INOS GENE TRANSFECTION IN PULMONARY HYPERTENSION
INOS 基因转染治疗肺动脉高压
基本信息
- 批准号:2878912
- 负责人:
- 金额:$ 16.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1999
- 资助国家:美国
- 起止时间:1999-04-01 至 2004-03-31
- 项目状态:已结题
- 来源:
- 关键词:Adenoviridae enzyme activity gene expression gene therapy genetic transduction hypoxia immunocytochemistry inhalation drug administration intravenous administration laboratory rat lung lavage muscle cells nitric oxide nitric oxide synthase nonhuman therapy evaluation polymerase chain reaction pulmonary circulation pulmonary hypertension respiratory disease /disorder therapy transfection /expression vector vascular smooth muscle vasoconstriction
项目摘要
Pulmonary hypertension (PH) is a significant cause of morbidity and
mortality affecting a broad range of patients. Neonatal pulmonary
hypertension is the second leading cause for admission to neonatal
intensive care units for respiratory support. In adults, PH causes
significant morbidity and mortality in patients with chronic obstructive
pulmonary disease. In all patients, PH is characterized by cellular
proliferation and altered vasoreactivity in the pulmonary vascular bed.
The objectives of this proposal are to evaluate the vasodilator efficacy
and toxicity of NO produced by virally mediated inducible nitric oxide
synthase (iNOS) gene transfection in the lung and to determine the
effect of virally transfected iNOS on the pathogenesis of PH. The
general hypothesis is that virally transfected iNOS will result in
sufficient NO formation to modulate pulmonary vasoconstriction and
attenuate pulmonary vascular changes associated with pulmonary
hypertension, but insufficient NO formation to result in toxicity.
Utilizing human iNOS gene and, as a control, the E. coli lac Z reporter
gene coding for beta-galactosidase (beta-gal) adenovirus constructs our
goals set forth in this proposal are: 1) to optimize iNOS gene delivery
and expression in the rat lung, 2) to determine the role of transfected
iNOS on the development of pulmonary hypertension, and 3) to compare
intravascular and intratracheal delivery of the iNOS gene in terms of
gene expression, vascular reactivity and toxicity. These goals are
addressed in the following specific aims: Specific Aim number 1: Assess
the effectiveness of adenovirus-mediated iNOS gene transfection in
attenuating acute pulmonary vasoconstrictor responses. Specific Aim
number 2: Assess iNOS gene transfection-mediated effects on the
development of chronic hypoxia-induced pulmonary hypertension. Specific
Aim number 3: Assess the efficacy and toxicity of intravascularly and
intratracheally administered adenoviral iNOS constructs.
The methods will involve using adenovirus constructs containing the gene
for iNOS or beta-gal that will be administered intravascularly; the
lungs will then be studied to determine vascular reactivity, NO
production, and localization of transfected iNOS. Some rats will be
transfected and exposed to chronic hypoxia. Finally, intravascular and
intratracheal delivery will be compared in terms of gene localization
and toxicity.
肺动脉高压(PH)是发病率和死亡率的重要原因
死亡率影响广泛的患者。 新生儿肺
高血压是导致新生儿入院的第二大原因
重症监护病房提供呼吸支持。 在成人中,PH 会导致
慢性阻塞性肺疾病患者的发病率和死亡率显着
肺病。 在所有患者中,PH 的特点是细胞
肺血管床增殖和血管反应性改变。
该提案的目的是评估血管扩张剂的功效
病毒介导的诱导型一氧化氮产生的 NO 和毒性
合酶(iNOS)基因转染肺并确定
病毒转染的 iNOS 对 PH 发病机制的影响。 这
一般假设是病毒转染的 iNOS 会导致
足够的一氧化氮形成来调节肺血管收缩
减弱与肺相关的肺血管变化
高血压,但 NO 形成不足而导致毒性。
利用人类 iNOS 基因和大肠杆菌 lac Z 报告基因作为对照
编码 β-半乳糖苷酶 (β-gal) 腺病毒的基因构建了我们的
该提案提出的目标是:1) 优化 iNOS 基因传递
以及在大鼠肺中的表达,2)确定转染的作用
iNOS 对肺动脉高压发展的影响,以及 3) 比较
iNOS 基因的血管内和气管内递送
基因表达、血管反应性和毒性。 这些目标是
具体目标 1:评估
腺病毒介导的 iNOS 基因转染的有效性
减弱急性肺血管收缩反应。 具体目标
第 2 项:评估 iNOS 基因转染介导的对
慢性缺氧引起的肺动脉高压的发展。 具体的
目标 3:评估血管内注射和注射药物的功效和毒性
气管内施用腺病毒 iNOS 构建体。
该方法将涉及使用含有该基因的腺病毒构建体
对于血管内给药的 iNOS 或 β-gal;这
然后将研究肺部以确定血管反应性、NO
转染的 iNOS 的生产和本地化。 有些老鼠会
转染并暴露于慢性缺氧。 最后,血管内和
气管内递送将在基因定位方面进行比较
和毒性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('LOUIS G CHICOINE', 18)}}的其他基金
Mechanisms of PRMT regulation of pulmonary endothelial cell function
PRMT调节肺内皮细胞功能的机制
- 批准号:
9130380 - 财政年份:2015
- 资助金额:
$ 16.15万 - 项目类别:
Pulmonary Vascular Targeting of Gene Delivery Using Directed Evolution of AAV
利用 AAV 定向进化进行肺血管基因递送靶向
- 批准号:
7455860 - 财政年份:2007
- 资助金额:
$ 16.15万 - 项目类别:
Pulmonary Vascular Targeting of Gene Delivery Using Directed Evolution of AAV
利用 AAV 定向进化进行肺血管基因递送靶向
- 批准号:
7315308 - 财政年份:2007
- 资助金额:
$ 16.15万 - 项目类别:
INOS GENE TRANSFECTION IN PULMONARY HYPERTENSION
INOS 基因转染治疗肺动脉高压
- 批准号:
6183176 - 财政年份:1999
- 资助金额:
$ 16.15万 - 项目类别:
INOS GENE TRANSFECTION IN PULMONARY HYPERTENSION
INOS 基因转染治疗肺动脉高压
- 批准号:
6788676 - 财政年份:1999
- 资助金额:
$ 16.15万 - 项目类别:
INOS GENE TRANSFECTION IN PULMONARY HYPERTENSION
INOS 基因转染治疗肺动脉高压
- 批准号:
6536564 - 财政年份:1999
- 资助金额:
$ 16.15万 - 项目类别:
INOS GENE TRANSFECTION IN PULMONARY HYPERTENSION
INOS 基因转染治疗肺动脉高压
- 批准号:
6388543 - 财政年份:1999
- 资助金额:
$ 16.15万 - 项目类别:
INOS GENE TRANSFECTION IN PULMONARY HYPERTENSION
INOS 基因转染治疗肺动脉高压
- 批准号:
6638102 - 财政年份:1999
- 资助金额:
$ 16.15万 - 项目类别:
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