The Mechanism of Excess Neural Crest-Derived Craniofacial Bone Formation in a Mou

描述（由申请人提供）：结节性硬化症（TSC）是一种以多器官存在良性先天性肿瘤为特征的遗传性疾病，由TSC1和TSC2两个基因之一的突变引起。TSC的骨性病变以骨骼和颅面骨的骨硬化改变为特征。TSC骨性病变的机制以及mTOR信号对骨代谢的调节机制尚不清楚。我们发现，在神经嵴来源的细胞中，TSC1 （mTOR信号的负调节因子）的条件缺失导致神经嵴来源的颅面骨量的终身积累。我们提出的研究的长期目标是了解调节生理和病理骨代谢的信号转导机制。拟议项目有两个具体目标：目标1。确定TSC/ mtorc1信号调控骨生长的细胞机制。我们将确定TSC1缺失后mTORC1活性的改变；确定雷帕霉素的表型修复机制；确定导致骨生长异常的细胞功能改变；目标2。确定TSC/mTORC1信号在多大程度上调节成骨细胞能量代谢。我们将确定mTORC1信号增强对成骨细胞线粒体生物发生的影响；确定活性氧（ROS）是否在mTORC1调控成骨细胞功能中发挥作用。健康相关性：TSC影响美国多达25,000至50,000人，全球约有100至200万人。TSC的骨性表现非常常见（超过60%）。本研究不仅对确定TSC的骨性病变机制和TSC的治疗有价值，而且还使我们能够定义新的骨获取信号，这对于开发治疗骨质疏松症等其他骨疾病的新疗法具有重要意义。

DESCRIPTION (provided by applicant): 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.