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.