Growth Plate Cellular Function Following Radiotherapy

放射治疗后生长板细胞功能

• 批准号: 7388969
• 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
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-20 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7388969
• 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

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预防性治疗，但其在生长肢体中的使用经常导致致残肢体长度差异或成角畸形。 我们的初步工作已经建立了生长板辐射效应的体内模型，并记录了通过分级和放射防护剂氨磷汀[WR-2721]、戊茶碱、米索前列醇、硒和IL-1a保留生长板功能。 即使联合使用，这些辐射前治疗也不能完全逆转辐射的破坏作用。 我们的研究使用在体内免疫组织化学，组织形态计量学，体视学技术表明，生长板损伤后的恢复的潜力是由PTHrP主要驱动，其次是由FGF 2和TGF-β。 这最初导致基质的积累，紧接着出现再生增殖性克隆，其恢复似乎与肢体长度差异的减少直接相关。 然而，生长板辐射恢复的进一步改善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生长板radiorecovery最初是由PTHrP及其下游信号级联驱动的假设，并且随后的再生克隆由来自储备区软骨细胞的正常功能的软骨细胞组成。 我们的第二个具体目标是在体外和体内测试的假设，刺激抑制PTHrP轴放疗后将改善生长板恢复。 第三个具体的目的是检验这一假设，即使用放射防护和放射恢复策略的联合治疗将提供比单独使用任何一种策略更好的生长板功能。 该项目的长期目标是确定一种辐射防护和辐射恢复的组合策略，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。

项目成果

Combinations of radioprotectants spare radiation-induced damage to the physis.

辐射防护剂的组合可以避免辐射对身体造成的损害。

• DOI: 10.1097/01.blo.0000131247.18112.0f
• 发表时间: 2004
• 期刊: Clinical orthopaedics and related research
• 影响因子: 4.2
• 作者: Damron,TimothyA;Spadaro,JosephA;Horton,JasonA;Margulies,BryanS;Strauss,JudithA;Farnum,CorneliaE
• 通讯作者: Farnum,CorneliaE

Connective tissue growth factor and insulin-like growth factor 2 show upregulation in early growth plate radiorecovery response following irradiation.

结缔组织生长因子和胰岛素样生长因子 2 在照射后的早期生长板放射恢复反应中表现出上调。

• DOI: 10.1159/000105673
• 发表时间: 2007
• 期刊: Cells, tissues, organs
• 作者: Wang,Yan;Zhang,Mingliang;Middleton,FrankA;Horton,JasonA;Pritchard,Meredith;Spadaro,JosephA;Farnum,CorneliaE;Damron,TimothyA
• 通讯作者: Damron,TimothyA

Precision and accuracy of DXA and pQCT for densitometry of the rat femur.

DXA 和 pQCT 用于大鼠股骨密度测定的精度和准确度。

• DOI: 10.1385/jcd:6:4:381
• 发表时间: 2003
• 期刊: Journal of clinical densitometry : the official journal of the International Society for Clinical Densitometry
• 作者: Horton,JasonA;Murray,GayleM;Spadaro,JosephA;Margulies,BryanS;Allen,MatthewJ;Damron,TimothyA
• 通讯作者: Damron,TimothyA

Physeal bystander effects in rhabdomyosarcoma radiotherapy: experiments in a new xenograft model.

横纹肌肉瘤放射治疗中的骺旁观者效应：新异种移植模型中的实验。

• DOI: 10.1155/2011/815190
• 发表时间: 2011
• 期刊: Sarcoma
• 作者: Horton,JasonA;Strauss,JudithA;Allen,MatthewJ;Damron,TimothyA
• 通讯作者: Damron,TimothyA

Growth plate zonal microarray analysis shows upregulation of extracellular matrix genes and downregulation of metalloproteinases and cathepsins following irradiation.

生长板区域微阵列分析显示，辐射后细胞外基质基因上调，金属蛋白酶和组织蛋白酶下调。

• DOI: 10.1007/s00223-007-9025-1
• 发表时间: 2007
• 期刊: Calcified tissue international
• 影响因子: 4.2
• 作者: Zhang,Mingliang;Wang,Yan;Middleton,FrankA;Horton,JasonA;Farnum,CorneliaE;Damron,TimothyA
• 通讯作者: Damron,TimothyA