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:9240762
- 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 ArteriesCatalytic DomainCell ProliferationCell membraneCellsCenters for Disease Control and Prevention (U.S.)CholesterolCicatrixClinical TrialsCoagulation ProcessComplementCritical ThinkingCytoskeletal ProteinsDiagnosisDietDiseaseEffectivenessElderlyEndothelial CellsFoundationsFunctional disorderFundingGenerationsGoalsGrantHeart DiseasesHigh Fat DietIn VitroInflammatoryInjuryInterventionKnowledgeLaboratoriesLeadershipLengthLipidsLysophosphatidylcholinesMembraneMentorsMethodsModelingMolecular and Cellular BiologyMusOperative Surgical ProceduresOutcomePatientsPhosphatidylinositolsPlayPopulationProceduresProtein IsoformsProteinsPulmonary HypertensionQuality of lifeRNAReactive Oxygen SpeciesResearchResearch PersonnelRoleSiteSite-Directed MutagenesisSmall Interfering RNASmooth Muscle MyocytesStentsSurfaceSystemic hypertensionTNFRSF5 geneTechniquesTestingTherapeuticThrombosisTransfectionTreatment ProtocolsUnited StatesUnited States National Institutes of HealthVascular DiseasesVascular GraftVeteransWild Type MouseWritingatherogenesisbasecareercareer developmentcell motilityclinical practiceexperiencehealinghigh rewardhypercholesterolemiaimprovedimproved outcomein vivoinhibitor/antagonistinjuredkinase inhibitormacrophagenoveloverexpressionoxidationoxidized lipidoxidized low density lipoproteinpreventreceptorrestenosisskillssuccesstherapy outcomevoltage 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.
心血管疾病是一种严重影响寿命和生活质量的破坏性疾病。
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:
10265334 - 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: