An innate system for detection of aberrant tissue growth

用于检测异常组织生长的先天系统

• 批准号: 8839472
• 负责人: Laura A Johnston
• 金额: $ 35.43万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8839472
• 关键词: Animals; Apoptosis; Behavior; Binding; Biochemical; Cancerous; Cell Communication; Cell Death; Cell Proliferation; Cell physiology; Cells; Cessation of life; ChIP-seq; Choristoma; Code; Data; Detection; Development; Diagnostic Neoplasm Staging; Drosophila genus; Effector Cell; Event; Foundations; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic; Genetic Heterogeneity; Goals; Growth; Growth Factor; Homeostasis; Homologous Gene; Immune; Immune system; Invaded; Lead; Life; Malignant Neoplasms; Mediating; Methods; Modeling; Molecular; Molecular Genetics; New Territories; Normal Cell; Oncogenes; Outcome; Pathway Analysis; Pathway interactions; Population; Premalignant; Process; Production; Research; Residencies; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Staging; Supporting Cell; System; Techniques; Testing; Tissues; Tumor Suppressor Proteins; Variant; Work; animal tissue; cancer cell; cell type; combinatorial; cytokine; differential expression; fitness; human disease; killings; mutant; neoplastic; novel; novel therapeutics; prevent; programs; public health relevance; receptor; receptor function; research study; transcription factor; transcriptome sequencing; transmission process; tumor; tumor progression; tumorigenesis; tumorigenic

 DESCRIPTION (provided by applicant): The overall goal of this research is to elucidate the mechanisms that underlie tissue homeostasis during growth and to understand how this process goes awry in human diseases such as cancer. We and others have shown that genetic heterogeneity within growing tissues can lead to competitive interactions that eliminate the weaker population and stimulate expansion of the stronger. A guiding principle of our work is that such competition functions in a homeostatic role to eliminate cells that are potentially dangerous to the tissue and animal. We hypothesize that incipient cancer cells exploit this mechanism to gain an advantage and overtake tissues. Our preliminary data indicate that the death of wild-type cells stimulates the proliferation of the high-Myc cells via production of secreted cytokines and/or growth factors. Here, we propose studies to investigate our recent discovery that an NFB transcription factor, four different Toll related receptors, and a conserved cytokine - all components of the innate immune system - mediate the competitive cellular interactions between cells of different fitness, and trigger the death of the less fit cels. However, critical molecular mechanisms and targets of this pathway remain to be defined. This work has the potential to elucidate essential molecular and cellular events that determine whether pre-cancerous cells will be eliminated from growing tissues or are able to establish themselves and progress into fully neoplastic tumors.

 描述（由申请人提供）：本研究的总体目标是阐明生长过程中组织稳态的机制，并了解这一过程在人类疾病（如癌症）中是如何出错的。我们和其他人已经表明，生长组织内的遗传异质性可以导致竞争性相互作用，从而消除较弱的群体并刺激较强群体的扩张。我们工作的指导原则是，这种竞争在体内平衡中起作用，以消除对组织和动物有潜在危险的细胞。我们假设早期的癌细胞利用这种机制获得优势并超越组织。我们的初步数据表明，野生型细胞的死亡通过分泌细胞因子和/或生长因子的产生刺激高Myc细胞的增殖。在这里，我们提出的研究，调查我们最近的发现，一个NF κ B B转录因子，四种不同的Toll相关受体，和一个保守的细胞因子-先天免疫系统的所有组件-介导的竞争性细胞之间的相互作用不同的健身，并触发死亡的不太适合的人。然而，该途径的关键分子机制和靶点仍有待确定。这项工作有可能阐明基本的分子和细胞事件，这些事件决定癌前细胞是否会从生长的组织中消除，或者能够建立自己并发展成完全的肿瘤。