Probing the role of aging in basal cell carcinoma development and treatment response

探讨衰老在基底细胞癌发展和治疗反应中的作用

• 批准号: 9203505
• 负责人: ANDRZEJ A. DLUGOSZ
• 金额: $ 6.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9203505
• 关键词: Address; Affect; Age; Age-Years; Aging; Aging-Related Process; Animals; Apoptosis; Basal cell carcinoma; Behavior; Binding; Biological; Biomedical Research; Breeding; Caucasians; Cell Proliferation; Cells; Development; Diagnosis; Disease; Dose; Elderly; Embryonic Development; Erinaceidae; Experimental Designs; Feasibility Studies; Foundations; Future; Gene Expression; Gene Targeting; Genes; Genetic; Goals; Growth; Healthcare Systems; Histopathology; Human; Image; Incidence; Individual; Ligands; Light; Link; Maintenance; Malignant Neoplasms; Measures; Modeling; Molecular; Mus; Mutation; Neoplastic Cell Transformation; Oncogenes; Oncogenic; Operative Surgical Procedures; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Physiological; Pilot Projects; Process; Proteins; Publishing; Recurrence; Reporting; Repression; Residual state; Role; Signal Transduction; Skin; Skin Aging; Skin Cancer; Tamoxifen; Testing; Transcriptional Activation; Transgenes; Tumor Biology; Work; age related; aged; base; cohort; gain of function mutation; human disease; loss of function mutation; mouse model; neoplastic cell; older patient; receptor; research study; response; smoothened signaling pathway; therapy development; tissue regeneration; transcription factor; transgene expression; treatment response; tumor; tumorigenesis

Relatively young mice are used for most biomedical research studies investigating human disease, even if the disease under study is much more common in aging patients. For example, basal cell carcinoma (BCC) is an extremely common skin cancer strongly associated with aging in humans, and yet mouse models of BCC examining the molecular basis and biology of these tumors routinely use young experimental animals. The goal of this proposal is to determine whether BCCs that develop in aged mice are different than BCCs arising in young mice; specifically, whether the tumors arising in aged mice are a more accurate model of human BCC. The age-related increase in human BCC incidence has been attributed to the gradual accumulation of mutations in genes encoding proteins in the Hedgehog pathway, which is deregulated in essentially all BCCs. However, multiple alterations take place both at the organismal level and in skin during the aging process, raising the possibility that aged skin responds differently than young skin to the same oncogenic signal. To produce BCCs in young as well as old mice, we will use a well-characterized, highly tractable, genetically- inducible mouse model that leads to uncontrolled activation of Hedgehog signaling, the oncogenic driver in BCC. During the first phase (UH2) of this project, we will breed mice to generate a sufficiently large cohort of experimental animals for tumor induction studies, which will be performed once these mice have aged to the equivalent of 55-60 years of age in humans. We will perform pilot studies to establish conditions needed to achieve transgene expression levels comparable to those measured in young mice that are usually used for these studies, and will obtain a preliminary assessment of tumor development in aged mice. During the second phase (UH3), we will perform transgene induction studies in aged as well as young mice and perform a detailed characterization of the resultant tumors. Since our mouse model allows for reversible activation of transgene expression, we will also assess tumor responses to shut-down of oncogenic Hedgehog signaling as an indicator of treatment response. The successful completion of the proposed studies will establish whether aging influences BCC tumor development in a genetic mouse model, and help determine whether the use of older animals provides a more faithful model of this common age-related human cancer. Our findings may have profound implications for the experimental design of studies using mouse models of BCC and potentially other skin cancers, and will provide a foundation for future work aimed at shedding light on how the aging process affects skin tumorigenesis.

大多数研究人类疾病的生物医学研究都使用相对年轻的小鼠，即使 正在研究的疾病在老年患者中更为常见。例如，基底细胞癌（BCC）是一种 在人类中极其常见的皮肤癌与衰老密切相关，但基底细胞癌的小鼠模型 检查这些肿瘤的分子基础和生物学通常使用年轻的实验动物。这 该提案的目标是确定老年小鼠中形成的 BCC 是否与出现的 BCC 不同 在年轻小鼠中；具体来说，老年小鼠身上产生的肿瘤是否是人类更准确的模型？ 密件抄送。人类基底细胞癌发病率与年龄相关的增加归因于 Hedgehog 通路中编码蛋白质的基因发生突变，该通路基本上在所有 BCC 中都失调。 然而，在衰老过程中，机体和皮肤都会发生多种变化， 增加了老化皮肤与年轻皮肤对相同致癌信号的反应不同的可能性。 为了在年轻和年老的小鼠中产生 BCC，我们将使用一种特征良好、高度易处理的、遗传- 诱导小鼠模型导致刺猬信号不受控制的激活，刺猬信号是致癌驱动因素 密件抄送。在该项目的第一阶段（UH2），我们将培育小鼠以产生足够大的群体 用于肿瘤诱导研究的实验动物，一旦这些小鼠老化到 相当于人类55-60岁。我们将进行试点研究，以创造必要的条件 达到与通常用于年轻小鼠中测量的转基因表达水平相当的水平 这些研究，并将获得对老年小鼠肿瘤发展的初步评估。第二次期间 阶段（UH3），我们将在老年和年轻小鼠中进行转基因诱导研究，并进行 由此产生的肿瘤的详细特征。由于我们的小鼠模型允许可逆激活 转基因表达，我们还将评估肿瘤对致癌 Hedgehog 信号传导关闭的反应： 治疗反应的指标。拟议研究的成功完成将确定是否 衰老会影响遗传小鼠模型中 BCC 肿瘤的发展，并有助于确定是否使用 年长的动物为这种常见的与年龄相关的人类癌症提供了更忠实的模型。我们的研究结果可能 对于使用 BCC 小鼠模型进行研究的实验设计具有深远的影响，并有可能 其他皮肤癌，并将为未来的工作奠定基础，旨在揭示衰老是如何发生的 过程影响皮肤肿瘤的发生。