Mechanisms of stem cell aging that contribute to clonal outgrowth in head and neck tissues

项目总结/摘要 到2050年，预计美国将有7200多万65岁或65岁以上的人。 占人口的20%。这种快速的，世界范围内的，人口年龄变化有许多社会， 经济和公共卫生影响。最常见的慢性病和病理性疾病之一 随着年龄的增长而出现的症状是癌症。头颈部癌（HNC），特别是， 癌症是全球第七大常见癌症，每年导致超过50万人死亡。发生率 HNC在40岁以上的个体中显著增加，并且在男性中更常见。此外，个人 既往诊断为血液学癌症并接受过造血干细胞（HSCT）治疗的患者 HNC发展的风险增加。HNC的主要治疗方法是手术和/或放疗 但是这些治疗对吞咽功能和言语有破坏性的影响。多重因果 在老年个体和HSCT后可能存在HNC发展的途径。一个可能 促进衰老和癌症的机制是表观遗传修饰的获得和积累 以及头部和颈部组织干细胞内的遗传改变。克隆扩张 突变的干细胞可能会加速老年人和那些患有HNC的人的发病率。 接受HSCT。 这项建议的目的是确定潜在的细胞和系统机制，有助于 头颈部组织（口腔、舌、咽、食管、颈部）癌症的发展， 衰老和HSCT后，并确定相关组织干细胞中的体细胞突变是否驱动克隆性 扩增、HNC起始和肿瘤发展。我们的假设是头部和颈部 随着年龄的增长和HSCT治疗后，组织干细胞将显著减少， 头部和颈部组织干细胞的表观遗传和遗传修饰将1）显著增加 在随年龄和HSCT后的频率中，2）在雄性和雌性小鼠中表现出差异，以及3） 当引入相关组织干细胞时能够驱动克隆生长/HNC出现 人口。为了解决这些假设，本提案有3个具体目标：1）确定细胞内 老年雄性和雌性小鼠头颈部体组织干细胞的克隆进化机制，2） 检查环境对体组织干细胞的表观遗传和遗传特征的影响，以及3）检查 在头颈部组织中体内引入体细胞突变是否能够驱动克隆性 组织干细胞的生长和HNC起始。总之，这项研究将提供重要的新知识， 关于随着年龄的增长和HSCT后导致HNC的机制，并能够开发有针对性的 有效的治疗方法。

Project Summary/Abstract By the year 2050, it is projected that over 72 million people will be 65 years or older in the United States, representing 20% of the population. This rapid, worldwide, demographic shift in age has many societal, economic, and public health implications. One of the most common chronic illnesses and pathological conditions experienced with increasing age is cancer. Head and neck cancer (HNC), in particular, is the seventh most common cancer worldwide and accounts for more than 500,000 deaths annually. Incidence of HNC significantly increases in individuals over the age of 40 and is more common in men. Further, individuals with a prior hematologic cancer diagnosis who have undergone hematopoietic stem cell (HSCT) treatments have an elevated risk for the development of HNC. Primary treatments for HNC are surgery and/or radiation therapy, but these treatments have devastating effects on swallowing function and speech. Multiple causal pathways likely exist for the development of HNC in aged individuals and following HSCT. One likely mechanism promoting both aging and cancer is the acquisition and accumulation of epigenetic modifications and genetic alterations within resident tissue stem cells in the head and neck. Clonal expansion of these mutated stem cells may accelerate the incidence of HNC in the aging population and in those who have undergone HSCT. The purpose of this proposal is to identify underlying cellular and systemic mechanisms contributing to the development of cancer in head and neck tissues (oral cavity, tongue, pharynx, esophagus, neck) with aging and following HSCT, and determine whether somatic mutations in relevant tissue stem cells drive clonal expansion, HNC initiation, and tumor development. Our hypotheses are that frequency of head and neck tissue stem cells will be significantly reduced with increasing age and following HSCT treatment and that epigenetic and genetic modifications of head and neck tissue stem cells will be 1) significantly increased in frequency with age and following HSCT, 2) differentially represented in male and female mice, and 3) capable of driving clonal outgrowth/HNC emergence when introduced into relevant tissue stem cell populations. To address these hypotheses, this proposal has 3 specific aims: 1) determine cell-intrinsic mechanisms of clonal evolution in head and neck somatic tissue stem cells in aged male and female mice, 2) examine effects of environment on epigenetic and genetic profiles of somatic tissue stem cells, and 3) examine whether in vivo introduction of somatic mutations in head and neck tissues are capable of driving clonal outgrowth of tissue stem cells and HNC initiation. Altogether, this study will provide significant new knowledge regarding mechanisms contributing to HNC with age and following HSCT, and enable development of targeted and effective therapies.