Mouse models of genomic instability and birth defects

基因组不稳定性和出生缺陷的小鼠模型

• 批准号: 7651663
• 负责人: Catherine ELIZABETH Keegan
• 金额: $ 31.02万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7651663
• 关键词: Accounting; Alleles; Anus; Apoptosis; Binding Proteins; Biological Models; Blood Vessels; Cardiac; Cell Death; Cell Survival; Chimera organism; Congenital Abnormality; Data; Defect; Development; Dysplasia; Embryo; Embryonic Development; Environmental Risk Factor; Erythroid; Excision; Exhibits; Family member; Fanconi' s Anemia; Female; Fetal Liver; Functional disorder; Genes; Genetic; Genome; Genome Stability; Genomic Instability; Goals; Growth; Hematopoietic stem cells; Human; Hydronephrosis; Infant Mortality; Kidney; Knock-out; Laboratories; Lead; Limb structure; Link; Maintenance; Malignant Neoplasms; Mediating; Modeling; Multiprotein Complexes; Mus; Mutant Strains Mice; Mutate; Mutation; Organogenesis; Other Genetics; Patients; Pattern; Perinatal; Phenotype; Play; Population; Pregnancy; Prevention; Protein Isoforms; Proteins; Reporting; Role; Rothmund-Thomson syndrome; Secondary to; Stem cells; Study models; Syndrome; TP53 gene; Tamoxifen; Testing; Tracheoesophageal Fistula; Transgenes; Transgenic Mice; United States; Work; critical period; in vivo; infant death; insight; malformation; mouse model; mutant; novel; pregnant; progenitor; public health relevance; research study; spine bone structure; stem; stem cell population; telomere

DESCRIPTION (provided by applicant): Adrenocortical dysplasia (acd) is a spontaneous autosomal recessive mouse mutation that exhibits a pleiotropic phenotype that includes embryonic and perinatal lethality. The embryologic defects in acd mutant embryos consist of truncation of the posterior body axis, vertebral segmentation defects, hydronephrosis, and limb anomalies, resembling common malformations observed in humans with caudal regression syndrome (CRS) and VACTERL (vertebral, anal, cardiac, tracheo-esophageal fistula, renal, limb anomalies) association. In addition, acd mutant embryos exhibit growth retardation, widespread apoptosis, vascular patterning defects, and abnormalities in hematopoietic stem cell populations. The Acd gene encodes a novel telomeric binding protein (also known as TPP1) that functions in a multiprotein complex to maintain telomere integrity. Consistent with this function, acd mutant mice have evidence of telomere dysfunction, indicative of genomic instability. While the association between genomic instability and cancer is well documented, the association between genomic instability and birth defects in humans is unexplored. VACTERL and VACTERL-like defects have been reported in other genetic syndromes characterized by genomic instability, including Fanconi anemia and Rothmund-Thomson syndrome; however, the mechanisms that lead to birth defects in these syndromes are unknown. The overall goal of this project is to understand the mechanisms that lead to birth defects resulting from genomic instability, including CRS and VACTERL, using the acd mouse as a model system. The acd mouse is an outstanding model for these studies because it exhibits cellular evidence of genomic instability and malformations that resemble CRS and VACTERL. This work is important because the underlying mechanisms leading to CRS and VACTERL in humans are likely to be similar. In Aim 1, interactions between Acd and p53 family members, which have a well-known role in maintaining genomic stability, will be explored. These studies will build upon prior work in this laboratory showing that aspects of the acd phenotype, specifically the vertebral anomalies and limb hypoplasia, are due to p53-dependent apoptosis. In Aim 2, the hypothesis that normal Acd function is critical during early organogenesis will be tested using an inducible targeted knockout of the Acd gene during development. Aim 3 will investigate the role of Acd in hematopoietic stem cell survival and maintenance. In Aim 4, domain-specific phenotypes of Acd will be examined in vivo using transgenic mouse models. The use of the acd mouse model to elucidate the mechanisms underlying common birth defects in humans, such as CRS and VACTERL, is a critical step toward identification of causative genetic and environmental factors in humans. The information gained from these studies may ultimately lead to treatment and prevention of these birth defects. PUBLIC HEALTH RELEVANCE: Birth defects are the leading cause of infant mortality in the United States, accounting for 1 in 5 infant deaths annually. The adrenocortical dysplasia (acd) mouse is a model for caudal regression syndrome and VACTERL (vertebral, anal, cardiac, tracheo-esophageal fistula, renal, and limb anomalies) association in humans, and the Acd gene encodes a protein that has a role in telomere protection and genome stability. The role of genomic instability as a cause of birth defects is unexplored; therefore, the goal of this proposal is to use the acd mouse model to help understand the link between genomic instability and birth defects. The information gained from these studies will be a critical step toward identification of causative genetic and environmental factors that lead to birth defects in humans and may ultimately lead to treatment and prevention of these birth defects.

