Modulating retinal lipid biogenesis in diabetes for therapeutic effects
调节糖尿病视网膜脂质生物合成以获得治疗效果
基本信息
- 批准号:10672366
- 负责人:
- 金额:$ 38.88万
- 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:2022-08-01 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:ATF6 geneAblationAccelerationAcetyl-CoA CarboxylaseAddressAdenosine MonophosphateAdultAffectAgonistAgreementAnabolismBiogenesisBlindnessCalciumCatabolismCellsCellular StressClinicalDataDevelopmentDiabetes MellitusDiabetic RetinopathyDiseaseEndoplasmic ReticulumEnzymesFatty-acid synthaseGlucoseGoalsHealthHomeostasisHumanHyperglycemiaImageInjuryIon ChannelLinkLipidsMammalian CellMass Spectrum AnalysisMedium chain fatty acidMetabolicMetabolismMetforminModelingModernizationModificationMolecularOnset of illnessPalmitatesPalmitic AcidsPathogenesisPathologicPathologyPathway interactionsPatientsPatternPhosphotransferasesPhotoreceptorsPost-Translational Protein ProcessingPrevalenceProcessProductionProteinsPublic HealthReportingRetinaRetinal DiseasesRodRyanodine Receptor Calcium Release ChannelSeveritiesSignal TransductionSignaling MoleculeStressTestingTherapeutic EffectTissuesTransgenic OrganismsVisionVisualVisual impairmentcalcium indicatorcostdiabeticdisabilityendoplasmic reticulum stressexperimental studygain of functiongenetic manipulationimprovedinhibitorlipid biosynthesislipid metabolismnew therapeutic targetnon-diabeticnovelpalmitoylationpreventpublic health relevancerelease of sequestered calcium ion into cytoplasmretinal rodstargeted treatmenttherapy developmentvisual cycle
项目摘要
Project Summary
Diabetic retinopathy is an increasingly common cause of visual impairment and blindness among
adults. Modern therapy has become increasingly effective, but remains insufficient to prevent vision loss in a
sizable proportion of patients. Early-acting and efficacious new remedies are needed, especially since the
prevalence of worldwide disease is increasing. A barrier to accomplishing this goal is a poor understanding of
the earliest causes of retinal injury in diabetes. In this application, we will address this barrier by studying early
changes in retinal metabolism during diabetes – changes that are likely to contribute to disease onset and that
can be targeted for therapeutic purposes.
Hyperglycemia is the hallmark of all forms of diabetes and is directly related to its complications,
including diabetic retinopathy. Since glucose is the primary fuel of the retina, we investigated what pathological
effects might occur due to its excess supply in diabetes. Specifically, we discovered that diabetes is associated
with a fundamental shift in retinal metabolism away from tissue break down (catabolism) and towards tissue
building (anabolism). Among the largest changes is that of lipid biosynthesis, a pathway responsible for
generating a ubiquitous medium-chain fatty acid in mammalian cells, palmitate. In diabetes, retinal palmitate
synthesis is elevated by 70% compared to non-diabetic controls. Using targeted genetic manipulation of the
enzymes in the synthesis pathway, we determined that reduction of palmitate prevents vision loss in diabetes
whereas elevating its production accelerates the onset of visual abnormalities. We now ask how such signals
are related to disease development and what specific molecules are involved. Towards these goals, we
recently found that excess palmitate in the diabetic retina impacts several retinal enzymes that are regulated
by S-palmitoylation. The largest change was seen in retinal Ryanodine Receptor 2 (Ryr2) – an intracellular ion
channel that regulates calcium homeostasis – as it is hyper-palmitoylated in diabetes compared to non-diabetic
controls. In this application we will determine whether this molecular change is associated with pathology and
whether it can be reversed for therapeutic effects.
We will address three major aims: (1) define the effect of diabetes on retinal Ryr2 palmitoylation and its
functional consequences; (2) delineate whether Ryr2-associated calcium flux in rods is dependent on retinal
lipid biogenesis; and (3) determine whether improving retinal lipogenic signaling in diabetes reduces diabetic
retinopathy severity. By accomplishing these aims, we could uncover essential root causes of diabetic
retinopathy and we may introduce novel targets for therapy directed at a very early stage of the disease
process.
