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.

相对年轻的小鼠用于大多数研究人类疾病的生物医学研究，即使 研究中的疾病在衰老的患者中更为普遍。例如，基底细胞癌（BCC）是 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常规使用年轻的实验动物。这 该提案的目标是确定在老年小鼠中发育的BCC是否与BCC产生的BCC是否不同 在年轻的老鼠中；具体而言，在老年小鼠中产生的肿瘤是否是人类的更准确模型 BCC。与年龄有关的人类BCC发病率的增加归因于 在刺猬途径中编码蛋白质的基因突变，该蛋白质基本上在所有BCC中进行了调节。 但是，在衰老过程中，在生物水平和皮肤上都会发生多种改变， 提高年龄皮肤的反应与年轻皮肤对相同的致癌信号的反应不同。 为了在年轻小鼠和老鼠中产生BCC，我们将使用良好的，高度疗法的，遗传的 - 可诱导小鼠模型导致刺猬信号的激活不受控制 BCC。在该项目的第一阶段（UH2），我们将繁殖小鼠以产生足够大的队列 实验动物进行肿瘤诱导研究，一旦这些小鼠老化 相当于人类的55-60岁。我们将进行试点研究，以确定所需的条件 达到基因表达水平，可与通常用于年轻小鼠中测量的转基水平相当 这些研究将对老年小鼠的肿瘤发育进行初步评估。在第二个 阶段（UH3），我们将对年龄和年轻小鼠进行转基因诱导研究，并执行 所得肿瘤的详细表征。由于我们的鼠标模型允许可逆激活 转基因表达，我们还将评估肿瘤对关闭的致癌刺猬信号的反应 治疗反应的指标。拟议研究的成功完成将确定是否是否 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 老年动物提供了这种常见年龄相关的人类癌症的更忠实的模型。我们的发现可能 使用BCC的小鼠模型对研究具有深远的影响，并有可能 其他皮肤癌，并将为未来的工作奠定基础，以阐明衰老 过程影响皮肤肿瘤发生。