MECHANISM OF BYSTANDER MUTAGENESIS

旁观者诱变机制

• 批准号: 8281639
• 负责人: Tom K. Hei
• 金额: $ 36.8万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8281639
• 关键词: Abdomen; Abdominal Cavity; Address; Animals; Apoptosis; Area; Bystander Effect; Cell Culture Techniques; Cell Nucleus; Cells; Chest; Communication; Connexins; Control Animal; Cytoplasm; DNA; Data; Diagnostic radiologic examination; Dinoprostone; Dose; Embryo; Fibroblasts; Gap Junctions; Gene Expression; Genes; Genetic; Genomic Instability; Goals; Health; High Pressure Liquid Chromatography; Human; In Vitro; Incidence; Instruction; Ionizing radiation; Low Dose Radiation; Mammalian Cell; Mammary Gland Parenchyma; Mediating; Mediator of activation protein; Mitochondria; Mitochondrial DNA; Modeling; Mus; Mutagenesis; Mutate; Mutation; NF-kappa B; Nuclear; Oxidative Stress Induction; Patients; Play; Point Mutation; Population; Process; Proteins; Radiation; Radiation therapy; Reverse Transcriptase Polymerase Chain Reaction; Risk Assessment; Roentgen Rays; Role; Sampling; Series; Signal Pathway; Signaling Molecule; Signaling Pathway Gene; Signaling Protein; Small Interfering RNA; Staging; Structure of parenchyma of lung; Time; Tissue Stains; Tissues; Transgenic Mice; Universities; cancer risk; cellular targeting; cyclooxygenase 1; cyclooxygenase 2; human NOS2A protein; human tissue; in vivo; irradiation; micronucleus; mitochondrial DNA mutation; novel; oxidative DNA damage; programs; response; theories

PROJECT SUMMARY (See instructions): Radiation induced bystander effects have been demonstrated with a variety of endpoints using mammalian cell cultures as well as 3D human tissues. However, neither the mechanism nor the relevance of the bystander response to human health is clear. While gap junction communication and presence of soluble mediator(s) are known to play an important role in the bystander response, the precise signaling molecules have yet to be identified. The overall goals of this project are to define the incidence and mechanism of radiation-induced bystander mutagenic response in vivo (non-targeted response); to clarify the role of cyclooxygenase-2(COX-2) signaling pathways in the process; and to examine the incidence of genomic instability in bystander tissues in wild type and in genetic susceptible animals. The central testable hypothesis is that COX-2 mediates radiation induced bystander mutagenesis in vivo and that the bystander cells are genomically unstable in ATM homozygously mutated animals. A series of five inter-related specific aims are proposed to address these goals. The novel gpt delta ttansgenic mice and embryo fibroblasts from these animals will be used to conelate the findings under both in vitro and in vivo conditions. A small 1 cm by 1 cm zone in the lower abdominal area will be inadiated with graded doses of X-rays and the expression of COX-2 levels as well as incidence and types of Spi (deletions) and gpt (point mutations) mutations will be examined in the non-targeted lung and breast tissues. Bystander response as a result of nuclei and cytoplasmic targeting in MEF cells from wild type and COX-2knock out mice will be conducted with a microbeam to delineate specific gene signaling pathways. To further define genomic instability in bystander tissues, incidence of gpt and Spi mutations will be examined over a period of several weeks post-irradiation in wild type as well as y47Mknock out mice. Extensive program interaction with Projects 1 and 3 are planned in that the role of Rad9 (Project 1) and the connexin protein (TCTP, Project 3) in modulating COX-2 function will be examined. Radiation induced bystander effects represent a paradigm shift in our understanding of the basic radiobiological principle and target theory of ionizing radiation. A better understanding of the mechanism of the bystander effect is important for an accurate assessment of cancer risk associated with low dose radiation exposure.

项目概述（见说明）：