Growth Plate Cellular Function Following Radiotherapy

放射治疗后生长板细胞功能

• 批准号: 6923084
• 负责人: TIMOTHY A DAMRON
• 金额: $ 25.84万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6923084
• 关键词: DNA repair; X ray; apoptosis; cell proliferation; chemoprevention; chondrocytes; epiphysis; fibroblast growth factor; free radical scavengers; genetic markers; immunocytochemistry; interleukin 1; laboratory rat; limbs; nonhuman therapy evaluation; parathyroid hormone related protein; pharmacokinetics; radiation protection; radiography; radioprotective agents; transforming growth factors; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Radiotherapy is employed as adjunctive treatment for childhood malignancies, but its use in a growing limb frequently results in crippling limb length discrepancy or angular deformity. Our initial work has established an in vivo model for radiation effects on the growth plate and documented sparing of growth plate function by fractionation and the radioprotectants amifostine [WR-2721], pentoxifylline, misoprostol, selenium, and IL-1a. Even used in combination, these pre-radiation treatments have provided incomplete reversal of the damaging effects of irradiation. Our studies using in vivo immunohistochemical, histomorphometric, and stereologic techniques have suggested that the potential for recovery following growth plate injury is driven by PTHrP primarily, and by FGF2 and TGF-b secondarily. This results initially in accumulation of matrix followed closely by appearance of regenerative proliferative clones, the restoration of which appears to be directly related to reduction of limb length discrepancy. However, the potential for further improvements in growth plate radiation recovery appears to lie in combining radioprotectant with radiorecovery approaches, and the latter has not been investigated in the growth plate. Our first specific aim is to use laser microdissection and molecular biology techniques to test the hypotheses that growth plate radiorecovery is driven initially by PTHrP with its downstream signaling cascade and that the consequent regenerative clones are comprised of normally functioning chondrocytes derived from reserve zone chondrocytes. Our second specific aim is to test both in vitro and in vivo the hypothesis that stimulating the depressed PTHrP axis after radiotherapy will improve growth plate recovery. The third specific aim is to test the hypothesis that combination therapy using radioprotection and radiorecovery strategies will provide significantly better growth plate function than either strategy alone. The long term objectives of this project are to identify a combination strategy of radioprotection and radiorecovery that will act by complementary mechanisms upon the growth plate to maintain as close to normal growth plate function as possible during needed radiotherapy treatment.

描述（由申请人提供）：放射治疗被用作儿童恶性肿瘤的辅助治疗，但其在日益增长的肢体中的使用经常导致肢体长度差异或角度畸形。 我们的最初工作已经建立了一种体内模型，用于对生长板的辐射效应，并通过分离和放射治疗剂amifostine [WR-2721]，五氧化磷脂，米索前列醇，硒和IL-1A证明了生长板功能的保留。 即使是结合使用，这些预辐射治疗也提供了不完全逆转辐射的破坏作用。 我们使用体内免疫组织化学，组织形态和立体学技术的研究表明，生长板损伤后的恢复潜力主要由PTHRP驱动，第二次由FGF2和TGF-B驱动。 这最初导致矩阵的积累紧随其后的是再生增殖克隆，其恢复似乎与肢体长度差异的减少直接相关。 然而，进一步改善生长板辐射回收的潜力似乎在于将放射保护剂与放射性发现方法相结合，而后者尚未在生长板中进行研究。 我们的第一个具体目的是使用激光显微解剖和分子生物学技术来检验假设，即生长板放射发现最初是由PTHRP驱动的，其下游信号传导级联反应，随之而来的再生克隆由正常正常运行的软骨细胞源自储备区域内侧的软骨细胞。 我们的第二个具体目的是测试体外和体内的假设，即放射治疗后刺激抑郁的PTHRP轴将改善生长板的恢复。 第三个具体目的是检验以下假设：使用放射保护和放射线发现策略的组合治疗将比单独的任何一种策略提供明显更好的生长板功能。 该项目的长期目标是确定一种放射保护和放射线发现的组合策略，该策略将通过互补的机制在生长板上起作用，以在所需的放射治疗期间保持尽可能接近正常生长板的功能。