Endothelin-1 System Activation and Retinal Microvascular Dysregulation during Early Diabetes
早期糖尿病期间内皮素-1 系统激活和视网膜微血管失调
基本信息
- 批准号:10504529
- 负责人:
- 金额:$ 37.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-30 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdultAgeAnimal ModelAnimalsBlindnessBlood Flow VelocityBlood VesselsBlood flowClinicalComplications of Diabetes MellitusDataDevelopmentDiabetes MellitusDiabetic AngiopathiesDiabetic RetinopathyDiseaseElectroretinographyEndothelin-1Endothelin-converting enzyme 1EndotheliumEventEyeEye diseasesFamily suidaeFunctional disorderGoalsHealthHumanInflammatoryInsulin-Dependent Diabetes MellitusIschemiaKnowledgeLeadLinkMAPK8 geneMicrocirculationMicrovascular DysfunctionModelingMolecularMolecular TargetMorphologyN-terminalNeural RetinaNeuronsNutrientOcular PhysiologyOutcomeOxygenPathologyPathway interactionsPerfusionPhosphotransferasesPhysiologicalProductionProteinsROCK1 geneRegulationResearchRetinaRetinal DiseasesRho-associated kinaseRoleSignal PathwaySignal TransductionSignaling MoleculeStreptozocinStructureSystemTestingTimeUnited StatesVasoconstrictor AgentsVasomotorVisionagedarteriolebaseblood damageconstrictiondiabeticdifferential expressioneffective therapyexperienceextracellularimprovedinnovationinsightknock-downnovelp38 Mitogen Activated Protein Kinasepreservationrelating to nervous systemresponseretinal damageretinal ischemiasight restorationstress kinasetargeted treatmenttreatment strategytype I diabeticvasoconstrictionvenule
项目摘要
Diabetes mellitus causes microvascular complications in the retina and is a leading cause of blindness in the United
States. Treatments to restore vision are limited. Reduced retinal blood flow occurs in early diabetes, suggesting
that vasomotor dysregulation of retinal arterioles and/or venules leading to ischemia may contribute to later retinal
damage. However, no study has examined both arteriolar and venular vasomotor function together in the retina of
same diabetic subjects. Thus, a gap in knowledge is the limited understanding of mechanisms for retinal
arteriolar/venular vasomotor dysregulation in early diabetes to yield treatment before overt pathology. Excessive
production of vasoconstrictor and inflammatory agent endothelin-1 (ET-1) in the retina occurs in early diabetes,
so in-depth insight into molecular events regulating vasomotor responses to ET-1 in health and disease has
clinical implication. This proposal is based on evidence in type 1 diabetic pigs showing reduced retinal blood flow
at 2-wk diabetes, along with elevated retinal lactate and diminished oscillatory potentials in the electroretinogram,
indicating retinal ischemia and neural abnormality. Also, vitreous ET-1 level and retinal arteriolar endothelin-
converting enzyme-1 (ECE-1) activity were elevated in diabetic pigs. Because ET-1 is derived from ECE-1 and causes
vasoconstriction via Rho kinase (ROCK) signaling, activation of ECE-1/ROCK may lead to retinal vasomotor
dysregulation and flow deficiency in early diabetes. Interestingly, diabetes enhances retinal venular, but not arteriolar,
constriction to ET-1 by activating reverse-mode Na+-Ca2+ exchanger (NCX), possibly involving Na+-H+ exchanger-1
(NHE1) and stress kinases (p38 and JNK). Thus, the objective of this study is to unveil the sequential molecular
pathways for vasomotor dysregulation of retinal arterioles and venules that promote retinal ischemia in early
diabetes. The central hypothesis is that early diabetes activates microvascular ECE-1 leading to enhanced ET-
1 production, which promotes retinal arteriolar constriction via Ca2+-dependent ROCK2/JNK signaling. In early
diabetes, the elevated ET-1 not only elicits retinal venular constriction via Ca2+-dependent ROCK1/JNK axis but
also augments the response by further promoting Ca2+ entry through activation of the p38/NHE1/NCX axis. The
cooperative promotion of arteriolar and venular constrictions to elevated ET-1 contributes to retinal ischemia and
neural abnormality. Two specific aims will be pursued to support the hypothesis: (1) Determine roles of ET-1
system activation and its molecular signaling in promoting retinal arteriolar constriction and consequent retinal
ischemia via Ca2+-dependent ROCK2/JNK axis in early diabetes. (2) Determine roles of ET-1 system activation
and its molecular signaling to augment retinal venular constriction with consequent retinal ischemia via Ca2+-
dependent ROCK1/JNK axis and activated p38/NHE1/NCX signaling pathway in early diabetes. Outcomes will
advance the knowledge of diabetes-induced retinal complications and suggest effective molecular targets for
improving and protecting retinal microvascular perfusion of the retina in early-stage diabetes before development
of retinal structure damage.
