Molecular mechanisms controlling cell proliferation during tissue turnover and ca

组织更新过程中控制细胞增殖的分子机制

基本信息

批准号：
8770763
负责人：
Nestor J Oviedo
金额：
$ 15.9万
依托单位：
UNIVERSITY OF CALIFORNIA, MERCED
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8770763
关键词：
Abnormal Cell Address Adult Affect Age Animals Anterior Apoptosis Area Basic Science Behavior Biological Biological Models Body Regions Cancer Model Candidate Disease Gene Carcinogens Cell Cycle Progression Cell Death Cell Proliferation Cell division Cell model Cells Cessation of life Clinical Cues DNA Damage DNA Double Strand Break DNA Repair Degenerative Disorder Development Diagnostic Neoplasm Staging Double Strand Break Repair Down-Regulation Employee Strikes Evaluation Exhibits Functional disorder Gene Targeting Genes Genomics Goals Growth Head Homologous Gene Human In Situ Injury Investigation Knowledge Location Maintenance Malignant Neoplasms Measures Mediating Modeling Molecular Molecular Genetics Mus Mutate Natural regeneration Normal Cell Nutritional status Organism PTEN gene Pathway interactions Phenotype Physiological Physiology Planarians Platyhelminths Population Process Proliferating Protein p53 Proteins RNA Interference Regulation Role Signal Pathway Signal Transduction Staging Stem cells Stress Tail Technology Testing Thoracic cavity structure Tissues Transferase Transplantation Tumor Suppressor Genes Tumor Suppressor Proteins Tumor stage Vertebrates Whole Organism adult stem cell base cancer therapy cell motility design in vivo innovation insight interdisciplinary approach melanoma migration neoplastic cell novel strategies public health relevance regenerative regional difference research study response tissue regeneration tool transcriptomics tumor tumorigenesis

项目摘要

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.

描述（由申请人提供）：该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因子。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了解有限，限制了专门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（例如：细胞更新年龄、损伤、营养状况等）的影响。增殖反应中存在显着差异正常细胞和肿瘤细胞取决于它们沿前后 (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。该项目研究了整个生物体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。我们利用独特的模型系统——涡虫，它表现出包括人类在内的脊椎动物的信号通路的进化保守性，并且具有可获取的成体干细胞（成体干细胞），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中唯一的分裂细胞，支持高细胞更新率和再生率。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。所提出的方法为癌症发展和生理细胞更新的系统研究提供了高度创新且更简化的模型。该项目基于综合的跨学科方法，研究整个生物体复杂性中的成体干细胞，考虑调节其行为的局部和系统内源信号。它在评估组织再生和细胞更新过程以及癌症等异常情况下的细胞调节方面具有独特的作用。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信号。目标 1 将评估位置信息对组织更新过程中干细胞增殖行为的影响和肿瘤发生。将在 AP 极性异常、DNA 修复机制功能失调和过度增殖表型的动物中测量细胞增殖、迁移和分化。目标 2 将确定异常细胞增殖的区域差异是否是通过肿瘤抑制因子介导的。我们的实验旨在识别参与肿瘤形成早期阶段的内源信号和细胞群。这些研究的主要影响将是阐明复杂的细胞增殖调节基本机制整个有机体的功能，以便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。