eNOS-Dependent Mechanoregulation of Intraocular Pressure
eNOS 依赖性眼压机械调节
基本信息
- 批准号:9346080
- 负责人:
- 金额:$ 42.16万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-04-01 至 2021-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAnteriorBenchmarkingBlindnessBlood VesselsBypassCaliberCellsCiliary MuscleClinical TrialsDataDevelopmentDevicesDiseaseDistalDrainage procedureEndothelial CellsEtiologyExhibitsFeedbackFree RadicalsFundingGenerationsGlaucomaGoalsHemeHomeostasisHumanIndividualInterventionInvestigationKnowledgeLocationMediatingMedicalMolecularNOS3 geneNitric OxideNitric Oxide DonorsOcular HypertensionOutcome StudyPathway interactionsPatientsPerfusionPermeabilityPharmaceutical PreparationsPhysiologic Intraocular PressurePhysiologic pulsePhysiologicalPrimary Open Angle GlaucomaProductionRegulationRelaxationResistanceRoleSignal PathwaySignal TransductionSmooth Muscle MyocytesStentsStructure of sinus venosus of scleraTestingTherapeuticTissuesTopical applicationTrabecular meshwork structureVariantVasodilationVasodilator AgentsVenousVenous Pressure levelbaseblood pressure regulationdesignexperimental studygenetic linkageglaucoma surgeryinhibitor/antagonistminimally invasivenew technologynovelpressureresponseshear stresssuccesstargeted deliverytargeted treatmenttherapeutic target
项目摘要
Project Summary
Clinical trials demonstrate that significant, sustained intraocular pressure (IOP) reduction in people with
glaucoma is neuroprotective, slowing or halting vision loss, even in patients with normal-tension glaucoma.
While the etiology of ocular hypertension in glaucoma is known to reside in the conventional outflow pathway,
the cellular mechanisms responsible for generation of extra outflow resistance remain unknown. Yet, it seems
likely that the homeostatic mechanisms regulating IOP, which presumably become defective in ocular
hypertension, are similar to those involved in regulating blood pressure, including those affecting vascular tone.
A key molecule is nitric oxide (NO), a free radical that is produced by vascular endothelia and acts as a potent
vasodilator and inhibitor of contractility. Importantly, NO production by endothelia is regulated by shear stress.
We demonstrated in our first funding period that IOP strongly influences the magnitude of shear stress within
Schlemm's canal (SC), triggering release of NO from SC cells. We also showed that NO relaxes trabecular
meshwork cells to decrease outflow resistance. Thus, shear-induced NO release acts within a dynamic
“feedback loop” that regulates conventional outflow resistance and IOP and appears compromised in some
glaucomatous individuals. Our central hypothesis is that NO released from SC cells provides a
mechanosensitive feedback signal that maintains IOP homeostasis, thereby functioning as an intraocular
“barostat”; and that directed therapeutic modulation of NO signaling in the glaucomatous outflow pathway
significantly lowers IOP. During the first funding period, we discovered that additional "factors", including
oscillatory shear stress and trabecular meshwork (TM) stiffness, modulate the shear stress acting on SC cells,
and hence influence their NO production. We also identified an additional NO target (distal vascular tone) in
the conventional tract that lowers total outflow resistance.
As a result, we extend our examination of NO signaling in the conventional outflow tract to test effects of
oscillatory shear stress and TM stiffness on NO production and outflow resistance (Aim 1). Moreover, since
25-50% of total outflow resistance resides downstream of SC in distal vessels that are partly surrounded by
NO-sensitive smooth muscle cells, we will determine the role of NO in regulating outflow resistance in the
collector channels and intrascleral venous vessels in Aim 2. Knowing that NO is labile and needs close access
to resistance generating regions in the conventional outflow tract, Aim 3 is designed to develop targeted NO-
based therapeutics that increase conventional outflow at the level of the juxtacanalicular tissue, SC and/or
distal vessels. This is critical because non-targeted NO delivery to the anterior segment is likely counter-
productive by increasing episcleral venous pressure or relaxing ciliary muscle, both of which increase IOP. Our
results will define the mechanisms of NO-mediated homeostasis in outflow regulation, uncover therapeutic
targets for glaucoma therapy and generate novel technologies to modulate NO signaling and IOP.
