Phenotypes in mice lacking WRN, BLM and telomerase

缺乏 WRN、BLM 和端粒酶的小鼠的表型

• 批准号: 6547404
• 负责人: F. Brad Johnson
• 金额: $ 7.93万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6547404
• 关键词: Bloom syndrome; Werner's syndrome; aging; apoptosis; atrophy; blood; bone marrow; chemical stability; chemical structure; cytogenetics; gastrointestinal system; gene interaction; gene targeting; genetic disorder; genetically modified animals; germ cells; gonads; histology; laboratory mouse; phenotype; radiation sensitivity; skin; telomerase; telomere; tissue /cell culture; wound healing

Telomere shortening accompanies but plays an uncertain causal role in human aging. Werner syndrome and, to a lesser degree, Blood syndrome are diseases characterized by premature features of aging. The syndromes are caused by loss of the RecQ-family helicases WRN and BLM, respectively. Evidence is accumulating that Werner syndrome cells have defects in the maintenance of telomeres. In S. cerevisiae, mutants in SGS1, the yeast RecQ homologue, have defects in telomere maintenance, but only in cells that lack telomerase. In mice (mus musculus), telomere shortening appears not to cause aging, but if telomerase is inactivated genetically, telomeres shorten and phenotypes eventually arise after several generations. Compared with humans, mice have longer telomeres and more abundant telomerase. Thus the telomere biology of telomerase knock-out mice is more similar to that of most human cells. Remarkably, loss of WRN and BLM are well tolerated in mice, and a possible reason for this could be the differences between murine and human telomere biology. This is supported by the critical role of SGS1 at telomeres only in yeast cells lacking telomerase. For these reasons, the roles of MRN and BLM in mice lacking telomerase will be examined. We will ask whether mice that lack telomerase (the RNA component, TER) and WRN and BLM together develop earlier, more profound or event different defects that simply lack telomerase or WRN and BLM alone. We will focus on defects that are well-established to occur in telomerase or WRN and BLM alone. We will focus on defects that are well- established to occur in telomerase knockout mice. These include 1) dysfunction in highly proliferative tissues such as the gut, epidermis and hematopoietic system, 2) gonadal atrophy and germ cell apoptosis, 3) telomere shortening and 4) WRN and BLM at human telomeres and improve understanding of the role of telomeres in human aging. Long- term possible benefits of such understanding could include treatment for age-associated diseases.

端粒缩短伴随着人类衰老，但在人类衰老中发挥着不确定的因果作用。维尔纳综合征和血液综合征（程度较轻）是以过早衰老为特征的疾病。这些综合征分别由RecQ家族解旋酶WRN和BLM的丢失引起。越来越多的证据表明，沃纳综合征细胞在维持端粒方面存在缺陷。In S.酿酒酵母，SGS1的突变体，酵母RecQ同源物，在端粒维持方面有缺陷，但仅在缺乏端粒酶的细胞中。在小鼠（mus musculus）中，端粒缩短似乎不会导致衰老，但如果端粒酶在遗传上失活，端粒缩短，几代后最终出现表型。与人类相比，小鼠的端粒更长，端粒酶更丰富。因此，端粒酶敲除小鼠的端粒生物学与大多数人类细胞的端粒生物学更相似。值得注意的是，WRN和BLM的丢失在小鼠中耐受良好，其可能的原因可能是小鼠和人类端粒生物学之间的差异。这一点得到了SGS1仅在缺乏端粒酶的酵母细胞中在端粒上的关键作用的支持。由于这些原因，将检查MRN和BLM在缺乏端粒酶的小鼠中的作用。我们将询问缺乏端粒酶（RNA组分，TER）和WRN和BLM的小鼠是否共同发展更早，更深刻或事件不同的缺陷，只是缺乏端粒酶或WRN和BLM单独。我们将集中在缺陷是公认的发生在端粒酶或WRN和BLM单独。我们将集中在缺陷是公认的发生在端粒酶基因敲除小鼠。这些包括1）高度增殖性组织如肠、表皮和造血系统中的功能障碍，2）性腺萎缩和生殖细胞凋亡，3）端粒缩短和4）人端粒处的WRN和BLM，并提高对端粒在人类衰老中的作用的理解。这种理解的长期可能好处包括治疗与年龄有关的疾病。