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.

相对年轻的小鼠被用于大多数研究人类疾病的生物医学研究， 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）是一种恶性肿瘤。 一种非常常见的皮肤癌与人类的衰老密切相关，但BCC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幼的实验动物。的 这项提议的目的是确定老年小鼠中发生的BCC是否与老年小鼠中发生的BCC不同。 在年轻的小鼠中;具体地说，老年小鼠中出现的肿瘤是否是人类肿瘤的更准确模型。 BCC。人类BCC发病率的年龄相关性增加归因于以下因素的逐渐积累： 编码Hedgehog途径中蛋白质的基因突变，该途径在基本上所有BCC中都失调。 然而，在衰老过程中，在生物体水平和皮肤中都会发生多种变化， 增加了老化皮肤与年轻皮肤对相同致癌信号的不同反应的可能性。 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的、高度易处理的、遗传上- 可诱导小鼠模型，导致Hedgehog信号传导的不受控制的激活，Hedgehog信号传导是肿瘤的致癌驱动因子， BCC。在该项目的第一阶段（UH 2），我们将繁殖小鼠，以产生足够大的 用于肿瘤诱导研究的实验动物，一旦这些小鼠年龄达到 相当于人类55-60岁。我们将进行试点研究，以建立所需的条件， 获得与通常用于治疗的年轻小鼠中测量的那些相当的转基因表达水平。 这些研究，并将获得对老年小鼠肿瘤发展的初步评估。在第二 第三阶段（UH 3），我们将在老年小鼠和年轻小鼠中进行转基因诱导研究，并进行 详细描述所产生的肿瘤。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信号转导关闭的反应， 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 老年动物为这种常见的与年龄相关的人类癌症提供了更可靠的模型。我们的研究结果可能 对于使用BCC小鼠模型的研究的实验设计具有深远的意义， 其他皮肤癌，并将提供一个基础，为未来的工作，旨在阐明如何老化 过程影响皮肤肿瘤发生。