GENE AND CYTOKINE EXPRESSION IN THE CNS RADIORESPONSE

CNS 放射反应中的基因和细胞因子表达

• 批准号: 6192929
• 负责人: Philip Tofilon
• 金额: $ 20.82万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-01 至 2001-06-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6192929
• 关键词: antioxidants; astrocytes; central nervous system; cytokine; enzyme activity; enzyme inhibitors; free radical oxygen; gene expression; immunoprecipitation; ionizing radiation; laboratory rat; mitochondria; neurogenetics; nitric oxide synthase; nuclear factor kappa beta; oxidative stress; radiation genetics; radiation sensitivity; short chain fatty acid; spinal cord disorders; superoxide dismutase; tissue /cell culture; western blottings

The rational development of strategies for preventing or treating radiation injury in the central nervous system (CNS) will require a more complete understanding of the fundamental radiobiology of this critical normal tissue. After other types of CNS injury acute cell death is followed by the activation of secondary reactive processes that occur hours to days after the initial damage and contribute to lesion development. In addition, there is the activation of repair/recovery processes involving the induction of genes coding for a variety of protective cytokines. The working hypothesis of this proposal is that a similar scheme applies to the CNS injury induced by radiation. Proposed studies will address the induction of repair/recovery mechanisms and the activation of secondary processes that contribute to injury development. Regarding the activation of protective mechanisms, the focus will be on the transcription factor NF-kB. Radiation-induced activation of NF-kB in the CNS is followed by a refractory period during which the susceptibility of this transcription factor to activation by subsequent irradiation is significantly reduced. An aim of this proposal is to define the mechanisms that regulate radiation-induced NF-kB activation and to determine its significance in the radioresponse of the CNS. Regarding secondary processes, an aim is to define the incidence of oxidative stress in the rat spinal cord after irradiation. To address the significance of oxidative stress in radiation CNS injury, the effects of specific anti-oxidants on radiation-induced myelopathy will be investigated. Finally, mitochondrial function and metabolism will be investigated in primary cell cultures and in the spinal cord after irradiation. The hypothesis to be tested is that mitochondrial damage serves as a source of oxidative stress and contributes to the development of radiation injury. It is anticipated that delineating the secondary events that contribute to tissue injury and the intrinsic protection mechanisms will lead to identification of processes subject to manipulation and thus provide the basis for developing therapies for radiation induced CNS toxicity.

预防或治疗策略的合理发展 中枢神经系统（CNS）的辐射损伤将需要更多 完全了解这种关键正常的基本放射生物学 组织。其他类型的中枢神经系统损伤后，急性细胞死亡之后是 激活次级反应性过程，这些过程发生在几小时以后的几天 最初的损害并导致病变发育。另外，还有 涉及诱导基因编码的维修/恢复过程的激活 用于各种保护性细胞因子。该提议的工作假设 是否适用于辐射引起的中枢神经系统损伤。 拟议的研究将解决修复/恢复机制的诱导和 有助于损伤发展的次要过程的激活。 关于保护机制的激活，重点将放在 转录因子NF-KB。 CNS中NF-KB的辐射诱导的激活为 其次是难治时期，在此期间 通过随后的辐射来激活的转录因子显着 减少。该提议的目的是定义调节的机制 辐射引起的NF-KB激活，并确定其在 中枢神经系统的辐射响应。关于次要过程，目的是定义 辐照后大鼠脊髓中氧化应激的发生率。到 解决氧化应激在辐射中枢神经系统损伤中的重要性， 特定抗氧化剂对辐射引起的骨髓病的影响将是 调查。最后，线粒体功能和代谢将是 辐照后在原代细胞培养物和脊髓中进行了研究。 要检验的假设是线粒体损伤是 氧化应激并有助于辐射损伤的发展。这是 预计描述有助于组织的次要事件 伤害和内在保护机制将导致确定 进行操纵的过程，从而为发展提供基础 辐射诱导的中枢神经系统毒性的疗法。

项目成果

X-ray-mediated reduction in basic fibroblast growth factor expression in primary rat astrocyte cultures.

X射线介导的原代大鼠星形胶质细胞培养物中碱性成纤维细胞生长因子表达的减少。

• 发表时间: 1997
• 期刊: Radiation research
• 影响因子: 3.4
• 作者: Noel,F;Ijichi,A;Chen,JJ;Gumin,GJ;Tofilon,PJ
• 通讯作者: Tofilon,PJ

IkappaBalpha degradation is not a requirement for the X-ray-induced activation of nuclear factor kappaB in normal rat astrocytes and human brain tumour cells.

在正常大鼠星形胶质细胞和人脑肿瘤细胞中，X 射线诱导的核因子 kappaB 激活不需要 IkappaBalpha 降解。

• DOI: 10.1080/095530098141195
• 发表时间: 1998
• 期刊: International journal of radiation biology
• 影响因子: 2.6
• 作者: Raju,U;Gumin,GJ;Noel,F;Tofilon,PJ
• 通讯作者: Tofilon,PJ

Microglial cytokine gene induction after irradiation is affected by morphologic differentiation.

• 发表时间: 1997-11
• 期刊: Radiation medicine
• 作者: K. Hayakawa;P. Borchardt;S. Sakuma;A. Ijichi;H. Niibe;P. Tofilon

Salen Mn complexes mitigate radiation injury in normal tissues.

• DOI: 10.2174/187152011795677490
• 发表时间: 2011-05-01
• 期刊: Anti-cancer agents in medicinal chemistry
• 影响因子: 2.8
• 作者: Rosenthal RA;Fish B;Hill RP;Huffman KD;Lazarova Z;Mahmood J;Medhora M;Molthen R;Moulder JE;Sonis ST;Tofilon PJ;Doctrow SR
• 通讯作者: Doctrow SR

X-irradiation-induced loss of O-2A progenitor cells in rat spinal cord is inhibited by implants of cells engineered to secrete glial growth factor 2.

X 射线照射引起的大鼠脊髓中 O-2A 祖细胞的损失可以通过植入经过改造的细胞来分泌神经胶质生长因子 2 来抑制。

• DOI: 10.1097/00001756-199902250-00017
• 发表时间: 1999
• 期刊: Neuroreport
• 影响因子: 1.7
• 作者: Noel,F;Raju,U;Happel,E;Marchionni,MA;Tofilon,PJ
• 通讯作者: Tofilon,PJ