Tuberous sclerosis (TSC) is a genetic disorder characterized by the presence of benign congenital tumors in multiple organs and is caused by mutations in one of two genes, called TSC1 and TSC2. Osseous lesions in TSC are characterized by osteosclerotic changes in skeletal and craniofacial bones. The mechanisms underlying the osseous lesions in TSC and the regulation of bone metabolism by mTOR signaling is still unknown. We found that conditional deletion of TSC1, a negative regulator of mTOR signaling, in neural crest- derived cells led to lifelong accumulation of neural crest-derived craniofacial bone mass. The long-term goal of our proposed studies is to understand the signal transduction mechanisms that regulate physiological and pathological bone metabolism. There are two specific aims of the proposed project:
Aim 1. Determine the cellular mechanisms by which TSC/mTORC1signaling regulates bone growth. We will determine the mTORC1 activity alteration in response to TSC1 deletion;determine the mechanisms of phenotype rescue by rapamycin;determine the cellular function alterations that are responsible for the aberrant bone growth;
Aim 2. Determine to what extent TSC/mTORC1 signaling regulates osteoblast energy metabolism. We will determine the effects of enhanced mTORC1 signaling on mitochondria biogenesis in osteoblasts;determine whether reactive oxygen species (ROS) plays a role in the mTORC1 regulation of osteoblast function. Health relevence: TSC affects as many as 25,000 to 50,000 individuals in the United States and about 1 to 2 million individuals worldwide. Osseous manifestations of TSC are very frequent (more than 60%). The proposed study is not only valuable for determining the mechanisms of osseous lesion of TSC and benefit the treatment of TSC, it also allows us to define novel bone acquisition signals, which are fundamentally important for the development of new therapeutics to treat other bone diseases such as osteoporosis.

Public Health Relevance

Tuberous sclerosis (TSC) is a genetic disorder characterized by the presence of benign congenital tumors in multiple organs and is caused by mutations in one of two genes, called TSC1 and TSC2. Skeletal and craniofacial bone lesions are present in more than two thirds of the TSC patients. This proposed project will elucidate the mechanisms of the bone lesions in TSC patients. The pathways and mechanisms identified can be potentially utilized for the future novel treatment of bone lesions in TSC as well as osteoporosis patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Small Research Grants (R03)
Project #
5R03DE021718-02
Application #
8235804
Study Section
NIDCR Special Grants Review Committee (DSR)
Program Officer
Wan, Jason
Project Start
2011-04-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$116,625
Indirect Cost
$41,625
Name
University of Michigan Ann Arbor
Department
Biology
Type
Schools of Dentistry
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109