Novel System to Study Telomere Dynamics in Hemotopoiesis

描述(申请人提供)：大多数真核生物的终末 染色体由称为端粒的末端重复序列组成。这些重复 用来保护染色体的完整性并确保完全复制 基本基因。尽管衰老或复制的分子基础 衰老还没有完全被理解，人们认为端粒长度减少 发挥重要作用。例如，在体细胞中，端粒较短 来自年长个体的组织比来自年轻个体的组织。与生俱来的儿童 Hutchinson-Gilford早衰症是一种早期衰老综合征，端粒较短 而不是年龄匹配的对照组。在其他衰老-遗传学障碍中，例如 沃纳综合征和唐氏综合征，细胞在2到3岁时失去端粒 乘以年龄匹配的对照组的发病率。端粒重复序列从头开始产生 通过核糖核蛋白酶端粒酶。的异位表达 正常人体细胞中的端粒酶导致寿命延长和 抑制复制衰老。在造血术中端粒也会变短 正常衰老中的干细胞和年轻人的造血细胞中的干细胞 接受异基因骨髓移植的患者。我们假定 如果我们能在体外实验中延长正常人的端粒 造血细胞、复制能力和自我更新潜能可能 增加并因此改变与年龄相关的发病率和/或发病时间 造血障碍和免疫衰老。 我们建议开发一种小鼠模型系统，以允许研究 人类造血细胞中的端粒酶功能。为此，我们将使 NOD/SCID小鼠模型的应用 用人的造血干细胞进行重组。逆转录病毒方法将是 用来指导这些移植的造血细胞端粒酶活性的改变 干细胞及其成熟衍生品。 申请者是医学博士，将完成解剖学的住院医师资格。 在拟议的培训之前，接受血液病理学方面的专科培训 开始日期。他还拥有生物化学博士学位。这项研究将是 在Dana-Farber癌症内的癌症/衰老生物学实验室进行 哈佛医学院附属研究所，在 罗恩·德皮尼奥博士。

DESCRIPTION (provided by applicant): The termini of most eukaryotic chromosomes are composed of terminal repeats called telomeres. These repeats serve to protect chromosome integrity and ensure complete replication of essential genes. Although the molecular basis of aging or replicative senescence is not fully understood, reductions in telomere length are thought to play an important role. For example, telomeres are shorter in somatic tissues from older than from younger individuals. Children born with Hutchinson-Gilford progeria, an early-aging syndrome, have shorter telomeres than do age-matched controls. In other aging-genetics disorders, such as Werner's syndrome and Down's syndrome, cells lose telomeres at two to three times the rate in age-matched controls. Telomeric repeats are produced de novo by the ribonucleoprotein enzyme telomerase. The ectopic expression of telomerase in normal human somatic cells results in an extended lifespan and inhibition of replicative senescence. Telomeres also shorten in hematopoietic stem cells during normal aging and in the hematopoietic cells of young patients who have received allogenic bone marrow transplant. We postulate that if we can experimentally elongate the telomere ex vivo in normal human hematopoietic cells, replicative capacity and self-renewal potential may increase and thus alter the incidence and/or time of onset of age related hematopoietic disorders and immunosenescence. We propose to develop a mouse model system that permits the study of telomerase function in human hematopoietic cells. To this end, we will make use of the NOD/SCID mouse model in which the hematopoietic compartment can be reconstituted with human hematopoietic stem cells. Retroviral methods will be used to direct altered telomerase activity in these transplanted hematopoietic stem cells and their mature derivatives. The applicant is an M.D. who will have completed a residency in anatomic pathology with subspecialty training in hematopathology prior to the proposed start date. He also holds a Ph.D. in Biochemistry. The research will be carried out in a cancer/aging biology laboratory within the Dana-Farber Cancer Institute, an affiliate of the Harvard Medical School, under the mentorship of Dr. Ron DePinho.