Prevention of HPE in a mouse model susceptible to retinoic acid teratogenicity

在易受视黄酸致畸影响的小鼠模型中预防 HPE

• 批准号: 8729720
• 负责人: Anna Petryk
• 金额: $ 11.4万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-18 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8729720
• 关键词: A Mouse; Address; Affect; Apoptosis; Apoptotic; Bone Morphogenetic Proteins; Caring; Cell physiology; Characteristics; Child; Conceptus; Congenital Abnormality; Data; Defect; Dermatologic; Development; Disease; Dose; Embryo; Emotional; Environment; Environmental Risk Factor; Erinaceidae; Etiology; Exposure to; Extracellular Space; Face; Failure; Gene Mutation; Gene Targeting; Genes; Genetic; Goals; Growth; Holoprosencephaly; Human; In Situ Hybridization; Incidence; Individual; Infant; Intervention; Knowledge; Life; Mediating; Methods; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Outcome Study; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Penetrance; Phenotype; Predisposition; Prevention; Preventive; Preventive Intervention; Process; Prosencephalon; Research; Risk; Role; Signal Transduction; Teratogens; Testing; Tretinoin; Work; base; bone morphogenetic protein 5; clinical practice; computerized data processing; cost; craniofacial; design; gastrulation; gene environment interaction; improved; in utero; midfacial hypoplasia; mouse model; multidisciplinary; mutant; neural patterning; novel; offspring; pregnant; prevent; programs; public health relevance; relating to nervous system; response

DESCRIPTION (provided by applicant): There is a fundamental gap in understanding the mechanisms of gene-environment interactions in the pathogenesis of craniofacial defects. The existence of this gap hinders our ability to prevent defects in at risk individuals. Our long-term goal is to understand the underlying mechanisms that predispose patients to craniofacial defects in order to design targeted preventive interventions. A mouse model deficient in Twisted gastrulation (TWSG1) allows us to study the underlying mechanisms of these interactions because Twsg1-/- mice manifest HPE with a low penetrance of about 17%, which increases to 100% after exposure to subteratogenic doses of the retinoic acid (RA). The objective of this study is to characterize the mechanisms of increased susceptibility of TWSG1-deficient mice to RA-induced HPE. The central hypothesis is that dysregulation of bone morphogenetic protein (BMP) signaling in Twsg1 mutants reduces an apoptotic threshold, sensitizing the embryos to teratogenic effects of RA. Disrupting apoptotic pathways would be expected to be embryo-protective. The rationale for using this model is that environmental factors, unlike genetic aberrations, are modifiable in humans as long as the underlying mechanisms can be identified. Based on our preliminary data, the central hypothesis will be tested by pursuing three specific aims: 1) to examine the effects of in utero RA exposure on the molecular program that governs neural and midline facial development in Twsg1 mutant embryos; 2) to examine the impact of RA exposure on BMP signaling and cellular processes underlying the HPE phenotype in Twsg1 mutant embryos; 3) to understand the role of oxidative stress and p53 activation in mediating BMP/RA effects and their potential as targets for HPE prevention. The proposed research presents a novel concept that the BMP pathway may regulate embryonic susceptibility to environmental insults, such as RA. In addition, this study begins to address the role of p53 signaling in development, which is currently poorly understood. Finally, the preventive interventions that this project seeks to develop may have an impact on the current clinical practice. The expected outcomes of this study are: 1) elucidation of the mechanisms of gene-environment interactions in the pathogenesis of HPE, specifically how mutations with low penetrance can sensitize the embryos to environmental teratogens; 2) improved understanding of the interactions between BMP and RA signaling; 3) enhanced knowledge about the roles of the oxidative stress and p53 activation in HPE; and 4) establishment of a model for testing preventive interventions for embryonic teratogens. Such results are expected to have an important positive impact on prevention of craniofacial defects.

描述（由申请人提供）：在理解颅面缺陷发病机制中基因-环境相互作用的机制方面存在根本性差距。这种差距的存在阻碍了我们防止风险个体缺陷的能力。我们的长期目标是了解使患者易患颅面缺损的潜在机制，以便设计有针对性的预防干预措施。扭曲原肠胚形成（TWSG 1）缺陷的小鼠模型使我们能够研究这些相互作用的潜在机制，因为Twsg 1-/-小鼠表现出HPE，其具有约17%的低转化率，在暴露于亚致畸剂量的视黄酸（RA）后增加至100%。本研究的目的是描述TWSG 1缺陷小鼠对RA诱导的HPE的易感性增加的机制。核心假设是Twsg 1突变体中骨形态发生蛋白（BMP）信号的失调降低了凋亡阈值，使胚胎对RA的致畸作用敏感。破坏细胞凋亡途径预期具有胚胎保护作用。使用该模型的理由是，与遗传畸变不同，环境因素在人类中是可以改变的，只要可以确定潜在的机制。基于我们的初步数据，中心假设将通过追求三个具体目标来检验：1）检查子宫内RA暴露对Twsg 1突变胚胎中控制神经和中线面部发育的分子程序的影响; 2）检查RA暴露对Twsg 1突变胚胎中HPE表型的BMP信号传导和细胞过程的影响; 3）了解氧化应激和p53活化在介导BMP/RA效应中的作用及其作为HPE预防靶点的潜力。这项研究提出了一个新的概念，即BMP通路可能调节胚胎对环境损伤（如RA）的易感性。此外，这项研究开始解决p53信号在发育中的作用，这是目前知之甚少。最后，本项目寻求开发的预防性干预措施可能会对当前的临床实践产生影响。本研究的预期结果是：1）阐明HPE发病机制中基因-环境相互作用的机制，特别是低突变率的突变如何使胚胎对环境致畸剂敏感; 2）提高对BMP和RA信号之间相互作用的理解; 3）提高对氧化应激和p53激活在HPE中作用的认识;（4）建立胚胎致畸物预防性干预试验模型。这些结果有望对预防颅面缺损产生重要的积极影响。