GROWTH PLATE CELLULAR FUNCTION FOLLOWING RADIOTHERAPY

放射治疗经常被用作儿童骨和软组织恶性肿瘤的连续治疗，但其用于生长肢体经常导致致残肢体长度差异或成角畸形。 很少有人知道生长板的功能，在面对单独的放射治疗，甚至更少关于辐射防护策略的影响。 我们在大鼠中的初步工作记录了通过分级分离和通过放射防护剂氨磷汀（WR-2721）的额外保留来保留生长板功能。我们研究小组的成员已经将正常大鼠生长板的差异生长定义为软骨细胞动力学的多个参数的函数，但这种分析尚未用于辐照生长板的研究。 我们在动物模型中的初步组织形态学研究表明，生长板的照射导致几个事件的假设：短暂减少的生长和增殖，早期软骨细胞凋亡，通过增加基质产生维持一些骨生长，以及随后的活跃增殖细胞克隆的回归-所有这些都可以通过放射防护剂治疗来改善。第一个具体的目的是通过测量软骨细胞动力学和关键的免疫组织化学标记物在生长板中使用我们建立的单侧后肢X射线照射模型，在生长的大鼠，以测试上述机制的假设。第二个具体的目的，使用相同的研究设计，是测试的假设，即自由基清除剂氨磷汀维持增殖和减少凋亡时，立即给予照射前，它的作用与剂量分级的加性方式。 第三个具体目标是检验以下假设：米索前列醇（一种已知可改善DNA修复的辐射防护剂）和IL-1（一种已知可诱导原始祖细胞循环的辐射防护剂）将各自通过一种独特的机制（与分级分离和氨磷汀的机制不同，并具有相加作用）导致生长板免受辐射的保护。该项目的长期目标是确定辐射防护剂，其作用于生长板的不同和互补的机制，以测试这些辐射防护剂与分割相结合，从而制定策略，最终允许更安全和更有效的放射治疗生长中的儿童恶性肿瘤。

Radiotherapy is frequently employed as adjunctive treatment for childhood bone and soft-tissue malignancies, but its use in a growing limb frequently results in crippling limb length discrepancy or angular deformity. Little is known regarding growth plate function in the face of radiotherapy alone and even less regarding the effects of radioprotectant strategies. Our preliminary work in rats documented sparing of growth plate function by fractionation and additional sparing by the radioprotectant amifostine (WR-2721). Members of our research team have defined the differential growth of the normal rat growth plate as a function of multiple parameters of chondrocyte kinetics, but this analysis has not been used in the study of the irradiated growth plate. Our initial histomorphometric studies in an animal model suggest the hypothesis that irradiation of the growth plate results in several events: transiently decreased growth and proliferation, early chondrocyte apoptosis, maintenance of some bone growth by increased matrix production, and subsequent return of actively proliferating cellular clones --all of which can be improved by radioprotectant treatment. The first specific aim is to test the above mechanistic hypothesis by measuring chondrocyte kinetics and key immunohistochemical markers in the growth plate using our established unilateral hind limb x-irradiation model in the growing rat. The second specific aim, using the same research design, is to test the hypothesis that the free radical scavenger amifostine maintains proliferation and decreases apoptosis when given immediately preceding irradiation, and that it acts in an additive fashion with dose fractionation. The third specific aim is to test the hypotheses that misoprostol (a radioprotectant known to improve DNA repair) and IL-1 (a radioprotectant known to induce cycling of primitive progenitor cells) will each result in growth plate protection from irradiation by a mechanism unique from and additive to that of fractionation and amifostine. The long-term objectives of this project are to identify radioprotectants, which act by different and complementary mechanisms upon the growth plate, to test these radioprotectants in combination with fractionation and thereby develop strategies that will ultimately permit safer and more effective radiotherapy for malignancies in the growing child.