Endothelial Healing is Inhibited by PI3 Kinase-Induced Activation of TRPC6
PI3 激酶诱导的 TRPC6 激活抑制内皮愈合
基本信息
- 批准号:10265334
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-01-01 至 2021-12-31
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAdaptor Signaling ProteinAgingAmericanAngioplastyAnimalsAntineoplastic AgentsAreaArterial InjuryArteriesAwardBalloon AngioplastyBindingBiological AssayBiologyBiometryBlood VesselsCalcium ionCalpainCardiovascular DiseasesCardiovascular systemCarotid Artery InjuriesCatalytic DomainCell ProliferationCell membraneCellsCenters for Disease Control and Prevention (U.S.)CholesterolCicatrixClinical TrialsCoagulation ProcessComplementCritical ThinkingCytoskeletal ProteinsDiagnosisDietDiseaseEffectivenessEndothelial CellsEndotheliumFoundationsFunctional disorderFundingGenerationsGoalsGrantHeart DiseasesHigh Fat DietIn VitroInflammatoryInjuryInterventionKnowledgeLaboratoriesLeadershipLengthLipidsLysophosphatidylcholinesMembraneMentorsMethodsModelingMolecular and Cellular BiologyMusOperative Surgical ProceduresOutcomePatientsPhosphatidylinositolsPlayPopulationProceduresProtein IsoformsProteinsPulmonary HypertensionQuality of lifeRNAReactive Oxygen SpeciesResearchResearch PersonnelRoleSiteSite-Directed MutagenesisSmall Interfering RNASmooth Muscle MyocytesStentsSurfaceSystemic hypertensionTNFRSF5 geneTRP channelTechniquesTestingTherapeuticThrombosisTransfectionTreatment ProtocolsUnited StatesUnited States National Institutes of HealthVascular DiseasesVascular GraftVeteransWild Type MouseWritingatherogenesisbasecareercareer developmentcell motilityclinical practiceeffectiveness testingexperiencehealinghigh rewardhuman old age (65+)hypercholesterolemiaimprovedimproved outcomein vivoinhibitor/antagonistinjuredkinase inhibitormacrophagemilitary veterannoveloverexpressionoxidationoxidized lipidoxidized low density lipoproteinpreservationpreventrestenosisskillssuccesstherapy outcomethrombogenesisvoltage gated channel
项目摘要
Cardiovascular disease is a devastating disorder that has a major impact on length and quality of life.
According to the CDC, approximately 27 million Americans carry the diagnosis of heart disease. The number of
heart and vascular procedures (balloon angioplasties and vascular grafts) that will be performed in 2030 is ex-
pected to be nearly twice the number performed in 2010. Similar increases will occur in the veteran population
When a blood vessel is treated with angioplasty, the endothelial cells (EC) are removed. The cells must
migrate from the edge of the injury into the area of injury to heal it. If healing is delayed, the chance of
restenosis is increased. Lipid oxidation products accumulate in atherosclerotic arteries and at regions of injury,
cause cellular dysfunction, and inhibit EC migration in vitro and in vivo. Limited re-endothelialization contributes
to thrombogenicity, smooth muscle cell proliferation, and restenosis.
Oxidized lipids cause an inappropriate increase in intracellular free calcium ion concentration ([Ca2+]i)
through canonical transient receptor potential (TRPC) channels, specifically TRPC6. Activation of TRPC6 by
causes an increase in [Ca2+]i that results in activation of TRPC5 and a prolonged increase in [Ca2+]i. The
increased [Ca2+]i activates calpains that break down cytoskeletal proteins inhibiting EC migration. Studies in
TRPC6-/- mice provide compelling evidence of the importance of this cascade in vivo. Re-endothelialization of
injured carotid arteries is dramatically reduced in wild-type (WT) mice on a high fat diet compared with chow-
fed mice, but in TRPC6-/- mice, hypercholesterolemia does not inhibit re-endothelialization of the injury.
Considerable effort has been directed at identifying a TRPC6 inhibitor without success. Lipid oxidation
products induce TRPC6 externalization by activating phosphatidylinositol 3-kinase (PI3K), which generates
PIP3 (phosphatidylinositol (3,4,5)-trisphosphate). PIP3 is anchored in the cell membrane and binds to TRPC6,
which promotes TRPC6 translocation to the cell membrane and leads to increased [Ca2+]i. We hypothesize that
inhibition of PI3K can block the activation of TRPC6 channels by lipid oxidation products and restore EC migra-
tion in vitro and promote EC healing of arterial injuries in vivo. To test this, we will 1) identify the PI3K iso-
form(s) essential for TRPC6 activation, 2) investigate the effectiveness of isoform-specific PI3K inhibitors to re-
store EC healing of arterial injuries in hypercholesterolemic animals, and 3) investigate the mechanism through
which PIP3 interacts with TRPC6 to promote TRPC6 translocation to the membrane and activation to identify a
more specific method of TRPC6 inhibition. The long-term scientific goal is to improve the outcome of ther-
apeutic vascular interventions promoting endothelial surfacing of angioplasty sites, stents, and vascular grafts.
In terms of a research career development, my short-term research goal is to develop a foundation in a
focused research area that I can expand over the course of my career and which will serve as a complement to
my clinical practice. My knowledge of vascular wall biology will increase through seminars and I will expand my
experience in cellular molecular biology laboratory techniques over the course of the award, including protein
extraction and analysis, small-inhibitory RNA transfection, and site directed mutagenesis. Over the course of
the award, I will gain additional experience in biostatistics, scientific and grant writing, laboratory management
and leadership, and mentoring. I will also continue to develop the critical thinking skills necessary for
successful research plans.
