Suppressing Aneuploidy-associated phenotypes in Down syndrome

项目摘要 染色体数目异常或非整倍体是大多数自然流产的原因，如 在发育过程中，单个染色体的错误分离通常是癫痫。 分别导致帕托综合征和爱德华兹综合征的13号或18号染色体出生时就患有严重的 发育缺陷，出生后不久就会死亡。仅限21三体患者，该三体可导致Down 综合征可以活到成年，但表现为认知障碍、白血病风险增加、自身免疫 疾病，以及与过早衰老相关的临床症状。重要的是，该病的发病率 在表面健康的个体中，体细胞和生殖系组织中的非整倍体随着年龄的增长而增加。这个 非整倍体影响细胞功能导致唐氏综合症或促进衰老的机制有 我不明白。我们的初步数据显示，非整倍体破坏了细胞的完整性和形态 核膜。由于影响核形态的突变会导致过早衰老，我们 假设非整倍体对核驱动表型异常的影响与 唐氏综合征患者的早衰。在这里，我们计划确定非整倍体 影响核，研究异常核在三体的病理生理学中的作用 21，并靶向生化途径，以抑制三体中非整倍体相关的表型 21个细胞。

Project Summary An abnormal number of chromosomes or aneuploidy accounts for most spontaneous abortions as missegregation of a single chromosome during development is often lethal.Patients with trisomies for chromosomes 13 or 18, which cause Patau and Edwards syndromes, respectively, are born with severe developmental defects and die soon after birth. Only patients with trisomy 21, which causes Down syndrome can live to adulthoodbut show cognitive disabilities, increased risk for leukemias, autoimmune disorders, and clinical symptoms associated with premature aging. Importantly, the incidence of aneuploidy increases with age in both somatic and germline tissues in apparently healthy individuals. The mechanisms by which aneuploidy affects cellular functionto cause Down syndrome or promote aging are not understood. Our preliminary data reveal that aneuploidy disrupts the integrity and morphology of the nuclear membrane. Because mutations that affect nuclear morphology cause premature aging, we hypothesize that the aneuploidy effects on the nucleus drive phenotypic anomalies associated with premature aging in Down syndrome. Here, we plan to identify the mechanisms through which aneuploidy affects the nucleus, to investigate how an abnormal nucleus contributes to the pathophysiology of trisomy 21, and to target biochemical pathways so as to suppress aneuploidy-associated phenotypes in trisomy 21 cells.