DEVELOPMENT OF A TREATMENT FOR OSTEOGENESIS IMPERFECTA

这项研究的目标是使用动物模型来测试一种治疗一种被称为成骨不全(OI)的骨骼疾病的方法。在这些疾病中，患者编码L胶原蛋白的基因可能存在众多突变之一。这会导致L型胶原分子的异常产生，或者这种结构蛋白的数量不足，或者两者兼而有之。在任何情况下，患者的骨组织都可能出现实质性的软化。这会导致骨折，原因是(1)骨骼材料变弱，以及(2)骨骼试图通过重塑修复自身而产生过多的孔洞。OI患者只能通过纠正他们的基因组来治愈，这一前景即将出现，但不太可能很快影响到许多患者。同时，我们认为，通过控制骨骼的建模和重塑过程，以补偿和抑制对胶原蛋白缺陷的负面反应，儿童的这种疾病可以得到实质性的改善。我们建议使用的药物是阿伦磷酸钠，一种阻止骨吸收的双膦酸盐。这种药物可以通过阻断患者长骨干骺端表面的正常吸收过程，从而产生更大的骨骼，弥补皮质内薄弱的物质，从而使青少年OI患者受益。然而，不幸的是，阿伦磷酸钠也可能会干扰患者的生长，并在骨骼发育方面产生积极和消极的影响。具体目的是1)使用OIM转基因小鼠模型测试这种治疗方法并详细阐明其机制，2)确定儿童使用阿伦磷酸钠是否会对他们的生长产生负面影响。

The goal of this study is to use an animal model to test a method for treating a class of bone diseases known as osteogenesis imperfecta (OI). In these disorders, the patient has one of numerous possible mutations in the genes that code for Type l collagen. This results in the production of abnormal Type l collagen molecules, or insufficient amounts of this structural protein, or both. In any case, there can be substantial weakening of the patient's bone tissue. This leads to fractures caused by (1) the weakened bone material, and (2) excessive porosity produced by the bone's attempt to repair itself by remodeling. OI patients can only be cured through correction of their genome, a prospect on the horizon but unlikely to affect many patients soon. In the meantime, we propose that substantial amelioration of this disease can be achieved in children by controlling the bone modeling and remodeling processes so as to compensate for, and restrain negative responses to, the collagen defect. The agent we propose to use for this purpose is alendronate, a bisphosphonate that blocks bone resorption. This drug could benefit the juvenile OI patients by blocking the normal resorptive process on the metaphyseal surfaces of the patient's long bones, resulting in larger bones that compensate for the weak material within the cortex. Unfortunately, however, it is also possible that alendronate could interfere with the growth of the patient and produce negative as well as positive effects in terms of skeletal development. The specific aims are to 1) use the oim transgenic mouse model to test this method of treatment and elucidate its mechanisms in detail, and 2) determine whether the use of alendronate in children will have negative effects of their growth.