Growth Plate Cellular Function Following Radiotherapy

放射治疗后生长板细胞功能

基本信息

批准号：
7214629
负责人：
TIMOTHY A DAMRON
金额：
$ 24.5万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-12-01 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7214629
关键词：
Amifostine Apoptosis Appearance Biomechanics Bone Density Bromodeoxyuridine Cell physiology Cells Characteristics Child Childhood Chondrocytes Combined Modality Therapy Contralateral Cultured Cells Deformity Depressed mood Derivation procedure Differentiation and Growth End Point Ensure Epiphysial cartilage FGF2 gene Fibroblast Growth Factor 2 Fractionation Growth Growth Factor Immunohistochemistry In Situ Hybridization In Vitro Injury Label Lasers Length Limb structure Malignant Neoplasms Mediator of activation protein Microdissection Misoprostol Mitogens Modeling Molecular Biology Techniques PTHLH gene Parathyroid Hormones Pathway interactions Pentoxifylline Physiologic pulse Polymerase Chain Reaction Pulse taking Radiation Radiation therapy Radiation, Other Radioprotection Rate Recovery Research Personnel Reverse Transcriptase Polymerase Chain Reaction Selenium Signal Transduction Sprague-Dawley Rats Techniques Testing Time Tissues Week Work analog base bone cDNA Arrays cytotoxicity improved in vivo in vivo Model irradiation mRNA Expression parathyroid hormone-related protein programs radiation effect radiation recovery restoration

项目摘要

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）：放射疗法被用作儿童恶性肿瘤的辅助治疗，但其在肢体生长中的使用经常导致严重的肢体长度差异或角度畸形。我们的初步工作建立了辐射对生长板影响的体内模型，并记录了通过分馏和辐射防护剂氨磷汀 [WR-2721]、己酮可可碱、米索前列醇、硒和 IL-1a 对生长板功能的保护。即使组合使用，这些预辐射处理也不能完全逆转辐射的破坏作用。我们使用体内免疫组织化学、组织形态计量学和体视学技术的研究表明，生长板损伤后恢复的潜力主要由 PTHrP 驱动，其次由 FGF2 和 TGF-b 驱动。这最初导致基质积累，随后出现再生增殖克隆，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恢复的潜力似乎在于将辐射防护剂与辐射恢复方法相结合，而后者尚未在生长板中进行研究。我们的第一个具体目标是使用激光显微切割和分子生物学技术来测试以下假设：生长板放射恢复最初是由 PTHrP 及其下游信号级联驱动的，并且随后的再生克隆由来自保留区软骨细胞的正常功能软骨细胞组成。我们的第二个具体目标是在体外和体内测试以下假设：刺激放疗后抑制的 PTHrP 轴将改善生长板的恢复。第三个具体目标是检验以下假设：使用放射防护和放射恢复策略的联合治疗将比单独使用任一策略提供显着更好的生长板功能。该项目的长期目标是确定放射防护和放射恢复的组合策略，该策略将通过补充机制作用于生长板，以在所需的放射治疗期间尽可能保持接近正常的生长板功能。