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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：
10454367
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/10454367
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 Histology Homozygote Human In Situ Nick-End Labeling In Vitro Incidence Intervention Ligands Limb structure Link Live Birth Mammalian Oviducts Mediating 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 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.

项目总结/文摘