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更新和肿瘤发生过程中细胞增殖的系统调节剂。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学。然而，我们对整个生物体复杂性中控制细胞增殖的机制的有限理解限制了生物医学方法的实施，以特异性靶向异常细胞。细胞增殖受局部和全身信号的影响（例如：细胞更新年龄、损伤、营养状况等）。细胞的增殖反应存在显著差异， 正常和肿瘤细胞取决于它们沿着前后（AP）轴的位置。然而，正常细胞和肿瘤细胞生长区域差异的基本生物学机制尚不清楚。该项目致力于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。我们利用了一个独特的模型系统，扁虫，它表现出进化保守的信号通路与脊椎动物，包括人类，并具有可访问的成体干细胞（neoblast），可以在整个身体的复杂性进行研究。新母细胞是这种动物中唯一的分裂细胞，并支持高速率的细胞更新和再生。我们的方法操纵与DNA修复和癌症发展相关的进化上保守的信号通路，以研究整个生物体复杂性中异常细胞的起源和位置。所提出的方法提供了一个高度创新的和更简化的模型，癌症的发展和生理细胞营业额的系统调查。该项目是基于一个全面的跨学科的方法，研究成人干细胞在整个生物体的复杂性，考虑到本地和系统的内源性信号，调节他们的行为。它在评估组织再生和细胞周转过程中以及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。目的1将评估组织更新过程中位置信息对干细胞增殖行为的影响 和肿瘤发生。将在具有异常AP极性、功能失调的DNA修复机制和过度增殖表型的动物中测量细胞增殖、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介导。我们的实验旨在鉴定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在复杂环境中调节细胞增殖的基本机制。 整个生物体的生物医学方法，使目标不干扰生理功能的异常细胞的实施。

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.