Hedgehog-mediated regulation of cell adhesion

描述(申请人提供)：动物发育中的组织图案化需要促进和维持不同细胞群体的物理隔离的粘合机制。许多旁分泌形态原信号被提出用来说明细胞亲和力的差异和尖锐而稳定的边界的形成，而这些边界反过来又有助于在组织生长过程中保持形态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(无反应)细胞和HH反应(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，促进肿瘤的生长和转移。此外，恶性侵袭可能被认为是正常的细胞分离过程，在这种过程中，癌细胞和组织细胞之间存在交叉黏附。因此，这项研究不仅有助于我们了解组织构型的分子和细胞基础以及进一步了解HH信号通路本身，而且还将有助于揭示癌症进展的机制，可能有助于发现新的癌症治疗靶点。 果蝇翅膀形象盘分为前(A)室和后(P)室。P细胞分泌HH，同时对HH信号不敏感。相反，A细胞可以接受和应答HH，但不能自己表达HH。两个隔室的细胞在发育过程中不会混合。然而，不能响应HH信号的A细胞不再与P细胞分离。目前的观点是，对HH信号的反应导致了粘附性的变化，这种差异导致了A细胞和P细胞的分离。结合这个模型遗传系统和结合了强大的生化、分子和细胞技术的广泛的实验方法，研究人员建议：1)研究HH信号如何通过调节Ihog家族蛋白质的细胞表面水平直接改变HH分泌的P细胞和HH反应的A细胞之间的亲和力差异；2)确定其他参与调节A/P细胞分离的细胞黏附分子；以及3)确定Shh信号是否以及如何通过调节脊椎动物Ihog同源物的表达水平改变细胞亲和力。 项目简介：越来越多的证据表明，由某些人类癌细胞分泌的Hedgehog(HH)可能会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正常的细胞分离过程，在这种过程中，癌细胞和组织细胞之间存在交叉黏附。因此，这项研究HH信号定义特定细胞黏附的机制，不仅将有助于我们了解组织构型的分子和细胞基础，进一步了解HH信号通路，而且还将有助于阐明癌症进展的机制，可能有助于发现癌症的新治疗靶点。

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.