Novel System to Study Telomere Dynamics in Hemotopoiesis

描述（由申请人提供）：大多数真核生物的末端 染色体由称为端粒的末端重复序列组成。这些重复 保护染色体的完整性，并确保完整的复制 必需基因尽管衰老或复制的分子基础 衰老还没有完全理解，端粒长度的减少被认为是 发挥重要作用。例如，端粒在体细胞中较短， 年龄较大的个体的组织比年龄较小的个体的组织要多。出生时患有 Hutchinson-Gilford早衰症是一种早期衰老综合征， 年龄匹配的对照组。在其他衰老遗传疾病中，如 沃纳综合症和唐氏综合症，细胞在两到三个端粒丢失 乘以年龄匹配的对照组的比率。端粒重复序列是从头产生的 由核糖核蛋白酶端粒酶引起。的异位表达 正常人体细胞中的端粒酶导致寿命延长， 抑制复制性衰老。端粒也缩短造血 干细胞在正常老化和年轻的造血细胞 接受过同种异体骨髓移植的患者。我们推测 如果我们能在实验上延长正常人的端粒 造血细胞、复制能力和自我更新潜力可 增加，从而改变发病率和/或发病时间的年龄相关 造血障碍和免疫衰老。 我们建议开发一个小鼠模型系统，允许研究 端粒酶在人类造血细胞中功能。为此，我们将 使用NOD/SCID小鼠模型，其中造血区室可以 用人类造血干细胞重建逆转录病毒方法将是 用于指导这些移植的造血细胞中改变的端粒酶活性， 干细胞及其成熟衍生物。 申请人是一名医学博士。他将在解剖学中心完成住院医师培训 病理学与血液病理学亚专业培训之前，建议 开始日期。他还拥有博士学位。在生物化学。这项研究将 在丹娜-法伯癌症中心的癌症/衰老生物学实验室进行 该研究所隶属于哈佛医学院， 罗恩德皮纽医生。

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.