Suppressing Aneuploidy-associated phenotypes in Down syndrome

抑制唐氏综合症的非整倍体相关表型

基本信息

批准号：
10536927
负责人：
Eduardo Martin Torres
金额：
$ 172.03万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10536927
关键词：
Adult Affect Age Aging Aneuploid Cells Aneuploidy Autoimmune Diseases Biochemical Pathway Biological Birth Cell Fractionation Cell Nucleus Cell physiology Cells Chromosome 21 Chromosome abnormality Chromosomes Clinical Congenital Disorders Coupled Data Defect Development Diagnosis Disease Down Syndrome Edward&apos s syndrome Fibroblasts Functional disorder Gene Mutation Genes Genetic Diseases Genomic Instability Health Homeostasis Human Human Genetics Immune Immunity Incidence Individual Lipids Lymphocyte Mass Spectrum Analysis Measures Membrane Lipids Metabolism Morphology Mutation Nuclear Nuclear Envelope Patau&apos s syndrome Pathologic Pathology Patients Phenotype Physiological Play Premature aging syndrome Regulation Research Risk Role Spontaneous abortion Tissues Trisomy associated symptom chromosome number abnormality clinically relevant cognitive disability fitness improved insight leukemia lipid biosynthesis novel novel therapeutic intervention proteostasis senescence

项目摘要

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.

项目摘要大多数自发堕胎的染色体数量异常或非整倍性占发育过程中单个染色体的错误分析通常是致命的。染色体13或18，分别引起Patau和Edwards综合征，出生于严重发育缺陷和出生后不久死亡。只有21三体患者，这会导致综合症可以活着表现出表现出认知障碍，白血病的风险增加，自身免疫性疾病和临床症状与过早衰老有关。重要的是，发生率在明显健康的个体的体细胞和种系组织中，非整倍性随着年龄的增长而增加。这非整倍性会影响细胞功能引起唐氏综合症或促进衰老的机制是不理解。我们的初步数据表明，非整倍性破坏了核膜。因为影响核形态的突变会导致过早衰老，所以我们假设非整倍性对核驱动表型异常的影响唐氏综合症过早衰老。在这里，我们计划识别各个方倍性的机制影响细胞核，以研究异常核如何有助于三体病理生理学 21，靶向生化途径，以抑制三体性表型的三体表型 21个细胞。