Hedgehog-mediated regulation of cell adhesion

Hedgehog 介导的细胞粘附调节

• 批准号: 7962777
• 负责人: Xiaoyan Zheng
• 金额: $ 12.55万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7962777
• 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; Knowledge; 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; Research Personnel; 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

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.

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种群的物理隔离的粘合机制。 已经提出了许多旁分泌形态信号来指定细胞亲和力的差异以及锋利和稳定边界的形成，而尖锐和稳定的边界又有助于在组织生长过程中维持形态学组织者的位置和形状。 该项目的长期目标是了解刺猬（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（非反应）细胞的分离以及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可能会向周围组织发出信号并促进肿瘤的生长和转移。 此外，恶性侵袭可能被认为是相反的细胞分离过程，其中癌细胞和组织细胞之间存在交叉粘附。 因此，这项研究不仅将对我们对组织模式的分子和细胞基础的了解以及对HH信号途径的进一步了解，而且还将阐明癌症进展的机制，也许会导致发现新的治疗靶标。 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。 相反，一个细胞可以接收和响应HH，但不会单独表达HH。 在发育过程中，两个隔室的细胞不会混合。 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信号的响应诱导了粘附性的变化，并且这种差异导致细胞与P细胞的分离。 研究者建议将该模型的遗传系统与广泛的实验方法结合在一起，这些方法结合了强大的生化，分子和细胞技术，提议：1）研究HH信号如何直接改变分泌HH分泌P细胞和HH-通过调节IHOG家族蛋白蛋白的细胞表面水平的细胞之间的亲和力差异； 2）确定与调节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刺猬（HH）可能会向周围组织发出信号并促进肿瘤的生长和转移。 此外，恶性侵袭可能被认为是相反的细胞分离过程，其中癌细胞和组织细胞之间存在交叉粘附。 因此，这项研究是HH信号定义特定细胞粘附的机制，不仅将显着促进我们对组织模式的分子和细胞基础的了解以及对HH信号途径的进一步了解，还将阐明癌症进展的机制，也许会导致发现新的治疗靶标在Cancers中的新治疗靶标。