Deciphering the Role of Frizzled Receptors in Palatal Development

解读卷曲感受器在腭发育中的作用

基本信息

批准号：
10646407
负责人：
Megan Michalski
金额：
$ 10.93万
依托单位：
VAN ANDEL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646407
关键词：
Affect Alleles Biological Assay Birth Breeding Bromodeoxyuridine Cell Differentiation process Cell Lineage Cells Cephalic Chemotactic Factors Cleft Lip Cleft Palate Cleft lip with or without cleft palate Clustered Regularly Interspaced Short Palindromic Repeats Code Congenital Abnormality Congenital Disorders Control Animal Craniofacial Abnormalities Data Development Disease Embryo Embryonic Development Epithelial Cells FZD2 gene Failure Family Foundations Future Gene Targeting Genes Genetic Genetic Transcription Goals Healthcare Systems Heterozygote Histology Homozygote Human In Situ Nick-End Labeling In Vitro Incidence Intervention Ligands Limb structure Link Live Birth LoxP-flanked allele Mammalian Oviducts Mediating Membrane Mesenchyme Missense Mutation Modeling Molecular Morphology Mus Mutation Neural Crest Cell Newborn Infant Nonsense Mutation Open Reading Frames Palate Pathway interactions Patients Pattern Phenotype Play Process Publishing Rare Diseases Regulation Reporter Research Robinow syndrome Role Signal Pathway Signal Transduction Solid Structural Congenital Anomalies Syndrome Testing Tissues Transgenes Variant WNT Signaling Pathway WNT5A gene autosome beta catenin career development cell fate specification cell motility cleft lip and palate craniofacial development directional cell genome editing improved microCT migration mouse model mutant new technology novel therapeutic intervention nucleic acid delivery orofacial cleft palatal shelves palatogenesis planar cell polarity prevent programs receptor response single-cell RNA sequencing targeted treatment

项目摘要

PROJECT SUMMARY/ABSTRACT Cleft lip and/or cleft palate has an incidence of approximately 1 in 700 births making it one of the most common congenital birth defects. Gaining a more complete understanding of the genetics and signaling mechanisms involved will provide a foundation for improving treatment of patients with orofacial clefts, ultimately reducing an enormous burden on the healthcare system. Several signaling pathways intersect to regulate the proper development of the palate which makes developing targeted therapies to treat or prevent cleft palate challenging. Dissecting the components of each pathway involved will provide a more complete picture of palatogenesis. The Wnt signaling pathway is an important regulator of palatal development and regulates early patterning by cranial neural crest cells through regulation of induction, migration, and differentiation of these cells. Wnt signaling also intersects many morphogenic pathways that regulate palatal shelf elongation, elevation, and fusion. Frizzleds (FZDs) are transmembrane receptors for Wnt ligands and mutations in some of the 10 FZD genes have been identified in patients with both syndromic and non-syndromic cleft lip and/or palate. Specifically, heterozygous nonsense mutations in FZD2 have been identified in patient families with Robinow Syndrome (RS) or Autosomal Dominant Omodysplasia (ADO), syndromes which are characterized by limb reductions and craniofacial anomalies including cleft palate. While these mutations in FZD2 were thought to cause haploinsufficiency, heterozygous deletion of Fzd2 in mice does not lead to cleft palate. We will use mouse models harboring RS/ADO-associated mutations to better understand how FZD2 functions in the developing palate. Given the association of mutations in other Wnt pathway genes (WNT5A, ROR2, DVL) in RS and ADO, we hypothesize that these components signal together with FZD2 to regulate palatogenesis. We hypothesize that FZD2 regulates cell migration and palatal patterning through a non-canonical WNT5A- ROR2 pathway and further hypothesize that human RS- and ADO-associated Fzd2 mutations act dominantly to interfere with Fzd signaling. To achieve these research goals, we propose the following aims: 1) determine the phenotypic consequences of Fzd2 deletion and RS/ADO-Fzd2 mutations on palatal development in mice, and 2) determine the molecular mechanisms behind Fzd2 regulation of palate development. Data generated in this proposal will ultimately support the development of novel therapeutic approaches and interventions in Wnt signaling-related diseases. These research plan and career development activities proposed here will form a solid basis for my future independent research program.

项目概要/摘要唇裂和/或腭裂的发病率约为七百分之一，使其成为最常见的疾病之一先天性出生缺陷。更全面地了解遗传学和信号机制所涉及的将为改善口面部裂患者的治疗奠定基础，最终减少对医疗保健系统造成巨大负担。多个信号通路交叉以调节适当的腭的发育使得开发靶向疗法来治疗或预防腭裂具有挑战性的。剖析所涉及的每个途径的组成部分将提供更完整的图景腭发生。 Wnt信号通路是腭发育的重要调节因子，调节早期发育颅神经嵴细胞通过调节这些细胞的诱导、迁移和分化来形成模式细胞。 Wnt 信号传导还与许多调节腭架伸长的形态发生途径相交叉，提升、融合。卷曲蛋白 (FZD) 是 Wnt 配体的跨膜受体，并且某些配体发生突变 10 个 FZD 基因已在患有综合征性和非综合征性唇裂和/或味觉。具体而言，已在患有以下疾病的患者家族中发现了 FZD2 杂合无义突变： Robinow 综合征 (RS) 或常染色体显性遗传性发育不良 (ADO)，其特征为由肢体缩小和颅面异常（包括腭裂）引起。虽然 FZD2 的这些突变小鼠中 Fzd2 的杂合缺失被认为会导致单倍体不足，但不会导致腭裂。我们将使用含有 RS/ADO 相关突变的小鼠模型来更好地了解 FZD2 在正在发育的味觉。考虑到其他 Wnt 通路基因（WNT5A、ROR2、DVL）突变的关联在 RS 和 ADO 中，我们假设这些成分与 FZD2 一起发出信号来调节腭发育。我们假设 FZD2 通过非规范的 WNT5A- 调节细胞迁移和腭模式。 ROR2 通路并进一步假设人类 RS 和 ADO 相关的 Fzd2 突变占主导地位干扰 Fzd 信号。为了实现这些研究目标，我们提出以下目标：1）确定 Fzd2 缺失和 RS/ADO-Fzd2 突变对小鼠腭发育的表型影响， 2) 确定 Fzd2 调节上颚发育的分子机制。数据生成于该提案最终将支持 Wnt 新型治疗方法和干预措施的开发信号相关疾病。这里提出的这些研究计划和职业发展活动将形成一个为我未来的独立研究计划奠定了坚实的基础。