The mechanism of SOX2 in the development of neuroendocrine lineages and its regulation of cell pliancy

SOX2在神经内分泌谱系发育中的作用机制及其对细胞柔顺性的调节

• 批准号: 9767222
• 负责人: Michael S Kareta
• 金额: $ 30.02万
• 依托单位: SANFORD RESEARCH/USD
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9767222
• 关键词: Address; Adult; Binding; Biological Assay; Cancer Model; Cell Differentiation process; Cell Proliferation; Cells; Characteristics; Childhood; DNA Sequence Alteration; Data Set; Development; Disease; Embryo; Epithelial; Event; Future; Genes; Genetically Engineered Mouse; Genomics; Goals; Human Development; Investigation; Lead; Licensing; Life; Maintenance; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Mosaicism; Mus; Mutation; Neuroendocrine Cell; Neurosecretory Systems; Oncogenic; Pathogenesis; Pathway Analysis; Pathway interactions; Pediatric Research; Phenotype; Population; Process; Proteins; Refractory; Regulation; Regulator Genes; Reporter; Repression; Role; Somatotype; Tumor Initiators; cancer cell; cancer initiation; cancer prevention; cancer therapy; cell type; derepression; experimental study; innovation; neoplastic cell; nerve stem cell; new therapeutic target; next generation; novel; pluripotency; progenitor; retinoblastoma tumor suppressor; transcription factor; transcriptome; tumor; tumor initiation

PROJECT SUMMARY Cancer, especially pediatric cancer, is a devastating diseases effecting a broad swath of humanity and consequently we must be able to understand the development of cancer in a holistic manner to develop the next generation of therapies. While there has been significant progress in elucidating genetic mutations which drive cancer initiation, many genetically engineered mouse models of cancer have indicated that necessary genetic mutations are oftentimes insufficient for tumor formation, i.e. not all cells harboring the necessary mutations form a tumor. Therefore, there must be other factors which license a cell with the capacity to form a tumor when the necessary mutations are present. We hypothesize that these cells are licensed as a consequence of the prior development of the cell. A cell's development is guided in large part by master regulators which are the key genes to define cell identity. As master regulators can induce cells to switch identity, a process known as reprogramming and which shares many characteristics to tumor initiation, we expect that misregulation of master regulators throughout development may be involved in the licensing of cells for cancer formation. We have shown that the master regulator, Sox2, is required for the formation of tumors that are initiated by the loss of the retinoblastoma tumor suppressor (Rb). Notably Sox2 is the master regulator to define the few cell types which form tumors when Rb is lost, most commonly neuroendocrine cells. We will therefore investigate the regulation of Sox2 during development in these neuroendocrine lineages and determine if misregulation of Sox2 is responsible for cancer licensing. We will pursue this investigation by pursuing the following aims: 1) To understand the mechanism of Sox2 regulation during development and how this goes awry in tumor formation, and 2) To determine if Sox2 derepressed cells are tumor initiating upon Rb-loss. We anticipate that the successful completion of these aims will lead to a greater understanding of how development might induce cancer later in life, and provide new avenues for cancer therapies and preventation.

项目摘要 癌症，尤其是小儿癌，是一种毁灭性疾病，影响了广泛的人类和 因此，我们必须能够以整体方式理解癌症的发展，以发展下一个 产生疗法。虽然在阐明驱动基因突变方面取得了重大进展 癌症开始，许多基因工程的癌症模型表明必要的遗传 突变通常不足以形成肿瘤，即，并非所有具有必要突变形式的细胞 肿瘤。因此，必须有其他因素许可​​具有具有肿瘤能力的细胞的许可 存在必要的突变。我们假设这些细胞是由先前的 细胞的开发。细胞的开发在很大程度上由主监管机构指导，这是关键 定义细胞身份的基因。由于主调节器可以诱导细胞切换身份，因此 重新编程并具有许多特征与肿瘤开始的特征，我们期望主人 整个发育过程中的调节剂可能参与细胞形成的细胞许可。我们已经显示了 主调节剂SOX2是由损失损失引发的肿瘤所必需的 视网膜细胞瘤肿瘤抑制（RB）。值得注意的是Sox2是定义几个单元格类型的主调节器 丢失RB时形成肿瘤，最常见的是神经内分泌细胞。因此，我们将调查法规 在这些神经内分泌谱系中发育过程中Sox2的of sox2，并确定Sox2的不正当是否为 负责癌症许可。我们将通过追求以下目的来进行调查：1） 了解在发育过程中Sox2调节的机制以及在肿瘤形成中的出现如何变化， 2）确定Sox2穿压缩细胞是否在RB损伤时引发肿瘤。我们预计 这些目标的成功完成将导致对发展如何引起的更多了解 癌症之后的癌症，并为癌症疗法和预防提供新的途径。