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

唇腭裂(CLP)是最常见的头面部出生缺陷，导致显著 发病率高，需要广泛的医疗干预。除了面部畸形和继发性 CLP的并发症、中枢神经系统(CNS)异常以及认知和行为障碍有 已知是同时发生的。重要的是，CLP的病因学基础，以及相关CNS的原因和程度 人们对异常现象仍然知之甚少。这一知识鸿沟最好通过基础研究来解决。 然而，重大的研究进展受到两个主要限制的阻碍：缺乏合适的 动物模型，以及缺乏具有专业知识的研究人员，以整合传统上不同的概念和 实验方法。这一领域的一个重要进展是我们最近证明了在子宫内 暴露于Hedgehog(HH)信号拮抗剂环多巴胺，在小鼠中诱导CLP，模仿 临床表型。利用这一模型，本文提出的研究使用了高分辨率磁体 磁共振成像以确定与CLP共同发生的中枢神经系统畸形，并确定是否独特 这些异常的模式可以通过特定的面部表型来预测(目标1)。机械化验将会 测试环多巴胺暴露通过干扰导致相关的脑-面部异常的假设 发育中的前脑和面中部之间的感应信号(目标2)。HH途径的靶基因是 将确定和表征这些畸形的初始发病机制(目标3)，提供 一组候选基因在颅面发育和临床CLP的病因中的作用将是 在未来的研究中继续追寻。总而言之，预计这些研究将确定特定的中枢神经系统异常 它们存在于CLP患者中，并提供了基本的病因病理特征，将推动 未来的努力是研究化学和遗传扰动对HH信号通路的相互作用 CLP在临床人群中的发生。以增加候选人以前的毒物学经验和 细胞信号，这些研究目标与胚胎学的教学和实践培训部分相结合， 神经发育、临床和分子遗传学。本提案中概述的机会将 为候选人提供理想的多学科概念背景和实验工具集 慢性阻塞性肺病复杂病因的阐明。这些承诺的成功完成将是 在北卡罗来纳大学教堂山分校提供的特殊研究环境的推动下， 以及颅面/神经发育专家的指导和合作(凯瑟琳·苏利克博士)， 小动物成像(艾尔·约翰逊博士)、3D脸型分析(彼得·哈蒙德博士)、头面部遗传学 (Eric Everett博士)和临床遗传学(Arthur Aylsworth博士)。归根结底，承担和完成 这些努力将为候选人在以下背景下追求学术生涯的目标奠定基础 它结合了临床和基础科学家，以促进口腔和颅面健康。

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.