DEVELOPMENT OF A TREATMENT FOR OSTEOGENESIS IMPERFECTA

本研究的目的是使用动物模型来测试用于治疗被称为成骨不全（OI）的一类骨疾病的方法。在这些疾病中，患者在编码I型胶原蛋白的基因中具有许多可能的突变之一。这导致产生异常的I型胶原蛋白分子，或这种结构蛋白的量不足，或两者兼而有之。在任何情况下，患者的骨组织都可能显著弱化。这会导致骨折，原因是（1）骨材料变弱，以及（2）骨试图通过重塑进行自我修复而产生的过度孔隙。OI患者只能通过纠正他们的基因组来治愈，这是一个即将出现的前景，但不太可能很快影响到许多患者。与此同时，我们提出，通过控制骨建模和重建过程，以补偿和抑制对胶原蛋白缺陷的负面反应，可以在儿童中实现这种疾病的实质性改善。我们建议用于此目的的药物是阿仑膦酸盐，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，使青少年OI患者受益，从而产生更大的骨骼，以补偿皮质内的脆弱物质。 然而，不幸的是，阿仑膦酸钠也可能干扰患者的生长，并在骨骼发育方面产生负面和正面的影响。具体目的是1）使用oim转基因小鼠模型来测试这种治疗方法并详细阐明其机制，2）确定阿仑膦酸钠在儿童中的使用是否会对其生长产生负面影响。

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.