Etiology of cystic fibrosis bone disease

囊性纤维症(CF)患者的中位生存期已增加到约30岁。作为数量的 活到成年的人增加了，影响生活质量的疾病方面有 得到了突出的关注。一种这样的并发症是CFBD，其特征是 由于骨密度低和骨折发生率增加。慢性纤维性心脏病最基本的基因缺陷是功能丧失 Cf跨膜电导调节蛋白(CFTR)的突变-一种参与 许多细胞过程。然而，CFBD仍然具有最低限度的特征，并且对其 发病机制仍然有限。确定CFBD的病因存在固有的困难，因为 是多种因素，可以间接影响骨骼健康，通常存在于CF患者中。 然而，已发表的研究和我们的初步结果表明，CFTR功能丧失在 CFBD。 我们的研究目标是使用一种新的结构和细胞水平来表征CFBD 建立了肠道校正的CF小鼠模型。这些小鼠具有回肠杯状细胞的功能矫正和 隐窝细胞增生和cAMP刺激的氯化物分泌。因此，这种模式提供了一种独特的 寻找CF对骨骼的直接影响而不是吸收不良的混杂影响的机会 在先前的CFBD基因敲除小鼠模型中观察到。我们的具体目标是：1)描述骨骼的特征 活体CFBD的结构：2)确定体外骨骼改变的细胞机制； 以及3)确定CFTR在发育的哪个阶段在骨骼中表达和合成 原位杂交、逆转录-聚合酶链式反应和免疫组织化学。我们相信，我们的研究将导致 更深入地了解CFBD的病因，将导致有用的治疗干预措施。

Median survival for people with Cystic Fibrosis (CF) has increased to ~30 years of age. As the number of people surviving well into adulthood has increased, aspects of the disease which impact quality of life have received prominent attention. One such complication is CF bone disease (CFBD), which is characterized by low bone density and increased fracture rate. The fundamental gene defects in CF are loss of function mutations in the CF transmembrane conductance regulator protein (CFTR) - a chloride channel involved in many cellular processes. However, CFBD remains minimally characterized and an understanding of its pathogenesis remains limited. Identifying the etiology of CFBD presents inherent difficulties because there are multiple factors, which can indirectly impact bone health and are often present in CF patients. However, published studies and our preliminary results .suggest a primary role for CFTR loss of function in CFBD. Our research objective is to characterize CFBD at the structural and cellular levels using a newly developed gut-corrected CF mouse model. These mice have functional correction of ileal goblet cell and crypt cell hyperplasia and cAMP-stimulated chloride secretion. This model thus provides a unique opportunity to look for direct effects of CF on bone without the confounding effects of malabsorption observed in previous CFBD knock-out mice models. Our specific aims are to 1) characterize the skeletal structure of CFBD in vivo: 2) determine the cellular mechanism responsible for skeletal alterations in vitro; and 3) determine at what stage in development CFTR is expressed and synthesized in bone by utilizing in situ hybridization, RT-PCR, and immunohistochemistry. We believe that our research will result in a deeper understanding of the etiology of CFBD and will lead to useful therapeutic interventions.