RADIATION ARTERIOPATHY IN A TRANSGENIC AV FISTULA MODEL

转基因动静脉瘘模型中的放射性动脉病

• 批准号: 6393214
• 负责人: MICHAEL T LAWTON
• 金额: $ 12.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6393214
• 关键词: angiography; disease /disorder model; genetically modified animals; immunocytochemistry; in situ hybridization; laboratory mouse; laboratory rat; nitric oxide synthase; nonhuman therapy evaluation; pathologic arteriovenous shunt; radiation therapy; radiation therapy dosage; transforming growth factors

DESCRIPTION (Adapted From The Applicant's Abstract): A cerebral arteriovenous malformation (AVM) is an abnormal tangle of arteries connected directly to veins that shunts blood flow under high pressure and has a propensity to hemorrhage in otherwise healthy young adults. Small AVMs are treated with surgical resection or stereotactic radiation, but neither therapy is both safe and effective for large AVMs. A better understanding of vascular radiobiology may lead to new therapies for these lesions. AVM obliteration after radiation occurs as a result of progressive endothelial depletion and smooth muscle cell proliferation. The endothelial cells appear to be responsible for its radiosensitivity, and the smooth muscle cells appear to be responsible for its occlusion. The mechanism of radiation-induced AVM or arterial occlusion is some combination of smooth muscle cell proliferation, elaboration of secretory protein, and contraction that concentrically narrows the lumen and progressively occludes it. Specific genes and molecular factors that regulate smooth muscle cells have been implicated in this process, namely nitric oxide (NO) and transforming growth factor-beta I (TGF-beta I). TGF01 is a potent stimulator of smooth muscle cell proliferation, and NO is a potent inhibitor. If involved, deletion of these genes from arteries would modulate their response to radiation. Hypothetically, artery without the TGF-beta I gene would have a decreased occlusive response to radiation, whereas artery without the NO synthase gene would have an increased occlusive response. It is hypothesized that NO and TGF-betaI participate in radiationinduced arterial narrowing in a fistula model for AVMs, and that this response can be enhanced by decreasing the inhibitory influence of NO or by increasing the stimulatory influence of TGF-beta I on smooth muscle cells. This research aims to develop the transgenic arteriovenous fistula model, which is an animal model that replicates the angio-architecture and hemodynamics of a simple AVM, and that enables transgenic mouse artery to be inserted at the fistulous site and remain viable over time. The radiation dose and time required to induce occlusive arteriopathy will be established for this model. Finally, the model will be used to examine relative differences in radiation-induced arteriopathy in NOS knock-out, TGF-01 knock-out, and wild-type artery under conditions of fistulous blood flow. This research will determine whether modulating smooth muscle cell proliferation affects radiation-induced arterial occlusion and has therapeutic potential for AVMs. If NO and TGF-01 are involved in the radiation arteriopathy of AVMs, they might be used to enhance the efficacy of conventional stereotactic radiosurgery as part of a gene therapy for high-grade cerebral AVMs.

描述(摘自申请者摘要)：脑动静脉 畸形(AVM)是直接连接到的动脉的异常缠绕 在高压下分流血液的静脉，并倾向于 在其他方面健康的年轻人出现出血。小型动静脉畸形的治疗方法是 手术切除或立体定向放射治疗，但这两种治疗方法都不安全 并且对大型自动取款机有效。更好地了解血管放射生物学 可能会为这些损伤带来新的治疗方法。放射治疗后动静脉畸形闭塞术 发生于进行性内皮细胞耗竭和平滑肌细胞 扩散。血管内皮细胞似乎对其 对辐射的敏感性，而平滑肌细胞似乎是其 遮挡。辐射诱发的动静脉畸形或动脉闭塞的机制有一些 结合平滑肌细胞增殖，阐述分泌 蛋白质，以及向中心缩小管腔的收缩 逐渐地遮挡住它。调控的特定基因和分子因素 平滑肌细胞参与了这一过程，即一氧化氮。 (NO)和转化生长因子-βI(转化生长因子-βI)。TGF01是一种强有力的 是平滑肌细胞增殖的刺激因子，而NO是一种强有力的抑制因子。 如果参与其中，动脉中这些基因的缺失将调节它们的 对辐射的反应。假设，没有转化生长因子-βI基因的动脉 对辐射的闭塞反应降低，而没有NO的动脉 合酶基因将具有更强的闭塞反应。这是假设的 NO和转化生长因子-β参与辐射所致动脉狭窄 动静脉畸形的瘘管模型，这种反应可以通过减少 NO或通过增加NO的刺激作用而产生的抑制作用 转化生长因子-βI在血管平滑肌细胞上的表达。本研究旨在开发转基因生物。 动静脉瘘模型，这是一种复制 简单动静脉畸形的血管结构和血流动力学，这使得 转基因小鼠动脉将被植入瘘口并保持存活 随着时间的推移。诱发闭塞所需的辐射剂量和时间 将为该模型建立动脉病变模型。最后，模型将是 用于检测放射性动脉病变中一氧化氮合酶的相对差异 瘘管条件下的基因敲除、转化生长因子-01基因敲除和野生型动脉 血液流动。这项研究将确定是否调节平滑肌细胞 增殖影响辐射诱导的动脉闭塞并具有治疗作用 Avm的潜力。如果NO和转化生长因子-01参与放射性动脉病变 在动静脉畸形中，它们可能被用来增强传统的 立体定向放射外科作为高级别脑肿瘤基因治疗的一部分 自动取款机。