糖尿病导致视网膜微血管并发症,是美国致盲的主要原因。
各州。恢复视力的治疗是有限的。早期糖尿病患者视网膜血流量减少,提示
视网膜小动脉和/或小静脉的血管运动失调导致的缺血可能与晚期视网膜有关。
损坏。然而,还没有研究同时检查视网膜的微动脉和静脉血管运动功能。
同样的糖尿病患者。因此,知识上的差距是对视网膜机制的有限理解
早期糖尿病患者的小动脉/静脉血管运动失调,以便在明确病理之前进行治疗。过份
糖尿病早期视网膜产生血管收缩因子和炎性介质内皮素-1(ET-1),
因此,对调节健康和疾病中血管舒缩反应的分子事件的深入洞察
临床意义。这一建议是基于1型糖尿病猪表现出视网膜血流减少的证据。
在2周的糖尿病中,伴随着视网膜乳酸升高和视网膜电信号的振荡电位减弱,
说明视网膜缺血和神经异常。此外,玻璃体ET-1水平和视网膜小动脉内皮素-1-
转换酶-1活性在糖尿病猪中升高。因为ET-1是由ECE1衍生而来的,因此导致
通过Rho激酶(ROCK)信号途径的血管收缩,ECE1/ROCK的激活可能导致视网膜血管运动
早期糖尿病的调节失调和血流不足。有趣的是,糖尿病增加了视网膜的小静脉,但不是微动脉,
激活反向Na~+-Ca~(2+)交换器(NCX)对ET-1的收缩作用,可能涉及Na~+-H~+交换器-1
(NHE1)和应激蛋白(p38和JNK)。因此,本研究的目的是揭示序列分子
促进早期视网膜缺血的视网膜小动脉和小静脉血管运动失调的途径
糖尿病。中心假说是,早期糖尿病激活微血管内皮细胞-1,导致ET-1增强。
1的产生,通过钙依赖的ROCK2/JNK信号促进视网膜小动脉收缩。在早期
糖尿病时,升高的ET-1不仅通过钙依赖的ROCK1/JNK轴引起视网膜静脉收缩,而且
还通过激活p38/NHE1/NCX轴进一步促进钙离子进入,从而增强反应。这个
共同促进小动脉和小静脉收缩到升高的ET-1有助于视网膜缺血和
神经异常。我们将追求两个特定的目标来支持这一假说:(1)确定ET-1的作用
系统激活及其分子信号在促进视网膜小动脉收缩和继发性视网膜病变中的作用
早期糖尿病通过钙依赖的ROCK2/JNK轴发生缺血。(2)确定ET-1系统激活的作用
及其通过钙离子增强视网膜静脉收缩和继发视网膜缺血的分子信号。
早期糖尿病依赖ROCK1/JNK轴和激活p38/NHE1/NCX信号通路结果将会
提高对糖尿病视网膜并发症的认识,并提出有效的分子靶点
早期糖尿病患者发病前改善和保护视网膜微血管血流的研究
视网膜结构受损。
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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TRAVIS W HEIN其他文献
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{{ truncateString('TRAVIS W HEIN', 18)}}的其他基金
Endothelin-1 System Activation and Retinal Microvascular Dysregulation during Early Diabetes
早期糖尿病期间内皮素-1 系统激活和视网膜微血管失调
- 批准号:
10701883 - 财政年份:2022
- 资助金额:
$ 37.88万 - 项目类别:
Intravitreal ECE-1 siRNA Treatment for Retinal Dysfunction during Early Diabetes
玻璃体内 ECE-1 siRNA 治疗早期糖尿病视网膜功能障碍
- 批准号:
8821045 - 财政年份:2015
- 资助金额:
$ 37.88万 - 项目类别:
Roles of LOX-1 and Stress-Activated Kinases in Retinal Dysfunction during Early Diabetes
LOX-1 和应激激活激酶在早期糖尿病视网膜功能障碍中的作用
- 批准号:
8888305 - 财政年份:2015
- 资助金额:
$ 37.88万 - 项目类别:
Roles of LOX-1 and Stress-Activated Kinases in Retinal Dysfunction during Early Diabetes
LOX-1 和应激激活激酶在早期糖尿病视网膜功能障碍中的作用
- 批准号:
9330861 - 财政年份:2015
- 资助金额:
$ 37.88万 - 项目类别:
Roles of LOX-1 and Stress-Activated Kinases in Retinal Dysfunction during Early Diabetes
LOX-1 和应激激活激酶在早期糖尿病视网膜功能障碍中的作用
- 批准号:
9146954 - 财政年份:2015
- 资助金额:
$ 37.88万 - 项目类别:
Vasomotor Dysfunction of Retinal Arterioles in Diabetes
糖尿病视网膜小动脉血管舒缩功能障碍
- 批准号:
8631325 - 财政年份:2014
- 资助金额:
$ 37.88万 - 项目类别:
Vasomotor Dysfunction of Retinal Arterioles in Diabetes
糖尿病视网膜小动脉血管舒缩功能障碍
- 批准号:
9020236 - 财政年份:2014
- 资助金额:
$ 37.88万 - 项目类别:
Role of Endothelin System and NAD(P)H Oxidase in Retinal Arteriolar Dysfunction
内皮素系统和 NAD(P)H 氧化酶在视网膜小动脉功能障碍中的作用
- 批准号:
7926513 - 财政年份:2008
- 资助金额:
$ 37.88万 - 项目类别:
Role of Endothelin System and NAD(P)H Oxidase in Retinal Arteriolar Dysfunction
内皮素系统和 NAD(P)H 氧化酶在视网膜小动脉功能障碍中的作用
- 批准号:
7539150 - 财政年份:2008
- 资助金额:
$ 37.88万 - 项目类别:
Role of Endothelin System and NAD(P)H Oxidase in Retinal Arteriolar Dysfunction
内皮素系统和 NAD(P)H 氧化酶在视网膜小动脉功能障碍中的作用
- 批准号:
8005501 - 财政年份:2008
- 资助金额:
$ 37.88万 - 项目类别:
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