Lung radioprotection by inhibition of TNF-alpha and TGF-beta1

通过抑制 TNF-α 和 TGF-β1 来保护肺部辐射

基本信息

批准号：
8231479
负责人：
Ming Zhang
金额：
$ 30.97万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-12 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8231479
关键词：
Abbreviations American Cancer Society Amifostine Antisense Oligonucleotides Apoptosis Bioluminescence Bone Marrow Transplantation Cell Culture Techniques Cessation of life Clinical Collagen Collagen Type I Combined Modality Therapy Data Development Dose Enzymes FDA approved Failure Fibrosis Genes Genetic Goals Histology Hydroxyproline Image Immunohistochemistry Injury Intestines Kidney Knock-out Knockout Mice Liver Lung Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of thorax Manganese Superoxide Dismutase Matrix Metalloproteinases Measures Messenger RNA Methods Minority Monitor Mus Normal tissue morphology Organ Outcome Pathway interactions Patients Plasminogen Plasminogen Activator Inhibitor 1 Pneumonia Production Proteins Pulmonary function tests Radiation Radiation therapy Radioprotection Regimen Respiratory physiology Risk Role Schedule Small Interfering RNA Source Spleen Structure of parenchyma of lung System TNF gene Therapeutic Therapeutic Effect Thoracic Neoplasms Time Toxic effect Transforming Growth Factor beta Treatment Efficacy Treatment Protocols Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha Validation Xenograft Model Xenograft procedure advanced disease base cancer radiation therapy chemotherapeutic agent chemotherapy cytokine human TGFB1 protein human TNF protein improved inhibitor/antagonist insight killings macrophage mouse model public health relevance pulmonary function receptor research study tool treatment effect tumor tumor growth tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): In 2006, the American Cancer Society estimates a nationwide 174,470 new cases and 162,460 deaths from lung cancer, one of the most deadly malignancies that kills up to 3 millions annually worldwide. Radiation combined with chemotherapy is the treatment of choice for most patients with advanced disease. However, only a minority of them can receive high-dose radiation due to the risk of radiation-induced lung toxicity. Amifostine as the only FDA-approved radioprotector does not protect the lung and produces substantial toxicity by itself. Therefore, there is an urgent need for developing improved radioprotectors. We have made important findings. First, radiation increases lung TNF-alpha and TGF-beta1 productions that cause lung damage in mice. Reduction of lung TNF receptor 1 (TNFR1) by antisense oligonucleotide (ASO) or by genetic knock-out in mice is radioprotective by decreasing lung apoptosis and improving pulmonary function, in addition to the protection by inhibiting TGF-beta 1 activity. We hypothesize that combined TNF-alpha and TGF-beta1 targeted therapy may provide an improved radioprotection in the lung. The goals of this application are to understand the roles of TNF-alpha and TGF-beta1 and their receptors in radiation-induced lung toxicity and to develop therapeutic blocking agents as radioprotectors. In Specific Aim 1, we will study the roles of both cytokines and their receptors in radiation-induced lung toxicity such as fibrosis and reduced lung function in a mouse model. Knock-out mice for TNFR1 and Smad3 will be used to validate the radioprotection strategy. In Specific Aim 2, we will optimize the use of ASO for specific inhibition of TNFR1 and Smad3 pathways in mouse lung as protectors against a single dose and fractionated radiation. In Specific Aim 3, we will conduct therapeutic experiments to assess the potential benefit of combining TNFR1 and smad3 inhibition for protection against radiation in mice lung cancer xenograft model. Therapeutic effect will be determined by evaluating both normal lung protection and tumor sensitivity to radiation. These studies will provide insights on the mechanisms of radiation-induced lung tissue damage, leading to the development of improved radioprotectors. PUBLIC HEALTH RELEVANCE: Radiation-caused normal lung damage greatly limits the treatment effect of radiotherapy for thoracic cancers including lung cancer. Although the action of cytokine TGF-beta1 during radiation has been known to induce lung toxicity, blocking this action is not completely radioprotective because other mechanisms may also be involved. In this application, we propose to block actions for both TGF-beta1 and TNF-alpha, a pathway that we previously demonstrated be crucial in radiation lung toxicity, by using specific antisense oligonucleotides to achieve improved lung radioprotection.

描述（由申请人提供）： 2006年，美国癌症协会估计全国范围内有174,470例新病例和162,460人死于肺癌，肺癌是最致命的恶性肿瘤之一，每年在全世界夺走300万人的生命。放射联合化疗是大多数晚期疾病患者的治疗选择。然而，由于存在辐射引起的肺毒性风险，只有少数人可以接受高剂量辐射。氨磷汀作为唯一经 FDA 批准的放射防护剂，不能保护肺部，而且本身会产生大量毒性。因此，迫切需要开发改进的辐射防护剂。我们取得了重要的发现。首先，辐射会增加肺部 TNF-α 和 TGF-β1 的产生，从而导致小鼠肺损伤。在小鼠中，通过反义寡核苷酸 (ASO) 或通过基因敲除来减少肺 TNF 受体 1 (TNFR1)，除了通过抑制 TGF-β 1 活性来提供保护外，还可以通过减少肺细胞凋亡和改善肺功能来起到辐射保护作用。我们假设联合 TNF-α 和 TGF-β1 靶向治疗可以改善肺部的放射防护。该应用的目标是了解 TNF-α 和 TGF-β1 及其受体在辐射引起的肺毒性中的作用，并开发作为辐射保护剂的治疗阻断剂。在具体目标 1 中，我们将在小鼠模型中研究细胞因子及其受体在辐射引起的肺毒性（例如纤维化和肺功能下降）中的作用。 TNFR1 和 Smad3 的敲除小鼠将用于验证辐射防护策略。在具体目标 2 中，我们将优化 ASO 的使用，以特异性抑制小鼠肺部的 TNFR1 和 Smad3 通路，作为针对单剂量和分段辐射的保护剂。在具体目标 3 中，我们将进行治疗实验，以评估联合 TNFR1 和 smad3 抑制对小鼠肺癌异种移植模型免受辐射的潜在益处。治疗效果将通过评估正常的肺保护和肿瘤对辐射的敏感性来确定。这些研究将为辐射引起的肺组织损伤的机制提供见解，从而促进改进的辐射防护剂的开发。公共卫生相关性：放射线引起的正常肺损伤极大地限制了放疗对包括肺癌在内的胸部癌症的治疗效果。尽管众所周知，细胞因子 TGF-β1 在放射期间的作用会引起肺毒性，但阻断这种作用并不能完全起到放射防护作用，因为还可能涉及其他机制。在此应用中，我们建议通过使用特定的反义寡核苷酸来阻断 TGF-β1 和 TNF-α 的作用，以实现改善的肺辐射防护，我们之前已证明该途径在放射性肺毒性中至关重要。