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Imaging and mechanistic analyses of face-brain dysmorphology in a CLP model

CLP 模型中面脑畸形的成像和机制分析

基本信息

批准号：
8619710
负责人：
Robert Lipinski
金额：
$ 23.88万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8619710
关键词：
Address Animal Model Animals Apoptosis Attenuated Awareness Basic Science Behavioral Biological Assay Brain Candidate Disease Gene Caring Cell Proliferation Cleaved cell Clinical Cognitive Collaborations Complex Congenital Abnormality Congenital neurologic anomalies Coupled Defect Development Dorsal Dysmorphology Embryo Embryology Environment Environmental Risk Factor Erinaceidae Exhibits Exposure to Face Fetus Fostering Foundations Frontonasal Prominence Future Gene Expression Profiling Gene Targeting Genes Genetic Goals Growth Health Human Image In Situ Hybridization In Situ Nick-End Labeling Individual Intervention Investigation Knowledge Lateral Magnetic Resonance Magnetic Resonance Imaging Mediating Mediator of activation protein Medical Mentorship Microarray Analysis Microscopy Modeling Molecular Molecular Genetics Molecular Profiling Morbidity - disease rate Morphogenesis Mus Neuraxis North Carolina Oral Pathogenesis Pathway interactions Patients Pattern Perinatal Exposure Phenotype Population Prevalence Prosencephalon Research Research Personnel Resolution Reverse Transcriptase Polymerase Chain Reaction Role Scientist Shapes Signal Transduction Staining method Stains Structure Study models Surface Testing Time Tissues Toxicology Training Universities Validation Work base career chemical genetics cleft lip and palate clinical phenotype craniofacial cyclopamine design experience indexing malformation mouse model multidisciplinary neurodevelopment novel pregnant progenitor public health relevance relating to nervous system research study shape analysis smoothened signaling pathway spatiotemporal

项目摘要

Clefts of the lip and palate (CLP) are the most commonly occurring craniofacial birth defect, cause significant morbidity, and require extensive medical intervention. In addition to the facial malformations and secondary complications of CLP, central nervous system (CNS) abnormalities, and cognitive and behavioral deficits are known to co-occur. Importantly, the etiological basis of CLP, as well as the cause and extent of associated CNS abnormalities remain poorly understood. This knowledge gap is best addressed through basic research. However, significant research progress has been hampered by two major limitations: a paucity of suitable animal models, and a lack of investigators with the expertise to integrate traditionally disparate conceptual and experimental approaches. An important advance in this arena has been our recent demonstration that in utero exposure to the Hedgehog (Hh) signaling antagonist, cyclopamine, induces CLP in the mouse, mimicking clinical phenotypes. Employing this model, the studies proposed herein use high-resolution magnetic resonance imaging to define CNS dysmorphology that co-occurs with CLP and to determine whether unique patterns of these abnormalities can be predicted by specific facial phenotypes (Aim 1). Mechanistic assays will test the hypothesis that cyclopamine exposure induces associated brain-face abnormalities by disrupting inductive signals between the developing forebrain and midface (Aim 2). The Hh pathway target genes which mediate the initial pathogenesis of these malformations will be identified and characterized (Aim 3), providing a set of candidate genes whose function in craniofacial development and etiological role clinical CLP will be pursued in future studies. Cumulatively, it is expected that these studies will define specific CNS abnormalities that are present in patients with CLP and provide foundational etiopathological characterization that will drive future efforts to examine the interaction of chemical and genetic perturbations to the Hh signaling pathway in the genesis of CLP in clinical populations. To augment the candidate's previous experience in toxicology and cell signaling, these research aims are coupled with didactic and hands-on training components in embryology, neurodevelopment, and clinical and molecular genetics. The opportunities outlined in this proposal will provide the candidate with a multidisciplinary conceptual background and experimental toolset ideal for elucidation of the complex etiopathology of CLP. The successful completion of these undertakings will be fostered by the exceptional research environment provided at the University of North Carolina at Chapel Hill, and mentorship by and collaboration with experts in craniofacial/neurodevelopment (Dr. Kathleen Sulik), small animal imaging (Dr. Al Johnson), 3D face-shape analysis (Dr. Peter Hammond), craniofacial genetics (Dr. Eric Everett), and clinical genetics (Dr. Arthur Aylsworth). Ultimately, the undertaking and completion of these endeavors will provide a foundation for the candidate's goal of pursuing an academic career in a setting which incorporates clinical and basic scientists to advance oral and craniofacial health.

唇腭裂（CLP）是最常见的颅面先天性缺陷，原因显著