Hedgehog-mediated regulation of cell adhesion

描述（由申请人提供）：动物发育中的组织模式需要促进和维持不同细胞群的物理分离的粘附机制。 已提出许多旁分泌形态发生素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，这反过来又有助于在组织生长过程中维持形态发生素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并导致 Hh 分泌（非反应）细胞和 Hh 反应（非分泌）细胞分离的细胞和分子机制。 越来越多的证据表明，某些人类癌细胞分泌的 Hh 可能会向周围组织发出信号，促进肿瘤生长和转移。 此外，恶性侵袭可能被认为是细胞反向分离的正常过程，其中癌细胞与组织细胞之间存在交叉粘附。 因此，这项研究不仅将极大地促进我们对组织模式的分子和细胞基础的了解，以及进一步了解Hh信号通路本身，而且还将揭示癌症进展的机制，或许有助于发现癌症的新治疗靶点。 果蝇翼成虫盘分为前室（A）和后室（P）。 P 细胞分泌 Hh，同时对 Hh 信号产生抵抗。 相反，A细胞可以接收并响应Hh，但自身不表达Hh。 两个区室的细胞在发育过程中不会混合。 然而，无法响应 Hh 信号的 A 细胞不再与 P 细胞分离。 目前的观点是，对 Hh 信号的响应会引起粘附性的变化，并且这种差异导致 A 细胞与 P 细胞分离。 将该模型遗传系统与结合了强大的生化、分子和细胞技术的广泛实验方法相结合，研究人员建议：1）研究Hh信号如何通过调节Ihog家族蛋白的细胞表面水平来直接改变Hh分泌P细胞和Hh响应A细胞之间的亲和力差异； 2) 鉴定参与调节 A/P 细胞分离的其他细胞粘附分子； 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) 可能会向周围组织发出信号，促进肿瘤生长和转移。 此外，恶性侵袭可能被认为是细胞反向分离的正常过程，其中癌细胞与组织细胞之间存在交叉粘附。 因此，这项研究Hh信号定义特异性细胞粘附的机制，不仅将大大有助于我们了解组织模式的分子和细胞基础以及进一步了解Hh信号通路，而且还将揭示癌症进展的机制，或许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.