Molecular mechanisms controlling cell proliferation during tissue turnover and ca

描述(由申请人提供)：本项目的目标是描述细胞周转和肿瘤发生过程中细胞增殖的系统调节因素。理想的癌症治疗旨在消除异常增殖的细胞，而不干扰组织生理。然而，在整个生物体的复杂性中，我们对控制细胞增殖的机制的了解有限，限制了针对异常细胞的生物医学方法的实施。细胞增殖受到局部和全身信号的影响(例如：细胞周转年龄、损伤、营养状况等)。在增殖反应方面存在显著差异 正常细胞和肿瘤细胞取决于它们沿前后轴(AP)的位置。然而，正常细胞和肿瘤细胞生长的区域差异背后的基本生物学机制尚不清楚。这个项目解决了在整个生物体的复杂性中，成人组织维持和肿瘤发生过程中调节细胞增殖的基本机制。我们利用了一种独特的模式系统，扁虫，它展示了包括人类在内的脊椎动物信号通路的进化保守，并具有可访问的成体干细胞(新成体细胞)，可以在整个身体的复杂性中进行研究。新生细胞是这种动物唯一的分裂细胞，支持细胞的高周转率和再生率。我们的方法操纵与DNA修复和癌症发展相关的进化保守的信号通路，以研究异常细胞在整个有机体复杂性中的起源和位置。该方法为系统研究肿瘤的发展和生理细胞周转提供了一个高度创新和更加简化的模型。该项目基于一种综合的跨学科方法，在整个生物体的复杂性中研究成体干细胞，同时考虑调节它们行为的局部和系统内源性信号。它在评估组织再生和细胞周转过程中的细胞调节以及在癌症等异常情况下的细胞调节方面是独一无二的。该策略旨在跟踪体内特定的新生细胞群体，并操纵控制其行为的内源性信号。目标1将评估位置信息在组织更新过程中对干细胞增殖行为的影响 和肿瘤的发生。在AP极性异常、DNA修复机制障碍和过度增殖表型的动物中，将检测细胞的增殖、迁移和分化。目的2将确定异常细胞增殖的区域差异是否通过肿瘤抑制因子来调节。我们的实验旨在识别参与肿瘤形成早期阶段的内源性信号和细胞群。这些研究的一个主要影响将是阐明调控细胞增殖的基本机制的复杂性 能够在不干扰生理功能的情况下，实施针对异常细胞的生物医学方法。

DESCRIPTION (provided by applicant): The goal of this project is to describe systemic regulators of cell proliferation during cell turnover and tumorigenesis. The ideal cancer therapy aims at eliminating abnormally proliferating cells without disturbing tissue physiology. However, our limited understanding about the mechanisms controlling cell proliferation in the complexity of the whole organism restricts the implementation of biomedical approaches to specifically target abnormal cells. Cell proliferation is influenced by local and systemic signals (e.g.: cell turnover age, injury, nutritional status, etc.). Striking differences exist in the proliferative response of normal and neoplastic cells depending on their location along the anteroposterior (AP) axis. However, the basic biological mechanisms underlying regional differences in the growth of normal and tumor cells are unknown. This project addresses basic mechanisms regulating cell proliferation during adult tissue maintenance and tumorigenesis in the complexity of the whole organism. We capitalize on a unique model system, the planarian flatworm, which exhibits evolutionary conservation of signaling pathways with vertebrates including humans, and has accessible adult stem cells (neoblasts) that can be studied in the complexity of the whole body. The neoblasts are the only dividing cells in this animal and support high rates of cellular turnover and regeneration. Our approach manipulates evolutionarily conserved signaling pathways associated with DNA repair and cancer development to study the origin and location of abnormal cells in the complexity of the whole organism. The proposed approach provides a highly innovative and more simplified model for systematic investigation of cancer development and physiological cell turnover. This project is based on a comprehensive interdisciplinary approach that studies adult stem cells in the complexity of the whole organism considering both local and systemic endogenous signals that modulate their behavior. It is unique in assessing cell regulation during the process of tissue regeneration and cell turnover and in abnormal conditions such as cancer. The strategy is designed to follow specific neoblast populations in vivo and to manipulate endogenous signals that control their behavior. Aim 1 will assess the effect of positional information on the proliferative behavior of stem cells during tissue turnover and tumorigenesis. Cell proliferation, migration and differentiation will be measured in animals with abnormal AP polarity, dysfunctional DNA repair mechanisms and hyperproliferative phenotype. Aim 2 will determine whether regional differences in the proliferation of abnormal cells are mediated through tumor suppressors. Our experiments aim at identifying endogenous signals and cell populations involved in early stages of tumor formation. A major impact of these studies will be the elucidation of basic mechanisms regulating cell proliferation in the complexity of the whole organism to enable the implementation of biomedical approaches to target abnormal cells without disturbing physiological functions.