My primary long-term career goal is to transition to an independent investigator and compete for VA Merit
Review and NIH funding. My long-term research goal is to more clearly define the mechanisms by which
reactive oxygen species and the activation of TRPC channels inhibit endothelial cell healing. With progress in
this area, mechanism-based treatment regimens can be developed, transitioned into clinical trials, and
ultimately be carried into clinical practice to improve the long-term outcomes following vascular intervention.
心血管疾病是一种毁灭性的疾病,对生命的长度和质量有重大影响。
根据CDC的数据,大约有2700万美国人被诊断患有心脏病。的数量
心脏和血管手术(球囊血管成形术和血管移植术)将在2030年进行,
预计将是2010年的近两倍。类似的增长将发生在退伍军人人口中
当用血管成形术治疗血管时,内皮细胞(EC)被去除。细胞必须
从伤口边缘迁移到伤口区域进行愈合。如果愈合延迟,
再狭窄增加。脂质氧化产物在动脉粥样硬化动脉和损伤区域积聚,
导致细胞功能障碍,并抑制EC迁移在体外和体内。有限的再内皮化
血栓形成、平滑肌细胞增殖和再狭窄。
氧化脂质导致细胞内游离钙离子浓度([Ca 2 +]i)的不适当增加
通过典型瞬时受体电位(TRPC)通道,特别是TRPC 6。TRPC 6的激活
导致[Ca 2 +]i增加,导致TRPC 5活化和[Ca 2 +]i延长增加。的
增加的[Ca 2 +]i激活钙蛋白酶,钙蛋白酶分解抑制EC迁移的细胞骨架蛋白。研究
TRPC 6-/-小鼠提供了令人信服的证据,证明了这种级联反应在体内的重要性。再内皮化
与普通食物相比,高脂肪饮食的野生型(WT)小鼠中损伤的颈动脉显著减少,
喂食的小鼠中,但在TRPC 6-/-小鼠中,高胆固醇血症不抑制损伤的再内皮化。
相当大的努力已经指向识别TRPC 6抑制剂,但没有成功。脂质氧化
产物通过激活磷脂酰肌醇3-激酶(PI 3 K)诱导TRPC 6外化,
PIP 3(磷脂酰肌醇(3,4,5)-三磷酸)。PIP 3锚定在细胞膜上并与TRPC 6结合,
其促进TRPC 6易位至细胞膜并导致[Ca 2 +]i增加。我们假设
抑制PI 3 K可以阻断脂质氧化产物对TRPC 6通道的激活,恢复EC迁移。
体外实验表明,EC对动脉损伤有促进作用,体内实验表明EC对动脉损伤有促进作用。为了测试这一点,我们将1)识别PI 3 K iso-
TRPC 6激活所必需的形式,2)研究亚型特异性PI 3 K抑制剂重新激活的有效性
在高胆固醇血症动物中储存EC对动脉损伤的愈合,以及3)通过以下方式研究机制:
所述PIP 3与TRPC 6相互作用以促进TRPC 6易位至膜并活化以鉴定一种新的细胞,
TRPC 6抑制的更特异的方法。长期的科学目标是改善治疗结果-
血管介入促进血管成形术部位、支架和血管移植物的内皮表面化。
在研究职业发展方面,我的短期研究目标是在一个
重点研究领域,我可以在我的职业生涯中扩大,这将作为补充,
我的临床实践我的血管壁生物学知识将通过研讨会增加,我将扩大我的
在获奖过程中具有细胞分子生物学实验室技术的经验,包括蛋白质
提取和分析、小抑制RNA转染和定点诱变。过程中
通过该奖项,我将在生物统计学,科学和资助写作,实验室管理
领导力和指导力。我还将继续培养必要的批判性思维技能,
成功的研究计划。
我的主要长期职业目标是过渡到一个独立的调查员和竞争VA的优点
审查和NIH资助。我的长期研究目标是更清楚地定义
活性氧和TRPC通道的激活抑制内皮细胞愈合。中有进
在这一领域,可以开发基于机制的治疗方案,过渡到临床试验,
最终用于临床实践,以改善血管介入治疗后的长期结局。
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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Michael Aaric Rosenbaum其他文献
Michael Aaric Rosenbaum的其他文献
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{{ truncateString('Michael Aaric Rosenbaum', 18)}}的其他基金
Endothelial Healing is Inhibited by Activation of TRPC6 Channels
TRPC6 通道的激活会抑制内皮愈合
- 批准号:
10369226 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Endothelial Healing is Inhibited by Activation of TRPC6 Channels
TRPC6 通道的激活会抑制内皮愈合
- 批准号:
10526285 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Endothelial Healing is Inhibited by PI3 Kinase-Induced Activation of TRPC6
PI3 激酶诱导的 TRPC6 激活抑制内皮愈合
- 批准号:
9240762 - 财政年份:2017
- 资助金额:
-- - 项目类别:
Effect of Oxidized Lipids on Endothelial Migration and Vascular Graft Healing
氧化脂质对内皮迁移和血管移植物愈合的影响
- 批准号:
7328918 - 财政年份:2007
- 资助金额:
-- - 项目类别:
Effect of Oxidized Lipids on Endothelial Migration and Vascular Graft Healing
氧化脂质对内皮迁移和血管移植物愈合的影响
- 批准号:
7500876 - 财政年份:2007
- 资助金额:
-- - 项目类别: