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Comprehensive Analysis of Palatal Development for Cleft Palate Prevention

This project aims to analyze gene expression, Tgfb downstream targets, and signaling pathways to develop therapeutic strategies for cleft palate prevention. Utilizing sophisticated imaging analysis, the study focuses on rescuing altered palatogenesis using in vivo experiments.

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Comprehensive Analysis of Palatal Development for Cleft Palate Prevention

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  1. PI: Yang Chai Specific Aims: 1. To perform global and specific gene expression analysis. In parallel, we will use sophisticated imaging analysis to build a comprehensive data base of palatal development. 2. To perform high-throughput analysis of Tgfb downstream target genes that have specific functions in regulating the fate of CNC cells during palatogenesis and to test if manipulation of altered Tgfb downstream signaling molecule(s) can rescue cleft palate in vivo. 3. To integrate with the FaceBase Consortium and identify the point(s) of intersection where multiple signaling pathways converge in order to develop therapeutic strategies to prevent or restore palate formation.

  2. Cleft palate in humans Animal models Complete cleft of hard and soft palate Wnt1-Cre;Tgfbr2fl/fl Partial cleft of soft palate K14-Cre;Tgfbr2fl/fl

  3. Sophisticated dynamic imaging analysis of palatogenesis microCT microMRI Scott Fraser Wnt1-Cre;Tgfbr2fl/fl Control

  4. Altered gene expression profile analysis in Wnt1-Cre;Tgfbr2 mutant palatal mesenchyme Joe Hacia, Junichi Iwata, and Yang Chai Total: 147 genes

  5. Up-regulated genes in Wnt1-Cre;Tgfbr2 CKO mice at E14.5 TGF-beta NF-KB ERK Ingenuity Pathway Analysis

  6. Design of in vivo rescue experiment Target for rescue Tgf-b2 Wnt1-Cre;Tgfbr2fl/+ Tgfbr2fl/fl;Tgfb2+/- RII RI RIII b-spectrin P p38 JNK Wt Tgfbr2fl/fl;Wnt1-Cre Tgfbr2fl/fl;Wnt1-Cre;Tgfb2+/- ? P 14-3-3 Tgf-b2 Tgf-b2 Cleft palate Cleft palate

  7. Haploinsufficiency of Tgfb2 rescues cleft palate in Wnt1-Cre;Tgfbr2fl/fl mice Wt Tgfbr2fl/fl;Wnt1-Cre Tgfbr2fl/fl;Wnt1-Cre;Tgfb2+/- A Normal: Cleft palate: 105/105 (100 %) 0/106 (0 %) 0/16 (0 %) 16/16 (100 %) 15/15 (100 %) 0/15 (0 %) B Wt Tgfbr2fl/fl;Wnt1-Cre Tgfbr2fl/fl;Wnt1-Cre;Tgfb2+/-

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