Genomic Approaches to Aneuploidy

非整倍体的基因组方法

基本信息

批准号：
8440769
负责人：
Roger H Reeves
金额：
$ 53.85万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-03-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8440769
关键词：
Abbreviations Affect Agonist Aneuploidy Animal Model Appearance Atherosclerosis Attenuated Award Biological Biological Models Blood - brain barrier anatomy Breeding Candidate Disease Gene Cell Culture Techniques Cells Cerebellum Characteristics Chimera organism Chromosomes Chromosomes, Human, Pair 21 Clinical Colon Carcinoma Complex Development Down Syndrome Embryo Enteral Enteric Nervous System Epigenetic Process Erinaceidae Face Family Female Fertilization in Vitro Fibroblasts First Pharyngeal Arch Ganglia Gene Dosage Gene Expression Gene Silencing Generations Genes Genetic Genomics Growth Factor Health Heart Human Human Chromosomes Imaging technology Indium Individual Intestinal Neoplasms Libraries Life Malignant Neoplasms Maps Methods Modeling Mus Myocardial Infarction Neural Crest Neural Crest Cell Nuclear Open Reading Frames Pathway interactions Peripheral Phenotype Pigmentation physiologic function Placenta Ploidies Population Preclinical Drug Evaluation Prevention Process Regulation Reporting Repression Research Resistance Robertsonian Translocation Role Staging Stroke Structure Surveys Testing Time Tissues Trisomy Work Zebrafish base cell type craniofacial dosage expression vector granule cell melanoblast migration mouse Ts65Dn mouse model nerve supply prevent prophylactic protective effect public health relevance research study response transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): Trisomy 21 (Down syndrome, DS), is among the most complicated genetic situations compatible with substantial survival. The clinical presentation of DS represents the interaction of many triplicated genes throughout development. Understanding what individual genes do is a necessary component of approaches to therapy for features of Down syndrome, but it is not sufficient. The earlier periods of this award focused on creating and characterizing animal models in which to study DS, supporting assessment of all tissues at all stages of life. In the last award period we used these models and principles to make three significant advances. First, we determined that trisomic mice recapitulate (and predict) structural problems observed in the very small DS cerebellum, defined the timing, cell type, process and growth factor (SHH) responsible for this hypocellularity and then cured it in mice. Second, we provided the first experimental evidence that DS is a neurocristopathy by showing that the craniofacial hypoplasia in DS and in mouse models originates with problems in delamination, migration and proliferation of neural crest cells (NCC) in the first pharyngeal arch. Third, we provided biological evidence to answer a 50 year old statistical argument that people with DS get substantially (90%) less cancer than do euploid individuals and identified a single gene, Ets2, dosage for which is inversely correlated with intestinal tumor number in a model of colon cancer. Because NCC and SHH each affect many (overlapping) aspects of development, we will test the hypothesis that they represent "common denominators" of DS phenotypes. We will use a pharmacological approach to "cure" the NCC deficit leading to craniofacial hypoplasia. We have begun a survey of the entire Hsa21 gene set to determine gene dosage effects on early development in zebrafish. We will further characterize gene expression with regard to nuclear compartmentalization, a newly appreciated epigenetic regulatory mechanism. We will define more precisely the mechanism of Ets2 tumor repression, and screen for drugs that might act on this pathway as a prophylactic for cancer in everyone, regardless of ploidy.

描述（由申请人提供）：21 三体症（唐氏综合症，DS）是与大量生存相容的最复杂的遗传情况之一。 DS 的临床表现代表了整个发育过程中许多三重基因的相互作用。了解单个基因的作用是唐氏综合症特征治疗方法的必要组成部分，但这还不够。该奖项的早期重点是创建和表征用于研究 DS 的动物模型，支持对生命各个阶段的所有组织进行评估。在上一个奖项期间，我们利用这些模型和原则取得了三项重大进展。首先，我们确定三体小鼠重现（并预测）了在非常小的 DS 小脑中观察到的结构问题，定义了导致这种细胞减少的时间、细胞类型、过程和生长因子 (SHH)，然后在小鼠中治愈了它。其次，我们通过显示 DS 和小鼠模型中的颅面发育不全源于第一咽弓神经嵴细胞 (NCC) 的分层、迁移和增殖问题，提供了 DS 是一种神经嵴病的第一个实验证据。第三，我们提供了生物学证据来回答一个 50 年前的统计论点，即患有 DS 的人比整倍体个体患癌症的几率要低得多 (90%)，并确定了一个基因 Ets2，其剂量与肠道肿瘤数量呈负相关。结肠癌模型。由于 NCC 和 SHH 各自影响发育的许多（重叠）方面，因此我们将检验它们代表 DS 表型的“共同点”的假设。我们将使用药理学方法来“治愈”导致颅面发育不全的 NCC 缺陷。我们已经开始对整个 Hsa21 基因组进行调查，以确定基因剂量对斑马鱼早期发育的影响。我们将进一步表征核区室化的基因表达，这是一种新近认识的表观遗传调控机制。我们将更精确地定义 Ets2 肿瘤抑制机制，并筛选可能作用于该途径的药物，作为每个人（无论倍性）癌症的预防药物。