The Effects of CFTR Deficiency on Metabolic Bone Disease

描述（由申请人提供）：作为儿科内分泌领域的训练有素的医生，我将我的临床和研究专业化为囊性纤维化（CF）相关的内分泌疾病。这项工作是多年来在实验室和临床环境中自我指导和指导培训的产物。正是通过这些努力，我收集了支持这一建议的证据。 最近的数据表明囊性纤维化跨膜传导调节因子（CFTR）缺陷小鼠的骨代谢存在潜在缺陷。这与最近在负责人类骨代谢的细胞中鉴定CFTR的发现相呼应。CF具有显著的骨质疏松症发病率。此外，随着预期寿命的增加，疾病发病率也在增加。虽然已经确定和探索了有限数量的潜在机制，但其发病机制在很大程度上仍然未知。 我们认为骨代谢缺陷继发于CFTR功能缺失。在该模型中，提出的作用机制涉及负责骨转换的细胞的分化和调节;即成骨细胞和破骨细胞。该模型还承认其他影响，如在临床CF和Cftr缺陷（Cftr-/-）小鼠中发现的合成代谢刺激物的缺乏，将导致骨矿物质疾病特征恶化。 为了确定CFTR与骨矿物质疾病的关系，我们将检验CFTR的缺失干扰负责骨代谢的细胞的正常进化和功能的假设。这一假设将通过三个具体目标的实现来检验。第一个目的是解决CFTR缺陷小鼠中CFTR对成骨细胞和破骨细胞在基线时的细胞活性的影响。第二个目的是通过在成骨细胞和破骨细胞中使用CFTR细胞类型特异性条件性敲除来确定孤立的CFTR缺陷的贡献。第三个目的进一步阐明CFTR缺陷的全身作用，通过骨髓移植在成骨细胞和破骨细胞水平进行校正后。 这个提议的职业发展奖将提供必要的时间分配和额外的培训，以启动我的工作进入代谢性骨病领域。此外，拟议的计划将为理解CF骨病和CFTR对骨代谢的影响奠定不可或缺的基础。

DESCRIPTION (provided by applicant): As a trained physician in the field of pediatric endocrine, I have directed my clinical and research specialization on the endocrine disorders associated with cystic fibrosis (CF). This work is the product of multiple years of self-directed and mentored training in both the laboratory and clinical setting. It is through these efforts that I have collected evidence to support this proposal. Recent data suggests that an underlying defect exists in bone metabolism of cystic fibrosis transmembrane conductance regulator (CFTR) deficient mice. This echoes recent findings identifying CFTR in cells responsible for human bone metabolism. CF has a pronounced incidence of osteoporosis. Additionally, this increased disease rate has grown as the life expectancy increased. Although a limited number of potential mechanisms underlying this observation have been identified and explored, its pathogenesis remains largely unknown. It is our belief that defects in bone metabolism exist secondary to absence of CFTR function. Within this model, the proposed mechanism of action involves differentiation and regulation of cells responsible for bone turnover; namely osteoblasts and osteoclasts. The model also concedes other influences, such as absence of anabolic stimuli found in both clinical CF and the Cftr-deficient (Cftr-/-) mouse, would contribute and worsen the bone mineral disease profile. To identify involvement of CFTR in relation to bone mineral disease, we will test the hypothesis that the absence of CFTR interferes with normal evolution and function of cells responsible for bone metabolism. This hypothesis will be tested by performance of three specific aims. The first aim addresses the impact of CFTR on osteoblast and osteoclast cellular activity at baseline in Cftr-deficient mice. The second aim determines the contribution of isolated CFTR deficiency, through use of a CFTR cell type-specific conditional knockout in osteoblasts and osteoclasts. The third aim further delineates the systemic role of CFTR deficiency, after correction at the osteoblast and osteoclast level through bone marrow transfer. This proposed career development award will provide the necessary time allotment and additional training to launch my work into the field of metabolic bone disease. Additionally, the proposed plan will lay indispensable groundwork into the understanding of CF bone disease and the impact of CFTR on bone metabolism.