项目摘要
糖尿病视网膜病变是导致视力损害和失明的越来越常见的原因
成年人。现代疗法已经变得越来越有效,但仍然不足以预防视力丧失。
相当大比例的病人。需要及早行动和有效的新补救措施,特别是在
世界性疾病的流行正在增加。实现这一目标的一个障碍是对
糖尿病患者视网膜损伤的最早原因。在本应用程序中,我们将通过早期研究来解决这一障碍
糖尿病期间视网膜代谢的变化--这些变化可能有助于疾病的发生和发展
可以作为治疗的靶点。
高血糖是所有形式糖尿病的标志,并与其并发症直接相关,
包括糖尿病视网膜病变。由于葡萄糖是视网膜的主要燃料,我们调查了
这种影响可能是由于其在糖尿病中的过量供应而发生的。具体来说,我们发现糖尿病与
随着视网膜新陈代谢从组织分解(分解代谢)向组织转移
建筑(合成代谢)。其中最大的变化是脂质生物合成,这是一种负责
在哺乳动物细胞中产生一种普遍存在的中链脂肪酸棕榈酸酯。糖尿病患者,视网膜棕榈酸酯
与非糖尿病对照组相比,合成量增加了70%。使用有针对性的基因操作
在合成途径中的酶,我们确定棕榈酸酯的减少可以防止糖尿病患者的视力丧失
然而,提高它的产量会加速视觉异常的发生。我们现在问这样的信号是如何
与疾病的发展有关,以及涉及哪些特定分子。为了实现这些目标,我们
最近发现,糖尿病视网膜中过量的棕榈酸会影响几种受调节的视网膜酶
S-棕榈酰化。变化最大的是视网膜Ryanodine受体2(Ryr2)--一种细胞内离子
调节钙稳态的通道--因为与非糖尿病患者相比,糖尿病患者的钙离子高度棕榈酸化
控制。在本申请中,我们将确定这种分子变化是否与病理和
能否逆转以达到治疗效果。
我们将解决三个主要目标:(1)确定糖尿病对视网膜Ryr2棕榈酰化的影响及其
功能后果;(2)描述视杆细胞中Ryr2相关的钙流量是否依赖于视网膜
脂生物发生;以及(3)确定改善糖尿病患者的视网膜脂肪生成信号是否能降低糖尿病
视网膜病变严重程度。通过实现这些目标,我们可以揭示糖尿病的根本原因
视网膜病变,我们可能会引入新的靶点在疾病的早期阶段进行治疗
进程。
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 }}
Rithwick Rajagopal其他文献
Rithwick Rajagopal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('Rithwick Rajagopal', 18)}}的其他基金
Modulating retinal lipid biogenesis in diabetes for therapeutic effects
调节糖尿病视网膜脂质生物合成以获得治疗效果
- 批准号:
10503919 - 财政年份:2022
- 资助金额:
$ 38.88万 - 项目类别:
EARLY DETECTION OF DIABETIC RETINOPATHY BY PERIPHERAL BLOOD LIPID PROFILING
通过外周血脂分析早期检测糖尿病视网膜病变
- 批准号:
9197299 - 财政年份:2016
- 资助金额:
$ 38.88万 - 项目类别:
EARLY DETECTION OF DIABETIC RETINOPATHY BY PERIPHERAL BLOOD LIPID PROFILING
通过外周血脂分析早期检测糖尿病视网膜病变
- 批准号:
9033384 - 财政年份:2016
- 资助金额:
$ 38.88万 - 项目类别:
相似海外基金
Targeted ablation of cerebral atherosclerosis using supramolecular self-assembly
利用超分子自组装靶向消融脑动脉粥样硬化
- 批准号:
24K21101 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
心房細動に対するPulsed Field Ablationの組織創傷治癒過程を明らかにする網羅的研究
阐明房颤脉冲场消融组织伤口愈合过程的综合研究
- 批准号:
24K11201 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
遅延造影心臓MRIによる心房細動Ablation冷却効果の比較:28 vs. 31 mm Cryoballoon
使用延迟对比增强心脏 MRI 比较房颤消融冷却效果:28 毫米与 31 毫米 Cryoballoon
- 批准号:
24K11281 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
InSPACE-VT_Development and Validation of Virtual Pace Mapping to Guide Catheter Ablation of Ventricular Tachycardia
InSPACE-VT_虚拟起搏测绘的开发和验证以指导室性心动过速导管消融
- 批准号:
EP/Z001145/1 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
Fellowship
CAREER: Heat Penetration Depth and Direction Control with Closed-Loop Device for Precision Ablation
职业:利用闭环装置控制热穿透深度和方向,实现精确烧蚀
- 批准号:
2338890 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
Continuing Grant
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
- 批准号:
2334777 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
Continuing Grant
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
- 批准号:
2334775 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
Continuing Grant
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
- 批准号:
2334776 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
Continuing Grant
Cryo laser-ablation system (157+193nm) with 'triple-quad' plasma mass spectrometer, Cryo-LA-ICPMS/MS
带有“三重四极杆”等离子体质谱仪、Cryo-LA-ICPMS/MS 的冷冻激光烧蚀系统 (157 193nm)
- 批准号:
515081333 - 财政年份:2023
- 资助金额:
$ 38.88万 - 项目类别:
Major Research Instrumentation
MRI: Acquisition of a Laser Ablation - Inductively Coupled Plasma - Triple Quadrupole - Mass Spectrometer (LA-ICP-QQQ-MS) System For Research and Education
MRI:获取用于研究和教育的激光烧蚀 - 电感耦合等离子体 - 三重四极杆 - 质谱仪 (LA-ICP-MS/MS) 系统
- 批准号:
2320040 - 财政年份:2023
- 资助金额:
$ 38.88万 - 项目类别:
Standard Grant