Developmental mechanisms underlying genotype-phenotype correlations

基因型-表型相关性的发育机制

• 批准号: 8842017
• 负责人: Benedikt Hallgrimsson
• 金额: $ 41.52万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-27 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8842017
• 关键词: Accounting; Affect; Alleles; Animals; Attention; Basic Science; Brain; Cell Cycle Stage; Cell Death; Cell Proliferation; Cells; Cellular Assay; Complex; Congenital Abnormality; Coupled; Data; Development; Developmental Biology; Disease; Disease model; Dose; Ectoderm; Embryo; Erinaceidae; Exhibits; Face; Facial asymmetry; Gene Expression; Genes; Genetic Models; Genotype; Goals; Grant; Heterogeneity; Heterozygote; Holoprosencephaly; Incidence; Individual; Lead; Ligands; Mesenchyme; Methods; Modeling; Molecular; Morphology; Mus; Mutation; Neural Crest; Neural Crest Cell; Outcome; Outcome Measure; Pathway interactions; Pattern; Phenotype; Population; Principal Investigator; Series; Severities; Shapes; Signal Pathway; Signal Transduction; Sonic Hedgehog Pathway; Structural defect; System; Testing; Variant; Work; base; cell behavior; cell type; cilium biogenesis; craniofacial; craniofacial complex; design; human disease; improved; in vivo; malformation; mutant; novel; programs; public health relevance; research study; response; smoothened signaling pathway; therapeutic target

DESCRIPTION (provided by applicant): Phenotypic variation is a hallmark of craniofacial birth defects, but understanding the relationship between variable morphology and disease remains elusive. In this work we propose to test a model that may explain phenotypic variation within similar genotypes. This model is based on our preliminary data showing a nonlinear relationship between Sonic hedgehog (SHH) signaling and continuous phenotypic variation in the face. We hypothesize that small changes in SHH pathway activity produce large phenotypic changes that have increased variance due to heterogeneous cellular responses to compromised pathway activity. In the first Specific Aim of this grant we will focus on examining the extent to which nonlinear SHH signaling contributes to variation in cellular response. This will be done at the population and the individual cell level. In the Second and Third Specific Aims we will turn our attention to in vivo genetic models of graded SHH signaling. We will examine the phenotype of resulting embryos and we will determine the variance of the phenotypes. Our model predicts that as the nonlinearity in SHH signaling increases the potential to produce large variance also increases. The experiments designed in this application will directly test this prediction and will illuminate a potentially important mechanism that destabilizes complex developmental systems. The use of quantitative analyses such as, geometric morphometrics coupled with quantitative cellular assays and quantitative PCR, throughout this grant gives us the power to perform the analyses proposed in this application.

描述（由申请人提供）：表型变异是颅面出生缺陷的标志，但了解可变形态和疾病之间的关系仍然难以捉摸。在这项工作中，我们建议测试一个模型，可以解释相似基因型内的表型变异。该模型基于我们的初步数据，显示了Sonic hedgehog（SHH）信号与面部连续表型变异之间的非线性关系。我们假设SHH通路活性的小变化产生大的表型变化，这些变化由于对受损通路活性的异质细胞反应而增加了方差。在本基金的第一个具体目标中，我们将重点研究非线性SHH信号对细胞反应变化的贡献程度。这将在群体和单个细胞水平上进行。在第二和第三个具体目标中，我们将把注意力转向分级SHH信号传导的体内遗传模型。我们将检查所得胚胎的表型，并确定表型的方差。我们的模型预测，随着SHH信号的非线性增加，产生大方差的可能性也增加。本申请中设计的实验将直接测试这一预测，并将阐明一个潜在的重要机制，使复杂的发育系统不稳定。定量分析的使用，如几何形态计量学与定量细胞测定和定量PCR相结合，在整个授权中，使我们有能力进行本申请中提出的分析。

项目成果

Chronic Protein Restriction in Mice Impacts Placental Function and Maternal Body Weight before Fetal Growth.

小鼠的慢性蛋白质限制会影响胎儿生长前的胎盘功能和母亲体重。

• DOI: 10.1371/journal.pone.0152227
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Gonzalez PN;Gasperowicz M;Barbeito-Andrés J;Klenin N;Cross JC;Hallgrímsson B
• 通讯作者: Hallgrímsson B