描述（由申请人提供）：肾上腺皮质发育不良（acd）是一种自发性常染色体隐性遗传小鼠突变，表现出包括胚胎和围产期致死性在内的多效性表型。 acd突变胚胎中的胚胎学缺陷包括后体轴截断、椎体节段缺陷、肾积水和肢体异常，类似于在患有尾部退化综合征（CRS）和VACTERL（椎体、肛门、心脏、气管-食管瘘、肾、肢体异常）关联。此外，acd突变胚胎表现出生长迟缓、广泛的细胞凋亡、血管模式缺陷和造血干细胞群异常。 Acd 基因编码一种新型端粒结合蛋白（也称为 TPP1），该蛋白在多蛋白复合物中发挥作用以维持端粒完整性。与此功能一致，acd 突变小鼠有端粒功能障碍的证据，表明基因组不稳定。虽然基因组不稳定性与癌症之间的关联已有充分记录，但基因组不稳定性与人类出生缺陷之间的关联尚未被探索。 VACTERL 和 VACTERL 样缺陷已在其他以基因组不稳定为特征的遗传综合征中被报道，包括 Fanconi 贫血和 Rothmund-Thomson 综合征；然而，导致这些综合征出生缺陷的机制尚不清楚。该项目的总体目标是使用 acd 小鼠作为模型系统，了解因基因组不稳定导致出生缺陷的机制，包括 CRS 和 VACTERL。 acd 小鼠是这些研究的杰出模型，因为它表现出类似于 CRS 和 VACTERL 的基因组不稳定和畸形的细胞证据。这项工作很重要，因为导致人类 CRS 和 VACTERL 的潜在机制可能相似。在目标 1 中，将探讨 Acd 和 p53 家族成员之间的相互作用，这些成员在维持基因组稳定性方面具有众所周知的作用。这些研究将建立在该实验室先前的工作基础上，该工作表明 acd 表型的各个方面，特别是椎骨异常和肢体发育不全，是由于 p53 依赖性细胞凋亡造成的。在目标 2 中，正常 Acd 功能在早期器官发生过程中至关重要的假设将使用发育过程中 Acd 基因的诱导性靶向敲除进行测试。目标 3 将研究 Acd 在造血干细胞存活和维持中的作用。在目标 4 中，将使用转基因小鼠模型在体内检查 Acd 的域特异性表型。使用acd小鼠模型来阐明人类常见出生缺陷（例如CRS和VACTERL）的潜在机制，是识别人类致病遗传和环境因素的关键一步。从这些研究中获得的信息可能最终有助于治疗和预防这些出生缺陷。 公共卫生相关性：出生缺陷是美国婴儿死亡的主要原因，每年占婴儿死亡人数的五分之一。肾上腺皮质发育不良 (acd) 小鼠是人类尾部退化综合征和 VACTERL（椎骨、肛门、心脏、气管食管瘘、肾脏和肢体异常）关联的模型，Acd 基因编码的蛋白质在端粒保护和基因组稳定性。基因组不稳定性作为出生缺陷原因的作用尚未被探索。因此，该提案的目标是使用 acd 小鼠模型来帮助了解基因组不稳定性与出生缺陷之间的联系。从这些研究中获得的信息将是识别导致人类出生缺陷的致病遗传和环境因素的关键一步，并可能最终导致这些出生缺陷的治疗和预防。