Telomere Shortening and Stem Cell Maintenance

端粒缩短和干细胞维护

• 批准号: 7253367
• 负责人: Mary Y Armanios
• 金额: $ 14万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7253367
• 关键词: Address; Adult; Affect; Aging; Alveolar; Aplastic Anemia; Apoptosis; Apoptotic; Azoxymethane; Biological Assay; Blast Cell; Bleomycin; Bone Marrow; CAST/EiJ Mouse; Carcinogens; Carcinoma; Cell Count; Cell Death; Cell Maintenance; Cell physiology; Clinical; Complex; DNA-Directed DNA Polymerase; Defect; Development; Disease; Duct (organ) structure; Dyskeratosis Congenita; Dysphasia; Engineering; Enteral; Epidemiologic Studies; Epithelial; Failure; Family; Gastrointestinal tract structure; Generations; Genes; Genetic Anticipation; Genomic Instability; Glioblastoma; Hamman-Rich syndrome; Health; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Immune; Inbred Strain; Injury; Knock-out; Knockout Mice; Lead; Length; Lesion; Liver Fibrosis; Lower Gastrointestinal Tract; Lung; Maintenance; Malignant Neoplasms; Molecular; Mus; Mutation; Naphthalene; Naphthalenes; Neoplastic Processes; Numbers; Patients; Phenotype; Play; Property; Pulmonary Fibrosis; RNA; Rate; Research Personnel; Risk Factors; Role; Site; Solid Neoplasm; Somatic Cell; Stem cells; Symptoms; Telomerase; Telomerase Inhibitor; Telomerase RNA Component; Telomerase inhibition; Telomere Shortening; Testing; Tissues; Work; Xenograft procedure; cancer cell; cancer risk; cancer stem cell; cancer therapy; cytopenia; cytotoxic; gastrointestinal; genetic pedigree; human TERT protein; kindred; leukemia; lung injury; malignant breast neoplasm; mouse model; neoplastic; null mutation; outcome forecast; programs; prototype; reconstitution; research study; response; response to injury; senescence; telomerase reverse transcriptase; telomere; theories

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.

描述（由申请人提供）：尽管细胞毒性和靶向治疗的种类有所增加，但晚期恶性肿瘤患者的预后仍然很差。最近的工作支持了癌症干细胞理论，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积累的部位。干细胞在健康和癌症中的分子决定因素尚不清楚。端粒酶是一种特殊的 DNA 聚合酶，负责通过使用内在 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。最近，发现患有常染色体显性先天性角化不良的家族存在端粒酶RNA基因突变。这些家族表现出再生障碍性贫血、特发性肺纤维化的显性遗传以及癌症风险增加。此外，每一代人都会有预期，症状的出现会更早、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患有先天性角化不良的大家族，其携带端粒酶的蛋白质成分 hTERT 突变。该谱系预期显示再生障碍性贫血和特发性肺纤维化的显性遗传。以下建议利用了该谱系中的临床观察结果以及模拟这种疾病的端粒酶敲除小鼠的最新发现。与之前在近交系上改造的端粒酶敲除小鼠不同，端粒长度与人类相似的野生栗属小鼠在骨髓和胃肠道中表现出干细胞衰竭。在胃肠道中，基因敲除小鼠也会出现胃肠道微腺瘤并伴有严重的吞咽困难。以下提案探讨了端粒酶和端粒长度在维持骨髓、胃肠道和肺部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成为肿瘤过程的病灶的悖论。当端粒酶抑制剂被积极地用作抗癌疗法时，这些作用尤其重要。