Transcriptome and Network Analysis of Cleft Palate

腭裂的转录组和网络分析

基本信息

项目摘要

ABSTRACT Cleft palate is one of the most common structural birth defects. Surgical correction and medical and psychosocial care impose significant personal and societal burdens. Increased understanding of the etiology of cleft palate potentially will lead to improvements in diagnosis and treatment. Palatogenesis is enormously complex. Paired palatal shelves first extend vertically from the maxillary processes and must grow sufficiently so that upon horizontal elevation their medial edges come into contact. Epithelia covering the medial shelves disintegrate, allowing their fusion. Key processes involved include epithelial/mesenchymal interactions and transitions. Studies in humans and mice have identified at least 429 genes associated with oral clefting. Reductionist scientific approaches have provided detail about individual genes and pathways in palatogenesis, but the intuitive models generated are not sufficient to represent the enormous complexity of the process. We will employ transcriptome and network analyses to understand how biological components work together to produce system- wide outcomes of epithelial differentiation and adhesion, mesenchymal biomechanical properties affecting remodeling and shelf elevation, and anterior/posterior regionalization of epithelia and mesenchyme. These processes require the integration of multiple cross-regulating signaling pathways. Fibroblast growth factor (FGF) and sonic hedgehog (SHH) are two such pathways, and their information is integrated with other pathways by the transcription factor p63. We will generate bulk and single-cell RNA-seq libraries from the palatal shelves of wild type mice to discover gene coexpression and regulatory networks, and specific cell populations involved in normal palatogenesis. For bulk RNA-seq libraries we will separate anterior and posterior epithelial and mesenchymal compartments allowing region-specific analysis of transcriptional changes. We will use the same approach for four mutant mouse lines, exploiting these gene perturbations to identify key driver genes and interacting pathways within these networks. We will study two activating FGFR2 mutations that exert their differential effects from the epithelium or the mesenchyme (S252W or C342Y) and null mutations of SHH and p63, expressed in the epithelium. Complementary bulk and single-cell RNA-seq libraries will identify differential gene expression and novel key components and pathways critical to palatogenesis. We will use these datasets, in conjunction with publicly available palate-related datasets to build high-resolution, multiscale molecular networks that will be used to develop predictive, mechanistic models of palatogenesis. Novel molecular networks and key regulators identified through the multiscale network modeling approach will be validated by in situ hybridization, immunohistochemistry, palatal organ cultures, and mouse models. Our innovative approach to generating comprehensive datasets, using advanced systems biology technologies, and building multiscale network models of normal and abnormal palatogenesis will have a large impact on the clinical, craniofacial, -omics, and developmental biology fields.
摘要

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Ethylin Wang Jabs其他文献

Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans
患有黑棘皮病的克鲁宗综合征中的成纤维细胞生长因子受体 3(FGFR3)跨膜突变
  • DOI:
    10.1038/ng1295-462
  • 发表时间:
    1995-12-01
  • 期刊:
  • 影响因子:
    29.000
  • 作者:
    Gregory A. Meyers;Seth J. Orlow;Ian R. Munro;Kelly A. Przylepa;Ethylin Wang Jabs
  • 通讯作者:
    Ethylin Wang Jabs
Aural atresia associated with multiple congenital anomalies and mental retardation: A new syndrome
  • DOI:
    10.1016/s0022-3476(87)80017-3
  • 发表时间:
    1987-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Linda F. Cooper;Ethylin Wang Jabs
  • 通讯作者:
    Ethylin Wang Jabs
亚洲人群FOXF2基因多核苷酸多态位点与非综合征型唇腭裂关联的新证据
  • DOI:
  • 发表时间:
    2015
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Bo Zhang;Ethylin Wang Jabs;Alan F. Scott;Terri H. Beaty
  • 通讯作者:
    Terri H. Beaty
国际唇腭裂研究小组数据的基因及基因环境交互作用联合研究关于亚洲人群BMP4基因与非综合征型唇腭裂关联的新证据
  • DOI:
  • 发表时间:
    2014
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Ethylin Wang Jabs;Margaret M. Parker;Alan F. Scott;Terri H. Beaty
  • 通讯作者:
    Terri H. Beaty
A genome wide screen of Crohn's disease in a large pedigree shows evidence for linkages to chromosomes 11, 16, 8 and 15
  • DOI:
    10.1016/s0016-5085(98)83831-6
  • 发表时间:
    1998-04-15
  • 期刊:
  • 影响因子:
  • 作者:
    Steven R. Brant;Dan Nicolae;Michele C. LaBuda;Romulo Baltazar;Carter Fields;Geoffrey Ravenhill;Mike Pickles;Patrick M. Rohal;Ethylin Wang Jabs;Stephen B. Hanauer;Theodore M. Bayless;Judy H. Cho
  • 通讯作者:
    Judy H. Cho

Ethylin Wang Jabs的其他文献

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{{ truncateString('Ethylin Wang Jabs', 18)}}的其他基金

Cartilage and bone of the lower jaw in development and disease
下颌软骨和骨骼的发育和疾病
  • 批准号:
    10552606
  • 财政年份:
    2022
  • 资助金额:
    $ 79.34万
  • 项目类别:
Cartilage and bone of the lower jaw in development and disease
下颌软骨和骨骼的发育和疾病
  • 批准号:
    10357271
  • 财政年份:
    2022
  • 资助金额:
    $ 79.34万
  • 项目类别:
Genetic, Tissue, and Anatomical Interactions in Mandibulofacial Dysmorphogenesis
下颌面部畸形发生中的遗传、组织和解剖学相互作用
  • 批准号:
    10220643
  • 财政年份:
    2021
  • 资助金额:
    $ 79.34万
  • 项目类别:
Genetic, Tissue, and Anatomical Interactions in Mandibulofacial Dysmorphogenesis
下颌面部畸形发生中的遗传、组织和解剖学相互作用
  • 批准号:
    10663868
  • 财政年份:
    2021
  • 资助金额:
    $ 79.34万
  • 项目类别:
Genetic, Tissue, and Anatomical Interactions in Mandibulofacial Dysmorphogenesis
下颌面部畸形发生中的遗传、组织和解剖学相互作用
  • 批准号:
    10470325
  • 财政年份:
    2021
  • 资助金额:
    $ 79.34万
  • 项目类别:
Transcriptome and Network Analysis of Cleft Palate
腭裂的转录组和网络分析
  • 批准号:
    10314049
  • 财政年份:
    2020
  • 资助金额:
    $ 79.34万
  • 项目类别:
Interdisciplinary Training in Systems and Developmental Biology and Birth Defects
系统与发育生物学和出生缺陷的跨学科培训
  • 批准号:
    10159749
  • 财政年份:
    2013
  • 资助金额:
    $ 79.34万
  • 项目类别:
Interdisciplinary Training in Systems and Developmental Biology and Birth Defects
系统与发育生物学和出生缺陷的跨学科培训
  • 批准号:
    9260707
  • 财政年份:
    2013
  • 资助金额:
    $ 79.34万
  • 项目类别:
Interdisciplinary Training in Systems and Developmental Biology and Birth Defects
系统与发育生物学和出生缺陷的跨学科培训
  • 批准号:
    9751946
  • 财政年份:
    2013
  • 资助金额:
    $ 79.34万
  • 项目类别:
Interdisciplinary Training in Systems and Developmental Biology and Birth Defects
系统与发育生物学和出生缺陷的跨学科培训
  • 批准号:
    8640965
  • 财政年份:
    2013
  • 资助金额:
    $ 79.34万
  • 项目类别:

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激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
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