Human linkage studies have shown that genetic mutations related to cholesterol metabolism and high maternal cholesterol diets result in craniofacial bone deformities, suggesting that cholesterol metabolic aberrations may be a widely conserved mechanism in craniofacial developmental defects. However, it is still largely unknown how altered cholesterol metabolism causes craniofacial bone abnormalities. Therefore, the objective of this application is to define how cholesterol metabolic aberrations, through disruption of either the Dhcr7 gene (which encodes an enzyme involved in the last step of cholesterol synthesis and is the causative gene for Smith-Lemli-Opitz syndrome) or the Insig1 and Insig2 genes (which provide instructions for endoplasmic reticulum proteins that regulate lipid biosynthesis), cause osteoblast (OB) differentiation abnormalities, and to test the functional significance of downstream target molecules during craniofacial bone formation. The long- term goal of this project is to gain insight into the mechanisms of craniofacial bone formation and provide new medications and diagnostic tools for bone diseases. We will test our working hypothesis by using mouse genetics and cellular biology approaches. In our preliminary studies, we found that: 1) impaired cholesterol synthesis resulted in accelerated bone formation; 2) excess cholesterol synthesis resulted in decreased bone formation; 3) the formation of primary cilia, which play a crucial in sensing cell signals, was altered in OBs from Dhcr7 knockout (KO) and neural crest specific Insig1/2 conditional knockout (cKO) mice; 4) WNT signaling was altered in Dhcr7 KO and Insig1/2 cKO mice; and 5) normalization of cholesterol metabolic aberrations restored craniofacial bone defects in Dhcr7 KO and Insig1/2 cKO mice. Our hypothesis that proper cholesterol metabolism is crucial for normal craniofacial bone formation will be tested in the following specific aims: 1) to determine the role of cholesterol metabolism in craniofacial bone development; and 2) to determine the role of cholesterol metabolism in primary cilium formation in bone. This study will unravel a new mechanism of bone development and homeostasis and will lead to innovative methods of diagnosis, treatment, and prevention of skull deformities.

Public Health Relevance

Craniofacial skeletal defects are one of the most prominent genetic disorders. However, the etiology of these defects remains largely unclear. Our proposed study will provide a new insight into cholesterol metabolism in craniofacial skeletal development, and will hopefully have a significant impact on the therapeutics of various types of bone diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE026767-01
Application #
9288432
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Wan, Jason
Project Start
2017-04-01
Project End
2022-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
$365,750
Indirect Cost
$128,250
Name
University of Texas Health Science Center Houston
Department
Other Basic Sciences
Type
Schools of Dentistry
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77030
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