The Effects of CFTR Deficiency on Metabolic Bone Disease

CFTR 缺乏对代谢性骨疾病的影响

• 批准号: 8672636
• 负责人: Michael Shane Stalvey
• 金额: $ 15.01万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-08 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8672636
• 关键词: Address; Awareness; Belief; Bone Density; Bone Diseases; Bone Marrow; Bone Resorption; Bone remodeling; Caring; Cell physiology; Cells; Childhood; Clinical; Clinical Research; Comprehension; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Defect; Development; Disease; Endocrine; Endocrine System Diseases; Evolution; Future; Gene Delivery; Genes; Growth; Growth Factor; Homozygote; Human; In Vitro; Incidence; Individual; Inflammation; K-Series Research Career Programs; Knock-in Mouse; Knock-out; Knockout Mice; Laboratories; Life Expectancy; Lymphocyte; Measures; Mentors; Metabolic Bone Diseases; Metabolism; Minerals; Modeling; Mus; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Pathogenesis; Phenotype; Physicians; Process; Regulation; Research; Research Proposals; Residual state; Role; Secondary to; Stimulus; Subfamily lentivirinae; Testing; Time; TimeLine; Training; Work; bone; bone cell; bone health; bone metabolism; bone turnover; cell type; impression; improved; in vivo; insight; mRNA Expression; nutrition; performance tests; protein expression; skeletogenesis

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.

描述（由申请人提供）：作为一名儿科内分泌领域训练有素的医生，我的临床和研究专业方向是与囊性纤维化 (CF) 相关的内分泌疾病。这项工作是实验室和临床环境中多年自我指导和指导培训的产物。正是通过这些努力，我收集了支持这一提议的证据。 最近的数据表明，囊性纤维化跨膜电导调节器（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确定 CFTR 的发现相呼应。 CF 具有明显的骨质疏松症发病率。此外，随着预期寿命的延长，患病率也随之增加。尽管已经确定和探索了这一观察结果背后的有限数量的潜在机制，但其发病机制仍然很大程度上未知。 我们相信，骨代谢缺陷的存在继发于 CFTR 功能的缺失。在该模型中，所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，例如在临床 CF 和 Cftr 缺陷 (Cftr-/-) 小鼠中发现的合成代谢刺激的缺乏，将导致骨矿物质疾病状况恶化并使其恶化。 为了确定 CFTR 与骨矿物质疾病的关系，我们将检验以下假设：CFTR 的缺失会干扰负责骨代谢的细胞的正常进化和功能。这一假设将通过三个具体目标的表现来检验。第一个目标是解决 CFTR 对 Cftr 缺陷小鼠基线时成骨细胞和破骨细胞活性的影响。第二个目标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敲除来确定孤立的 CFTR 缺陷的影响。第三个目标是通过骨髓移植在成骨细胞和破骨细胞水平上进行校正后，进一步描述 CFTR 缺陷的系统作用。 拟议的职业发展奖将为我在代谢性骨病领域开展工作提供必要的时间分配和额外培训。此外，拟议的计划将为了解 CF 骨病和 CFTR 对骨代谢的影响奠定不可或缺的基础。