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.
糖尿病引起视网膜微血管并发症,是美国失明的主要原因。
States.恢复视力的治疗方法有限。视网膜血流量减少发生在早期糖尿病,这表明
视网膜小动脉和/或小静脉的血管调节异常导致缺血,可能有助于后期视网膜病变。
损害然而,还没有研究同时检查视网膜小动脉和小静脉血管功能,
同样的糖尿病患者因此,知识上的差距是对视网膜病变机制的有限理解。
早期糖尿病的小动脉/小静脉血管功能失调,以在明显病理学之前获得治疗。过度
视网膜中血管收缩剂和炎症剂内皮素-1(ET-1)的产生发生在早期糖尿病中,
因此,对健康和疾病中调节血管对ET-1反应的分子事件的深入了解,
临床意义这一建议是基于1型糖尿病猪显示视网膜血流量减少的证据
在糖尿病2周时,沿着视网膜乳酸升高和视网膜电图中振荡电位降低,
表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-
转化酶-1(ECE-1)活性升高。由于ET-1来源于ECE-1,
通过Rho激酶(ROCK)信号传导的血管收缩,ECE-1/ROCK的激活可导致视网膜血管收缩,
早期糖尿病的失调和血流缺乏。有趣的是,糖尿病会增强视网膜小静脉,而不是小动脉,
通过激活反向模式Na+-Ca 2+交换器(NCX)(可能涉及Na+-H+交换器-1)收缩ET-1
(NHE 1)和应激激酶(p38和JNK)。因此,本研究的目的是揭示序列分子
视网膜小动脉和小静脉的血管调节异常促进早期视网膜缺血的途径
糖尿病核心假设是,早期糖尿病激活微血管ECE-1,导致ET-1水平升高。
1的产生,其通过Ca 2+依赖性ROCK 2/JNK信号传导促进视网膜小动脉收缩。月初
糖尿病时,ET-1升高不仅通过Ca ~(2+)依赖的ROCK 1/JNK轴引起视网膜小静脉收缩,
还通过激活p38/NHE 1/NCX轴进一步促进Ca 2+进入而增强应答。的
协同促进小动脉和小静脉收缩以升高ET-1有助于视网膜缺血,
神经异常本研究的两个具体目标是:(1)确定ET-1的作用
系统激活及其分子信号传导在促进视网膜小动脉收缩和随后视网膜病变中的作用
糖尿病早期通过钙依赖ROCK 2/JNK轴引起缺血(2)确定ET-1系统激活的作用
以及其通过Ca 2 +-介导的增加视网膜小静脉收缩并随之发生视网膜缺血的分子信号传导。
依赖ROCK 1/JNK轴和激活p38/NHE 1/NCX信号通路在早期糖尿病中的作用。成果将
推进糖尿病引起的视网膜并发症的知识,并提出有效的分子靶点,
改善和保护发展前早期糖尿病视网膜的视网膜微血管灌注
视网膜结构损伤
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
TRAVIS W HEIN其他文献
TRAVIS W HEIN的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Developing a Young Adult-Mediated Intervention to Increase Colorectal Cancer Screening among Rural Screening Age-Eligible Adults
制定年轻人介导的干预措施,以增加农村符合筛查年龄的成年人的结直肠癌筛查
- 批准号:
10653464 - 财政年份:2023
- 资助金额:
$ 37.88万 - 项目类别:
Doctoral Dissertation Research: Estimating adult age-at-death from the pelvis
博士论文研究:从骨盆估算成人死亡年龄
- 批准号:
2316108 - 财政年份:2023
- 资助金额:
$ 37.88万 - 项目类别:
Standard Grant
Determining age dependent factors driving COVID-19 disease severity using experimental human paediatric and adult models of SARS-CoV-2 infection
使用 SARS-CoV-2 感染的实验性人类儿童和成人模型确定导致 COVID-19 疾病严重程度的年龄依赖因素
- 批准号:
BB/V006738/1 - 财政年份:2020
- 资助金额:
$ 37.88万 - 项目类别:
Research Grant
Transplantation of Adult, Tissue-Specific RPE Stem Cells for Non-exudative Age-related macular degeneration (AMD)
成人组织特异性 RPE 干细胞移植治疗非渗出性年龄相关性黄斑变性 (AMD)
- 批准号:
10294664 - 财政年份:2020
- 资助金额:
$ 37.88万 - 项目类别:
Sex differences in the effect of age on episodic memory-related brain function across the adult lifespan
年龄对成人一生中情景记忆相关脑功能影响的性别差异
- 批准号:
422882 - 财政年份:2019
- 资助金额:
$ 37.88万 - 项目类别:
Operating Grants
Modelling Age- and Sex-related Changes in Gait Coordination Strategies in a Healthy Adult Population Using Principal Component Analysis
使用主成分分析对健康成年人群步态协调策略中与年龄和性别相关的变化进行建模
- 批准号:
430871 - 财政年份:2019
- 资助金额:
$ 37.88万 - 项目类别:
Studentship Programs
Transplantation of Adult, Tissue-Specific RPE Stem Cells as Therapy for Non-exudative Age-Related Macular Degeneration AMD
成人组织特异性 RPE 干细胞移植治疗非渗出性年龄相关性黄斑变性 AMD
- 批准号:
9811094 - 财政年份:2019
- 资助金额:
$ 37.88万 - 项目类别:
Study of pathogenic mechanism of age-dependent chromosome translocation in adult acute lymphoblastic leukemia
成人急性淋巴细胞白血病年龄依赖性染色体易位发病机制研究
- 批准号:
18K16103 - 财政年份:2018
- 资助金额:
$ 37.88万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Doctoral Dissertation Research: Literacy Effects on Language Acquisition and Sentence Processing in Adult L1 and School-Age Heritage Speakers of Spanish
博士论文研究:识字对西班牙语成人母语和学龄传统使用者语言习得和句子处理的影响
- 批准号:
1823881 - 财政年份:2018
- 资助金额:
$ 37.88万 - 项目类别:
Standard Grant
Adult Age-differences in Auditory Selective Attention: The Interplay of Norepinephrine and Rhythmic Neural Activity
成人听觉选择性注意的年龄差异:去甲肾上腺素与节律神经活动的相互作用
- 批准号:
369385245 - 财政年份:2017
- 资助金额:
$ 37.88万 - 项目类别:
Research Grants