Saturday, December 7, 2024
12/7/2024
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
