Hedgehog-mediated regulation of cell adhesion

Hedgehog 介导的细胞粘附调节

• 批准号: 8593407
• 负责人: Xiaoyan Zheng
• 金额: $ 24.9万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8593407
• 关键词: Adhesions; Adhesiveness; Adhesives; Affect; Affinity; Animals; Anterior; Binding; Biochemical; Biological; Brothers; Cell Adhesion; Cell Adhesion Molecules; Cell Aggregation; Cell Separation; Cell surface; Cells; Cultured Cells; Development; Drosophila genus; Enhancers; Erinaceidae; Fibronectins; Genes; Genetic; Genetic Models; Genetic Screening; Goals; Growth; Homologous Gene; Human; Immunoglobulins; Lead; Light; Malignant - descriptor; Malignant Neoplasms; Mediating; Methods; Molecular; Molecular Profiling; Neoplasm Metastasis; Oncogenes; Pattern; Population; Positioning Attribute; Process; Property; Protein Family; Proteins; Refractory; Regulation; Shapes; Signal Transduction; System; Techniques; Time; Tissues; To specify; Wing; base; cancer cell; gain of function; imaginal disc; in vivo; morphogens; new therapeutic target; paracrine; promoter; receptor; receptor internalization; research study; response; segregation; smoothened signaling pathway; tumor growth; tumor progression

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 and 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, I propose: 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. 3) To investigate whether and how the Shh signal alters cell affinity by regulating expression levels of the vertebrate Ihog homologues.

动物发育中的组织模式需要促进和维持的粘附机制 不同细胞群的物理隔离。许多旁分泌形态发生素信号已被提出 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 在组织生长过程中保持形态发生素组织者的位置和形状。长期目标是 该项目旨在了解 Hedgehog (Hh) 信号定义的细胞和分子机制 特定的细胞亲和力并导致 Hh 分泌（无反应）细胞和 Hh 反应细胞的分离 （非分泌）细胞。越来越多的证据表明，某些人类癌细胞分泌的 Hh 可能发出信号 作用于周围组织，促进肿瘤生长和转移。此外，恶性侵袭可能是 被认为是细胞反向分离的正常过程，其中癌症之间存在交叉粘附 细胞和组织细胞。因此，这项研究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对 Hh 信号通路本身的进一步理解， 但也将揭示癌症进展的机制，也许会导致新的发现 癌症的治疗靶点。 果蝇翼成虫盘分为前室（A）和后室（P）。磷 细胞分泌 Hh，同时对 Hh 信号产生抵抗。相反，A细胞可以接收和 回应 Hh，但不自己表达 Hh。两个隔室的细胞不会混合 在开发过程中。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，并且这种变化 差异导致 A 细胞与 P 细胞分离。将该模型遗传系统与广泛的相结合 结合强大的生化、分子和细胞技术的实验方法，我建议： 1) 研究Hh信号如何直接改变Hh分泌P细胞和Hh-之间的亲和力差异 通过调节 Ihog 家族蛋白的细胞表面水平来响应 A 细胞。 2) 识别额外的细胞 粘附分子参与调节 A/P 细胞分离。 3) 调查是否以及如何嘘 信号通过调节脊椎动物 Ihog 同源物的表达水平来改变细胞亲和力。