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合机制 不同细胞群体的物理分离。已经提出了许多旁分泌形态学信号 指定细胞亲和力的差异以及尖锐而稳定的边界的形成，这些边界又用于 在组织生长过程中保持形态学组织者的位置和形状。长期目标 该项目是要了解刺猬（HH）信号的细胞和分子机制 特定的细胞亲和力，导致HH分泌（非反应）细胞和HH响应的分离 （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可能会发出信号 到周围组织并促进肿瘤生长和转移。此外，恶性入侵可能是 被认为是反向的正常细胞分离过程，其中癌症之间存在交叉粘附 细胞和组织细胞。因此，这项研究不仅会为我们对我们的知识做出重大贡献 组织模式的分子和细胞碱基，以及对HH信号途径的进一步了解 但也会阐明癌症进展的机制，也许会导致发现新的 癌症中的治疗靶标。 果蝇翼的想象盘细分为前（a）和后部（p）室。 p 细胞分泌HH，同时又对HH信号难治性。相比之下，单元可以接收和 回应HH，但不会单独表达HH。两个隔室的单元不相互融合 在开发过程中。但是，无法响应HH信号的细胞不再从P细胞中分离出来。 当前的观点是，对HH信号的响应引起了粘合性的变化，这是 差异导致细胞与P细胞的分离。将此模型遗传系统与广泛 我建议的实验方法结合了强大的生化，分子和细胞技术，我建议： 1）研究HH信号如何直接改变分泌HH的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反应细胞。 2）识别其他单元格 涉及调节A/P细胞分离的粘附分子。 3）调查SHH是否以及如何 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。