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Role of cellular metabolism in palate morphogenesis

细胞代谢在上颚形态发生中的作用

基本信息

批准号：
10398249
负责人：
Junichi Iwata
金额：
$ 36.68万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10398249
关键词：
7-dehydrocholesterol 7-dehydrocholesterol reductase Affect Cell Proliferation Cell membrane Cells Cholesterol Cholesterol Homeostasis Cilia Cleft Palate Clinical Complex Congenital Abnormality Craniofacial Abnormalities DNA Sequence Alteration Deformity Development Diagnosis Diet Embryo Environmental Risk Factor Erinaceidae Etiology Exhibits Foundations Gel Gene Expression Gene Expression Regulation Genes Genetic Human Impairment In Vitro Infant Knowledge Label Lead Limb structure Link Live Birth Lovastatin Mediating Membrane Mesenchymal Metabolic Metabolism MicroRNAs Micrognathism Morphogenesis Movement Mus Mutant Strains Mice Mutation Nose Palate Pathogenesis Patients Penetrance Pharmacology Phenocopy Phenotype Physiological Plant Roots Play Post-Transcriptional Regulation Post-Translational Protein Processing Pregnancy Prevalence Prevention Process Production Proteins Proteomics Ptosis Quantitative Reverse Transcriptase PCR Rab8 protein Regulation Reverse Transcriptase Polymerase Chain Reaction Risk Factors Role S-Phase Fraction SHH gene SMO gene Severities Smith-Lemli-Opitz Syndrome Sterols Structure Syndrome Testing Tooth structure Untranslated RNA Up-Regulation Vesicle Work base cholesterol biosynthesis craniofacial craniofacial development desaturase enhanced green fluorescent protein experimental study in vivo inhibitor innovation lathosterol malformation mutant novel strategies overexpression palatogenesis protein expression public health relevance rab11 protein receptor smoothened signaling pathway sonic hedgehog receptor transcriptome sequencing

项目摘要

Project Abstract Cleft palate is one of the most common congenital birth defects, with a prevalence of 1/700 live births worldwide. Human linkage studies have shown that either genetic mutations related to cholesterol metabolism or abnormal maternal cholesterol diets lead to craniofacial deformities such as cleft palate. However, it is largely unknown how disturbances in cholesterol production result in cleft palate. In our preliminary studies, we found that mice with loss of sterol-C5-desaturase (Sc5d) displayed cleft palate with complete penetrance through decreased cell proliferation during palate formation. Sonic hedgehog (SHH) signaling, which is crucial for normal palate formation, was compromised in Sc5d mutant mice. The primary cilium, an antenna-like structure receiving hedgehog signals on the plasma membrane, was deformed in palatal mesenchymal cells of Sc5d mutant mice. We also found that posttranscriptional protein modification and expression of non-coding RNAs was altered in the palate of Sc5d mutant mice. Interestingly, while cholesterol synthesis is inhibited similarly in mice deficient for the 7-dehydrocholesterol reductase (Dhcr7) gene, which is crucial for cholesterol synthesis right after SC5D, these mice display cleft palate with a penetrance lower than 10%. Based on this foundation, in this project we will test the hypothesis that lathosterol, a cholesterol precursor that is elevated in Sc5d mutant mice, plays crucial roles in the pathogenesis of cleft palate. We have three specific aims; (1) To determine how a specific cholesterol intermediate interferes with SHH signaling by testing how lathosterol, a cholesterol intermediate accumulated in Sc5d mutant mice, interferes with hedgehog receptor movement and primary cilium formation; (2) To identify altered proteins and modifications in the developing palate of Sc5d mutant mice by conducting proteomic analyses using the palate of Sc5d mutant, Dhcr7 mutant, and control mice; (3) To identify non-coding RNAs and their regulated genes influenced by impaired cholesterol metabolism through analysis of the regulatory mechanism(s) of microRNAs (short non-coding RNAs) and their regulation of genes associated with cleft palate that are specifically altered in Sc5d mutant mice. Building on our strong preliminary work, we expect this study will systematically investigate the roles of cholesterol metabolism (at the cellular, metabolic, proteomic, and post- transcriptional regulation levels) in cleft palate in mice, and the results will lead to innovations in the prevention, diagnosis, and treatment of cholesterol-related craniofacial birth defects.

项目摘要