Telomere Shortening and Stem Cell Maintenance

描述（由申请方提供）：尽管细胞毒性和靶向治疗的所有治疗方案有所增加，但晚期恶性肿瘤患者的预后仍然较差。最近的工作支持癌症的干细胞理论，并表明早期组织特异性干细胞是导致恶性肿瘤的遗传改变的积累部位。干细胞在健康和癌症中的分子决定因素尚不清楚。端粒酶是一种专门的DNA聚合酶，负责使用固有的RNA模板添加端粒。大多数癌症表达端粒酶以抵消端粒磨损。再生障碍性贫血是一种典型的干细胞衰竭性疾病，其特征是骨髓无细胞。近年来，常染色体显性遗传性先天性角化不良的家族被发现存在端粒酶RNA基因突变。这些家族表现出再生障碍性贫血、特发性肺纤维化以及癌症风险增加的显性遗传。此外，还有预期，每一代人的症状发作更早，更严重，这与端粒缩短有关。这种疾病强调了端粒在维持干细胞区室中的关键作用。我们最近发现了一个先天性角化不良的大家族，该家族在端粒酶的蛋白组分hTERT中存在突变。该家系显示再生障碍性贫血和特发性肺纤维化的显性遗传。下面的建议利用了在这个谱系中所做的临床观察以及最近在端粒酶敲除小鼠中的发现来模拟这种疾病。与之前在近交系上设计的端粒敲除小鼠不同，端粒长度与人类相似的野生型Castaneus小鼠在骨髓和胃肠道中表现出干细胞衰竭。在胃肠道中，基因敲除小鼠也会发生胃肠道微腺瘤并伴有严重的言语障碍。下面的建议探讨了端粒酶和端粒长度在维持骨髓、胃肠道和肺中干细胞区室中的作用。在此过程中，我们将研究端粒缩短限制组织更新能力以及作为肿瘤过程的病灶的矛盾。这些作用特别相关，因为端粒酶抑制剂被积极地用作抗癌疗法。

DESCRIPTION (provided by applicant): Despite an increase in the repertoire of cytotoxic and targeted therapies, the prognosis for patients with advanced malignancies remains poor. Recent work has supported a stem cell theory for cancer and suggests that an early tissue specific stem cell is the site of accumulation of the genetic alterations that lead to malignancy. The molecular determinants of stem cells in health and cancer are not known. Telomerase is a specialized DNA polymerase responsible for telomere addition by using an intrinsic RNA template. The majority of cancers express telomerase to offset telomere attrition. Aplastic anemia is the prototype stem cell failure disorder characterized by an acellular bone marrow. Recently, families with autosomal dominant dyskeratosis congenita have been found to have mutations in the telomerase RNA gene. These families display dominant inheritance of aplastic anemia, idiopathic pulmonary fibrosis as well as an increased risk of cancer. Furthermore, there is anticipation, an earlier and worse onset of symptoms with each generation, and this correlates with telomere shortening. This disease has underscored the critical role of telomeres in maintaining stem cell compartments. We recently identified a large kindred with dyskeratosis congenita that harbors a mutation in hTERT, the protein component of telomerase. This pedigree displays dominant inheritance of aplastic anemia and idiopathic pulmonary fibrosis with anticipation. The following proposal capitalizes on clinical observations made in this pedigree as well as on recent findings in a telomerase knockout mouse that models this disease. Unlike the previously engineered telomerase knockout mouse on the inbred strain, the wild-derived Castaneus mouse with telomere lengths similar to humans displays stem cell failure in the bone marrow and gastrointestinal tract. In the gastrointestinal tract, knockout mice also develop gastrointestinal microadenomas with severe dysphasia. The following proposal explores the role of telomerase and telomere length in the maintenance of stem cell compartments in the bone marrow, gastrointestinal tract as and in the lung. In doing so, we will examine the paradox of telomere shortening limiting tissue renewal capacity as well as being a nidus for neoplastic processes. These effects are particularly relevant as telomerase inhibitors are actively pursued as anti-cancer therapies.