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CF Bone Disease: Convergence of CFTR and PTH Signaling

CF 骨病：CFTR 和 PTH 信号传导的融合

基本信息

批准号：
8049169
负责人：
GREGORY A CLINES
金额：
$ 18.99万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8049169
关键词：
Animal Model Biological Assay Biology Bone Density Bone Diseases Bone remodeling Breeding Calvaria Cell membrane Chloride Ion Chlorides Chronic Chronic Disease Complex Complication Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Development Diabetes Mellitus Disease Disease Management Endocytosis Epidemiology Fracture G-Protein-Coupled Receptors Goals Hereditary Disease Hormones Hypogonadism In Vitro Infection Intestinal Obstruction Investigation Knockout Mice Kyphosis deformity of spine Life Link Lung Lung Inflammation Lung diseases Malnutrition Medical Modeling Mus Organ Culture Techniques Osteoblasts Osteoclasts Osteogenesis Parathyroid Hormone Receptor Parathyroid gland Patients Phenotype Prevalence Research Risk Role Series Signal Pathway Signal Transduction Testing Therapeutic Tumor necrosis factor receptor 11b Vitamin D Deficiency bone bone mass bone turnover cystic fibrosis patients disease-causing mutation high risk hormone therapy improved in vivo knockout animal member novel osteoblast differentiation osteoclastogenesis pre-clinical public health relevance receptor recycling response skeletal

项目摘要

DESCRIPTION (provided by applicant): Bone disease is a recently recognized complication of cystic fibrosis (CF), a recessive genetic disease caused by mutations in the cystic fibrosis transmembrane regulator (CFTR). CF bone disease results in low bone mineral density (BMD) and places patients at high risk for kyphosis and fracture. Other well-known complications of CF, chronic lung inflammation, malnutrition, vitamin D deficiency and hypogonadism, have all been proposed to cause CF bone disease. However, epidemiological investigations and knockout animal models now support a direct link between CFTR inactivation in bone and low BMD. We performed a series of preliminary studies investigating the biology of CFTR in bone. CFTR expression was expressed in the osteoblast and targeted CFTR inactivation reduced osteoblast-dependent new bone formation in vitro. Defective chloride conductance and secretory function are responsible for most CF-related diseases; however, our data indicate reduced bone formation from CFTR inactivation may originate from dysregulated parathyroid hormone (PTH) signaling. This exploratory proposal will investigate how CFTR regulates osteoblast function and PTH signaling. The first aim will examine the bone phenotype of mice with osteoblast and osteoclast-specific inactivation of CFTR. The second aim will examine whether CFTR inactivation disrupts parathyroid hormone receptor activation of osteoblast downstream signaling pathways. The last aim will test the bone anabolic effects of PTH in a preclinical therapeutic model of CF bone disease. PUBLIC HEALTH RELEVANCE: The impact of cystic fibrosis bone disease is expected to increase as cystic fibrosis patients are living longer due to improved lung disease management. This exploratory proposal will investigate a novel role of CFTR in regulating bone formation. Defining the mechanisms of CFTR in bone will further the development of targeted therapies to reduce cystic fibrosis-related fractures.

描述（由申请人提供）：骨病是最近认识到的囊性纤维化（CF）的并发症，囊性纤维化是一种隐性遗传疾病，由囊性纤维化跨膜调节因子（CFTR）突变引起。CF骨疾病导致低骨矿物质密度（BMD），并使患者处于脊柱后凸和骨折的高风险中。其他众所周知的CF并发症，慢性肺部炎症，营养不良，维生素D缺乏症和性腺功能减退症，都被认为是导致CF骨病的原因。然而，流行病学调查和基因敲除动物模型现在支持骨中CFTR失活和低BMD之间的直接联系。我们进行了一系列的初步研究，调查骨中CFTR的生物学。CFTR在成骨细胞中表达，靶向CFTR失活减少了体外成骨细胞依赖性新骨形成。氯离子传导和分泌功能缺陷是大多数CF相关疾病的原因;然而，我们的数据表明，CFTR失活导致的骨形成减少可能源于甲状旁腺激素（PTH）信号转导失调。这项探索性提案将研究CFTR如何调节成骨细胞功能和PTH信号传导。第一个目标是检查成骨细胞和破骨细胞特异性CFTR失活的小鼠的骨表型。第二个目的是检查CFTR失活是否破坏了成骨细胞下游信号通路的甲状旁腺激素受体激活。最后一个目的是在CF骨病的临床前治疗模型中测试PTH的骨合成代谢作用。公共卫生关系：囊性纤维化骨病的影响预计将增加，因为囊性纤维化患者由于肺部疾病管理的改善而活得更长。这个探索性的提议将研究CFTR在调节骨形成中的新作用。明确骨中CFTR的机制将进一步发展靶向治疗以减少囊性纤维化相关骨折。