The Effects of CFTR Dysfunction on Bone Formation

CFTR 功能障碍对骨形成的影响

• 批准号: 8174018
• 负责人: Marie E Egan
• 金额: $ 22.34万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8174018
• 关键词: Address; Adult; Age; Age-Years; Anabolic Agents; Animals; Architecture; Biological Preservation; Bone Density; Bone Diseases; Calcium; Cell Lineage; Cell membrane; Child; Chronic; Chronic Disease; Complex; Confounding Factors (Epidemiology); Consensus; Cultured Cells; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Defect; Dependence; Deposition; Development; Diabetes Mellitus; Disease; Evidence based intervention; Evolution; Fracture; Functional disorder; Generations; Glucocorticoids; Gonadal Steroid Hormones; Guidelines; Homeostasis; Human; Immunohistochemistry; In Situ Hybridization; In Vitro; Individual; Infection; Inflammation; Intervention Trial; Laboratories; Lesion; Lung diseases; Malnutrition; Minerals; Modeling; Morbidity - disease rate; Mus; Nature; Osteoblasts; Osteoclasts; Osteogenesis; Osteomalacia; Osteoporosis; Pancreatic Diseases; Parathyroid gland; Patch-Clamp Techniques; Pathogenesis; Pharmaceutical Preparations; Phenotype; Play; Practice Guidelines; Prevalence; Prevention; Primary Lesion; Process; Quality of life; Research Project Grants; Reverse Transcriptase Polymerase Chain Reaction; Role; Screening procedure; Secondary to; Serum Markers; Signal Transduction; Skeleton; Somatotropin; Staging; Supplementation; Vitamin D; aerosolized; base; bisphosphonate; bone; bone cell; bone health; bone mass; bone quality; bone turnover; cell type; cystic fibrosis patients; density; hormone deficiency; human disease; improved; mineralization; skeletal

DESCRIPTION (provided by applicant): Median survival for people with Cystic Fibrosis (CF) has increased to >35 years of age. As more CF patients survive well into adulthood poor bone quality has emerged as a challenging burden of this chronic disease. Low bone density and increased fracture rates in CF are well-documented but poorly understood. Although the prevalence for CFBD (Cystic Fibrosis bone disease) is high in adults, it is also present in children. Despite its prevalence, CFBD remains minimally characterized and an understanding of its pathogenesis remains limited. Our major objective is to fully characterize CFBD in a murine model of cystic fibrosis at the structural and cellular level, as it has the potential to provide a deeper understanding of the pathogenesis of CFBD. Murine models of CF are particularly useful for assessing the direct role of CFTR in skeletal homeostasis as these animals do not have severe pulmonary or pancreatic disease. Preliminary data generated demonstrate that from as early as 3 weeks of age through adulthood, these cftr-/- animals have decreased bone mass which is characterized by thinner trabeculae, and thinner cortical bone, as well as, decreased bone volume and strength thus providing a model similar to human disease. We hypothesize that this CF model will manifest a complex bone lesion with low bone density and increased bone fragility similar to that which is observed in CF patients. It is likely that altered CFTR function in a number of bone cell lineages plays a central role in CFBD in humans. However, based on our initial studies we believe the lack of CFTR in the osteoblast is likely to be the primary problem with alterations in osteoclast function a secondary consequence of inflammation. By employing in situ hybridization, RT-PCR, and immunohistochemistry as well as standard patch clamp techniques, the functional role of CFTR in osteoblasts and osteoclasts will be examined. In addition osteoblasts and osteoclasts will be examined in vitro to determine which cell type is responsible for the primary lesion. Lastly we will use a repetitive aerosolized LPS model to determine if chronic inflammation augments the skeletal phenotype of CFBD in the murine model by quantifying bone density and micro-architecture cellular activity using static and dynamic bone histomorphometry and serum markers of bone turnover. By clarifying the exact nature and evolution of the low BMD, and elucidating whether there is a primary defect in bone cell activity, more evidence-based intervention trials can be undertaken to address prevention and management of CFBD. With a stronger, healthier skeleton, the quality of life of patients with CF can be improved. PUBLIC HEALTH RELEVANCE: This research project, which aims to fully characterize cystic fibrosis bone disease (CFBD) in murine models of cystic fibrosis at the structural and cellular levels, has the potential to provide a deeper understanding of the pathogenesis of CFBD. By clarifying the exact nature and evolution of the low bone mass density and elucidating the contribution of the osteoblast and osteoclast to the disease process, more focused intervention trials can be done to address prevention and management of CFBD. The idea that the lack of functionally CFTR in either the osteoblast or osteoclast contributes directly to the observed bone disease is a shift in the current CF related bone disease paradigm.

描述（由申请人提供）：囊性纤维化患者（CF）的中位存活率已增加到> 35岁。随着越来越多的CF患者在成年期生存下来，骨质质量较差已成为这种慢性疾病的挑战负担。 CF的低骨密度和骨折率增加是有据可查的，但了解不足。尽管成人的CFBD（囊性纤维化骨疾病）的患病率很高，但它也存在于儿童中。尽管CFBD的流行率仍然很少，但对其发病机理的理解仍然有限。我们的主要目的是在结构和细胞水平的囊性纤维化鼠模型中充分表征CFBD，因为它有可能深入了解CFBD的发病机理。 CF的鼠模型对于评估CFTR在骨骼稳态中的直接作用特别有用，因为这些动物没有严重的肺部或胰腺疾病。产生的初步数据表明，从最早的3周到成年期，这些CFTR - / - 动物的骨骼质量减少，其特征是小梁较薄，皮质骨较薄，骨体积和强度降低，从而提供了一种。类似人类疾病的模型。我们假设该CF模型将表现出一个复杂的骨病变，其骨密度低，并且骨骼脆弱性的增加与CF患者中观察到的相似。许多骨细胞谱系中的CFTR功能可能改变的CFTR功能在人类的CFBD中起着核心作用。但是，根据我们的初步研究，我们认为成骨细胞中缺乏CFTR可能是破骨细胞功能改变的主要问题，这是炎症的次要结果。通过采用原位杂交，RT-PCR和免疫组织化学以及标准的贴片夹技术，将检查CFTR在成骨细胞和破骨细胞中的功能作用。另外，将在体外检查成骨细胞和破骨细胞，以确定哪种细胞类型负责原发性病变。最后，我们将使用重复的雾化LPS模型来确定慢性炎症是否通过使用静态和动态骨骼组态和动态骨骼形态和骨骼更换的血清标记来量化鼠模型中CFBD的骨骼表型。通过阐明低BMD的确切性质和演变，并阐明骨细胞活性中是否存在主要缺陷，可以进行更多基于证据的干预试验来解决CFBD的预防和管理。凭借更强，更健康的骨骼，可以改善CF患者的生活质量。 公共卫生相关性：该研究项目旨在在结构和细胞水平的囊性纤维化鼠模型中充分表征囊性纤维化骨病（CFBD），具有更深入地了解CFBD发病机理的潜力。通过阐明低骨质量密度的确切性质和演变，并阐明成骨细胞和破骨细胞对疾病过程的贡献，可以进行更集中的干预试验，以解决CFBD的预防和管理。成骨细胞或破骨细胞中缺乏功能性CFTR的想法直接导致观察到的骨骼疾病，这是当前CF相关骨病范式的转变。