A novel treatment of aortic disease in Marfan Syndrome targeting oxidative stress and PKG dysregulation
针对氧化应激和 PKG 失调的马凡综合征主动脉疾病的新疗法
基本信息
- 批准号:10453951
- 负责人:
- 金额:$ 73.16万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAdhesionsAdrenergic AgentsAdrenergic AntagonistsAdrenergic alpha-AntagonistsAffectAgeAllelesAneurysmAntioxidantsAortaAortic AneurysmAortic DiseasesAortic RuptureApoptosisAttenuatedCaliberCardiovascular AbnormalitiesCell physiologyCellsCessation of lifeChestCollagenComplementCyclic GMPCyclic GMP-Dependent Protein KinasesDNADataDepositionDevelopmentDiseaseDissectionDoseDrug Metabolic DetoxicationElastic FiberElastinEnzymesExtracellular MatrixExtracellular Matrix DegradationExtracellular Matrix ProteinsEye AbnormalitiesFBN1FibrosisFunctional disorderGene ExpressionGene Expression ProfileGenerationsGenetic DiseasesGoalsGrantHistologyHumanHuman MilkImpairmentIn VitroInheritedKnock-outLeadLegal patentLifeLipidsLoxP-flanked alleleMaintenanceMarfan SyndromeMatrix MetalloproteinasesMechanical StressMedialMicrofibrilsMitochondriaMusMutationNitric OxideNitric Oxide SynthaseOralOxidative StressPathologyPathway interactionsPatientsPeroxonitritePersonsPharmacologyPhenotypePlayPrevalenceProductionPropranololProtein IsoformsProteinsReactive Nitrogen SpeciesReactive Oxygen SpeciesReportingRoleScheduleSignal TransductionSmooth Muscle MyocytesSourceSuperoxide DismutaseSuperoxidesTamoxifenTestingThoracic Aortic AneurysmTimeTransgenesUp-RegulationVitamin B 12age relatedanalogascending aortabasecatalasecobinamidedrinking waterextracellularfibrillingain of function mutationimprovedin vivoinduced pluripotent stem cellinhibitorknock-downloss of function mutationmimeticsmouse modelmutantnitrosative stressnoveloverexpressionoxidationpostnatalprematurepreventpublic health relevancerepairedskeletal abnormalitysmall hairpin RNAstress kinasetreatment strategy
项目摘要
Summary
Aortic aneurysms and dissections are the most serious and deadly manifestations of Marfan Syndrome (MFS),
and current therapies to prevent aortic dilation are only moderately effective. MFS is caused by mutations or
deletions in fibrillin-1 (Fbn1), a component of extracellular microfibrils, which surround and connect elastic fibers
to smooth muscle cells (SMCs) in the aortic media. Reduced fibrillin function alters signaling between
extracellular matrix and SMCs, resulting in SMC apopotosis and extracellular matrix degradation. In addition, the
altered signaling leads to increased production of reactive oxygen species (ROS) and nitric oxide (NO),
increasing oxidative and nitrosative stress and activating protein kinase G (PKG) via the NO/cGMP pathway.
Although the increased ROS, reactive nitrogen species (RNS), and PKG activation contribute to aneurysm
formation in MFS, neither the sources of ROS/RNS nor the effects of oxidative/nitrosative stress on SMC
functions are fully understood. The vitamin B12 analog cobinamide, on which we hold several patents, is a strong
and versatile antioxidant that can neutralize ROS and RNS, including NO. During the last grant period, we
showed that mice with an activating PKG1 mutation (Prkg1R177Q) that causes thoracic aneurysms and dissections
in humans, develop aortic dilation associated with increased oxidative stress and media degeneration⸺elastic
fiber fragmentation, increased matrix metalloproteinase activity, media fibrosis, and SMC apoptosis; cobinamide
treatment completely prevented these changes. Preliminary data show that cobinamide also reduces aortic
dilation and prevents elastic fiber fragmentation and SMC apoptosis in a mouse model of MFS (Fbn1C1041G/+),
while reducing markers of oxidative stress and excess PKG signaling. We hypothesize that increased ROS/RNS
combined with PKG activation from increased NO synthase (NOS2) drive abnormal SMC functions and aortic
pathology in MFS, and that an optimized dose schedule of cobinamide will prevent aortic dilation and improve
survival in mice with MFS, especially when combined with a -blocker. In Aim 1, we will determine the mecha-
nisms and consequences of excess ROS/RNS generation in human fibrillin1-deficient or mutant (iPSC-derived)
SMCs, using shRNA knockdown and pharmacological approaches to inhibit ROS/RNS-generating enzymes and
PKG in vitro. We will assess contributions of excess NO synthase and PKG activity to the progression of aortic
disease in vivo, by inducing SMC-specific knockout of NOS2 or PKG1 in Fbn1C1041G/+ mice. We will also test
whether ROS detoxification by SMC-specific catalase overexpression ameliorates aortic pathology. In Aim2, we
will determine the optimal cobinamide dose and starting time to prevent aortic dilation and death from aortic
dissections in mice with moderate (Fbn1C1041G/+) and severe (Fbn1mgR/mgR) MFS, respectively. In addition, we will
combine cobinamide with the β-blocker propranolol, because cobinamide prevents aortic media degeneration,
while propranolol reduces mechanical stress without affecting degenerative changes in the media. These studies
could lead to considerably improved treatment of the aortic disease in patients with MFS.