项目摘要
临床试验表明,显著,持续的眼内压(IOP)降低,
青光眼是神经保护性的,减缓或阻止视力丧失,即使在正常眼压青光眼患者中也是如此。
虽然已知青光眼中高眼压的病因在于传统的流出途径,
负责产生额外流出阻力的细胞机制仍然未知。然而,
很可能是调节IOP的稳态机制,这可能是由于眼内分泌系统的缺陷,
高血压,类似于那些参与调节血压,包括那些影响血管张力。
一个关键的分子是一氧化氮(NO),一种由血管内皮细胞产生的自由基,
血管扩张剂和收缩抑制剂。重要的是,内皮细胞的NO产生受切应力的调节。
我们在第一个资助期内证明,IOP强烈影响内部剪切应力的大小,
Schlemm氏管(SC),触发SC细胞释放NO。我们还发现,NO松弛小梁,
网状细胞以减少流出阻力。因此,剪切诱导的NO释放在动态范围内起作用。
调节传统流出阻力和IOP的“反馈回路”,在某些情况下似乎受到损害。
昏迷的个体。我们的中心假设是,从SC细胞释放的NO提供了
机械敏感的反馈信号,其维持IOP稳态,从而起到眼内调节的作用。
以及指导治疗性调节昏迷流出途径中的NO信号传导
显著降低IOP。在第一个资助期内,我们发现,其他“因素”,包括
振荡剪切应力和小梁网(TM)刚度,调节作用于SC细胞的剪切应力,
从而影响其NO的产生。我们还确定了一个额外的NO靶点(远端血管张力),
降低总流出阻力的传统管道。
因此,我们扩展了我们对传统流出道中NO信号传导的检查,以测试
振荡剪切应力和TM刚度对NO产生和流出阻力的影响(目的1)。而且由于
总流出阻力的25-50%存在于SC下游的远端血管中,这些血管部分被
NO敏感的平滑肌细胞,我们将确定NO在调节流出阻力中的作用,
Aim 2中的收集器通道和巩膜内静脉血管。知道NO是不稳定的,需要近距离接触
针对传统流出道中产生阻力的区域,目标3旨在开发有针对性的NO-
- 基于治疗剂的治疗剂,其增加在小管组织水平的常规流出,SC和/或
远端血管这是至关重要的,因为非靶向NO递送到眼前节可能是反作用的。
通过增加巩膜外静脉压或松弛睫状肌来产生,这两者都增加IOP。我们
结果将明确NO介导的流出调节稳态的机制,
青光眼治疗的新靶点,并产生新的技术来调节NO信号和IOP。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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{{ truncateString('DARRYL R OVERBY', 18)}}的其他基金
eNOS-Dependent Mechanoregulation of Intraocular Pressure
eNOS 依赖性眼压机械调节
- 批准号:
10478264 - 财政年份:2012
- 资助金额:
$ 42.16万 - 项目类别:
eNOS-Dependent Mechanoregulation of Intraocular Pressure
eNOS 依赖性眼压机械调节
- 批准号:
8449089 - 财政年份:2012
- 资助金额:
$ 42.16万 - 项目类别:
eNOS-Dependent Mechanoregulation of Intraocular Pressure
eNOS 依赖性眼压机械调节
- 批准号:
10701730 - 财政年份:2012
- 资助金额:
$ 42.16万 - 项目类别:
eNOS-Dependent Mechanoregulation of Intraocular Pressure
eNOS 依赖性眼压机械调节
- 批准号:
8272122 - 财政年份:2012
- 资助金额:
$ 42.16万 - 项目类别:
eNOS-Dependent Mechanoregulation of Intraocular Pressure
eNOS 依赖性眼压机械调节
- 批准号:
10297523 - 财政年份:2012
- 资助金额:
$ 42.16万 - 项目类别:
eNOS-Dependent Mechanoregulation of Intraocular Pressure
eNOS 依赖性眼压机械调节
- 批准号:
9979893 - 财政年份:2012
- 资助金额:
$ 42.16万 - 项目类别:
eNOS-Dependent Mechanoregulation of Intraocular Pressure
eNOS 依赖性眼压机械调节
- 批准号:
8634103 - 财政年份:2012
- 资助金额:
$ 42.16万 - 项目类别:
eNOS-Dependent Mechanoregulation of Intraocular Pressure
eNOS 依赖性眼压机械调节
- 批准号:
9176805 - 财政年份:2012
- 资助金额:
$ 42.16万 - 项目类别:
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房水如何穿过施累姆氏管内壁?
- 批准号:
7296961 - 财政年份:2007
- 资助金额:
$ 42.16万 - 项目类别:
How Does Aqueous Humor Cross the Inner Wall of Schlemm's Canal?
房水如何穿过施累姆氏管内壁?
- 批准号:
7472427 - 财政年份:2007
- 资助金额:
$ 42.16万 - 项目类别:
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