Toll-like receptors in tissue-intrinsic defense against aberrant cells

Toll 样受体在组织内在防御异常细胞中的作用

• 批准号: 531052428
• 负责人: Professorin Dr. Anne-Kathrin Classen
• 金额: --
• 依托单位: CIBSS Centre for Integrative Biological Signalling Studies
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/531052428?language=en
• 关键词: Toll; like; receptors; tissue; intrinsic

Tissue-intrinsic tumor suppression and defense mechanisms, such as cell-cell competition, are crucial for maintaining tissue and organismal health. However, failure of these defense mechanisms can lead to the persistence of aberrant cells in tissues, ultimately resulting in cancer initiation and tumor formation. We have characterized a novel tissue-intrinsic defense mechanism called 'interface surveillance' that very specifically guards against cells which undergo inappropriate cell fate and differentiation programs. The proposal here aims to address the poorly understood question of how aberrant cells are detected and eliminated from epithelial tissues by 'interface surveillance'. Specifically, we will investigate the role of Toll-like receptors as molecular players in a cell surface code that enables epithelial cells to detect cell fate differences, identify abnormal cells and activate killing mechanisms to eliminate them. To achieve our goal, we will use a standard combination of molecular, cell, and developmental biology techniques, in conjunction with the excellent genetic tools available in Drosophila. We will first establish a comprehensive map of Toll-like receptor function during 'interface surveillance' in imaginal disc epithelia. We will then determine if Toll-like receptors are regulated by cell fate, oncogenic mutations, or tissue-intrinsic defense processes, such as classical cell-cell competition. We will subsequently uncover molecular mechanisms that transduce a Toll-like receptors mismatch between neighboring cell surfaces into 'interface surveillance' hallmarks. We will specifically examine potential downstream effects that result from signaling via Toll-induced NFkB-driven transcriptional responses, normally implicated in inflammatory and innate immune responses. Our work will thus provide a comprehensive understanding of molecular, cellular and tissue-level mechanisms underlying intrinsic defenses against aberrant cells, and insight into potential synergies between 'interface surveillance' and innate immunity. We will thereby contribute to new frontiers in the field of tissue-intrinsic tumor suppression and reveal potential clinical implications for inflammation, tumor initiation and cancer progression.

组织内在的肿瘤抑制和防御机制，如细胞-细胞竞争，对于维持组织和生物体健康至关重要。然而，这些防御机制的失败可能导致异常细胞在组织中的持续存在，最终导致癌症的发生和肿瘤的形成。我们已经描述了一种新的组织内在防御机制，称为“界面监视”，非常具体地防止细胞经历不适当的细胞命运和分化程序。这里的建议旨在解决如何通过“界面监控”从上皮组织中检测和消除异常细胞的知之甚少的问题。具体来说，我们将研究Toll样受体作为细胞表面密码中的分子参与者的作用，该密码使上皮细胞能够检测细胞命运差异，识别异常细胞并激活杀伤机制以消除它们。为了实现我们的目标，我们将使用分子，细胞和发育生物学技术的标准组合，结合果蝇中可用的优秀遗传工具。我们将首先建立一个全面的地图Toll样受体的功能，在'界面监视'在椎间盘上皮细胞。然后，我们将确定Toll样受体是否受细胞命运、致癌突变或组织内在防御过程（如经典的细胞-细胞竞争）的调控。随后，我们将揭示将Toll样受体在相邻细胞表面之间错配的分子机制纳入“界面监视”标志。我们将专门研究潜在的下游效应，通过Toll诱导的NF κ B驱动的转录反应，通常涉及炎症和先天性免疫反应的信号传导。因此，我们的工作将提供对分子，细胞和组织水平机制的全面理解，这些机制是针对异常细胞的内在防御，并深入了解“界面监视”和先天免疫之间的潜在协同作用。因此，我们将为组织内源性肿瘤抑制领域的新前沿做出贡献，并揭示炎症，肿瘤起始和癌症进展的潜在临床意义。