell segregation; and 3) to determine whether and how the Shh signal alters cell affinity by regulating expression levels of the vertebrate Ihog homologues. PROJECT NARRATIVE: Increasing evidence indicates that Hedgehog (Hh) secreted by certain human cancer cells may signal to surrounding tissue and promote tumor growth and metastasis. Furthermore, malignant invasion might be considered a normal process of cell segregation in reverse, in which there is cross-adhesion between cancer cells and tissue cells. Therefore, this study, mechanisms by which the Hh signal defines specific cell adhesion, will not only contribute significantly to our knowledge of the molecular and cellular bases of tissue patterning and further understanding of the Hh signal pathway, but will also shed light on the mechanisms of cancer progression, perhaps leading to the discovery of new therapeutic targets in cancers.