总结
主动脉瘤和夹层是马凡氏综合征(MFS)最严重和致命的表现,
并且目前防止主动脉扩张的疗法仅是中等有效的。MFS是由突变或
Fbn 1缺失,Fbn 1是细胞外微纤维的一种成分,它包围并连接弹性纤维
平滑肌细胞(SMC)在主动脉介质。降低的tumor in功能改变了
细胞外基质和平滑肌细胞,导致平滑肌细胞凋亡和细胞外基质降解。此外该
改变的信号传导导致活性氧(ROS)和一氧化氮(NO)的产生增加,
增加氧化和亚硝化应激并通过NO/cGMP途径激活蛋白激酶G(PKG)。
虽然增加的ROS、活性氮物质(RNS)和PKG活化有助于动脉瘤
在MFS中,ROS/RNS的来源和氧化/亚硝化应激对SMC的影响都不是MFS中ROS/RNS的来源,
功能完全理解。我们拥有多项专利的维生素B12类似物cobinamide是一种强效的
和多功能的抗氧化剂,可以中和活性氧和RNS,包括NO。在上一个赠款期间,我们
研究表明,具有激活PKG 1突变(Prkg 1 R177 Q)的小鼠会导致胸部动脉瘤和夹层,
在人类中,发生与氧化应激增加和中膜变性相关的主动脉扩张
纤维断裂、基质金属蛋白酶活性增加、中膜纤维化和SMC凋亡;考宾酰胺
治疗完全阻止了这些变化。初步数据显示,可宾酰胺还可降低主动脉
在MFS小鼠模型(Fbn 1C 1041 G/+)中扩张并防止弹性纤维断裂和SMC凋亡,
同时减少氧化应激和过量PKG信号传导的标志物。我们假设增加ROS/RNS
结合PKG激活从增加NO合酶(NOS 2)驱动异常SMC功能和主动脉
MFS的病理学,并且优化的Cobinamide剂量方案将防止主动脉扩张并改善
MFS小鼠的存活率,特别是与β受体阻滞剂联合使用时。在目标1中,我们将确定机甲-
人原纤维蛋白1缺陷型或突变型(iPSC衍生)中过量ROS/RNS产生的机制和后果
SMC,使用shRNA敲低和药理学方法抑制ROS/RNS生成酶,
体外PKG。我们将评估过量的NO合酶和PKG活性对主动脉粥样硬化进展的贡献。
通过在Fbn 1C 1041 G/+小鼠中诱导SMC特异性敲除NOS 2或PKG 1来体内治疗疾病。我们还将测试
SMC特异性过氧化氢酶的ROS解毒作用是否能改善主动脉病变。在目标2中,我们
将确定最佳的可宾胺剂量和开始时间,以防止主动脉扩张和主动脉死亡
分别在具有中度(Fbn 1C 1041 G/+)和重度(Fbn 1 mgR/mgR)MFS的小鼠中进行解剖。此外,我们将
联合收割机可宾胺与β-受体阻滞剂普萘洛尔联合使用,由于可宾胺可防止主动脉中膜变性,
而普萘洛尔降低机械应力而不影响介质的退行性变化。这些研究
可能会大大改善MFS患者主动脉疾病的治疗。
项目成果
期刊论文数量(0)
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{{ truncateString('RENATE B PILZ', 18)}}的其他基金
PKG Regulation of Sirtuin 1 as a Novel Treatment Strategy for Age-related Osteoporosis
Sirtuin 1 的 PKG 调节作为年龄相关性骨质疏松症的新型治疗策略
- 批准号:
10634657 - 财政年份:2021
- 资助金额:
$ 73.16万 - 项目类别:
PKG Regulation of Sirtuin 1 as a Novel Treatment Strategy for Age-related Osteoporosis
Sirtuin 1 的 PKG 调节作为年龄相关性骨质疏松症的新型治疗策略
- 批准号:
10296605 - 财政年份:2021
- 资助金额:
$ 73.16万 - 项目类别:
PKG Regulation of Sirtuin 1 as a Novel Treatment Strategy for Age-related Osteoporosis
Sirtuin 1 的 PKG 调节作为年龄相关性骨质疏松症的新型治疗策略
- 批准号:
10478942 - 财政年份:2021
- 资助金额:
$ 73.16万 - 项目类别:
Targeting defective NO/cGMP signaling as novel therapy for diabetic osteoporosis
针对缺陷的 NO/cGMP 信号作为糖尿病骨质疏松症的新疗法
- 批准号:
9899734 - 财政年份:2016
- 资助金额:
$ 73.16万 - 项目类别:
Targeting defective NO/cGMP signaling as novel therapy for diabetic osteoporosis
针对缺陷的 NO/cGMP 信号作为糖尿病骨质疏松症的新疗法
- 批准号:
9459312 - 财政年份:2016
- 资助金额:
$ 73.16万 - 项目类别:
A novel treatment of aortic disease in Marfan Syndrome targeting oxidative stress and PKG dysregulation
针对氧化应激和 PKG 失调的马凡综合征主动脉疾病的新疗法
- 批准号:
10588164 - 财政年份:2016
- 资助金额:
$ 73.16万 - 项目类别:
Targeting defective NO/cGMP signaling as novel therapy for diabetic osteoporosis
针对缺陷的 NO/cGMP 信号作为糖尿病骨质疏松症的新疗法
- 批准号:
9106282 - 财政年份:2016
- 资助金额:
$ 73.16万 - 项目类别:
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