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: 6224935
• 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/6224935
• 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（改编自申请人的摘要）：脑动静脉 畸形（AVM）是一种直接连接到血管的动脉异常缠结， 静脉在高压下分流血液流动，并倾向于 其他方面健康的年轻人出血。小AVM的治疗方法为 手术切除或立体定向放射治疗，但这两种疗法都不安全 对大型AVM有效。更好地理解血管放射生物学 可能会为这些病变带来新的治疗方法。放射后AVM闭塞 由于进行性内皮细胞和平滑肌细胞耗竭而发生 增殖内皮细胞似乎是负责其 放射敏感性，平滑肌细胞似乎负责其 闭塞辐射诱导的AVM或动脉闭塞的机制是一些 结合平滑肌细胞增殖，分泌 蛋白质，和收缩，同心缩小管腔， 逐渐封闭它。特定的基因和分子因子， 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-β I（TGF-β I）。TGF 01是一种有效的 平滑肌细胞增殖的刺激剂，NO是一种有效的抑制剂。 如果参与其中，从动脉中删除这些基因将调节他们的动脉粥样硬化。 对辐射的反应。假设没有TGF-β I基因的动脉 对辐射的闭塞反应降低，而没有NO的动脉 合酶基因的封闭反应会增加。据推测 NO和TGF-β I参与了辐射诱导的动脉狭窄， 动静脉畸形的瘘管模型，这种反应可以通过减少 NO的抑制作用或通过增加 平滑肌细胞上的TGF-β I。本研究旨在开发转基因 动静脉瘘模型，这是一种动物模型， 血管结构和血液动力学的一个简单的AVM， 将转基因小鼠动脉插入瘘管部位并保持活力 随着时间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。最后，模型将 用于检查NOS中放射性诱导的动脉病的相对差异 在瘘管条件下敲除、TGF-01敲除和野生型动脉 血流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， 潜在的AVM。如果NO和TGF-01参与了放射性动脉病变 它们可用于增强常规治疗的疗效， 立体定向放射外科作为基因治疗高级别脑胶质瘤的一部分 反车辆地雷。