Altered Mechanotransduction
Altered Mechanotransduction
批准号:
10378125
负责人:
DANIEL B RIFKIN
金额:
$43.79万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-03-01 至 2024-02-29
关键词:
AddressAffectAneurysmAnimalsAortaAortic DiseasesBindingBinding ProteinsBiochemicalBiogenesisBiomechanicsBirthBlood PressureBlood VesselsCell CommunicationCellsCharacteristicsChestComplementComplement Factor BComplexDefectDevelopmentDissectionEnvironmentEventExtracellular MatrixFailureFutile CyclingGene Expression ProfileGeneticGenotypeGleanHypertensionIn VitroIndividualInfusion proceduresKnowledgeLesionMarfan SyndromeMeasurementMechanical StressMechanicsMedialMediator of activation proteinModelingMonitorMusMutant Strains MiceMutationParticipantPharmacotherapyProductionPropertyProtein IsoformsProteinsResponse LatenciesSignal TransductionSignaling MoleculeStressStretchingStructureThoracic Aortic AneurysmThoracic aortaTransforming Growth Factor betaTransforming Growth FactorsVascular remodelingbasebiomechanical modelblood pressure elevationdrug developmentexperimental studygenetic approachhypertensiveinsightmechanical loadmechanotransductionmouse modelnovelpreservationpressurepreventprotective effectreceptorresponsesensortherapeutic target
中文摘要
项目摘要
我们试图阐明控制转化生长因子激活的生物力学机制。
转化生长因子β,胸主动脉瘤进展过程中的主要介体。在此PPG应用程序中
我们提出了一项具有挑衅性的建议,即细胞使用潜在的转化生长因子β,它位于
细胞外基质(ECM)作为生物力学变化的传感器。当周围的矩阵发生变化时
由于固有的结构突变或周围力量的变化,如血压,转化生长因子β是
动员起来重塑EMC。我们假设,为了理解潜伏的转化生长因子β的控制机制
在动员过程中,我们必须确定潜在的转化生长因子β复合体的特定个体成分。我们将重点关注
转化生长因子β在两种相辅相成的血管病变中的作用
患有马凡综合征(MFS)并死于TAA的突变小鼠。另一个模型使用的是正常小鼠
其大动脉被结扎以增加压力(缩窄模型),从而导致快速血管
我们提出的重塑,复制了压力相关的TAA促进的早期事件。因此,
一个模型代表了具有改变的ECM成分的基质的遗传缺陷,而第二个模型
表示因感应应力而重塑的法线矩阵。我们将在目标1中确定
转化生长因子β参与MFS小鼠的细胞外基质重塑和TAA的生物发生(项目1,核心B和C)。在……里面
目的2,我们将表征LTBP在MFS和高血压小鼠中的种类,基质重塑,
和动脉瘤的形成(项目4),并阐明LTBP是通过转化生长因子β还是通过额外的
结构功能(项目1和4以及核心B和C)。在目标3中,我们将了解ECM是否
MFS细胞和动物更容易释放活性的转化生长因子β,当放置在
机械应力(项目3和核心C)以及阻止TAA形成的ECM的变化也会影响
转化生长因子β发布(包括项目1和4以及核心C)。从这些实验中获得的信息将
让我们了解潜在的转化生长因子β是如何导致交通事故的,从而说明
药物治疗的发展。
好了!
英文摘要
Project Summary
We seek to elucidate the biomechanical mechanisms that control the activation of transforming growth factor
beta (TGFβ), a major mediator in the progression of thoracic aortic aneurysms (TAA). In this PPG application
we have put forward the provocative proposal that cells use the latent form of TGFβ, which resides in the
extracellular matrix (ECM), as a sensor of biomechanical changes. Upon alteration in the surrounding matrix
due to inherent structural mutations or changes in surrounding forces, such as blood pressure, TGFβ is
mobilized to remodel the EMC. We posit that to understand the mechanisms controlling latent TGFβ
mobilization, we must identify the specific individual components of the latent TGFβ complex. We will focus on
the properties of TGFβ in the development of two complementary types of vascular lesions; one involves
mutant mice that have Marfan syndrome (MFS) and die from TAA. The other model employs normal mice
whose aortas have been ligated to increase pressure (coarctation model) that results in rapid vascular
remodeling, which we propose duplicates the early events in pressure-related promotion of TAA. Therefore,
one model represents a genetic defect of the matrix with altered ECM composition, whereas the second model
represents a normal matrix remodeled because of an induced stress. We will in Aim 1 identify the isoform of
TGFβ involved in ECM remodeling and TAA biogenesis in MFS mice (with Projects 1 and Cores B and C). In
Aim 2, we will characterize the species of LTBP involved in MFS and hypertensive mice, matrix remodeling,
and aneurysm formation (with Project 4) and elucidate whether the LTBP acts via TGFβ or by an additional
structural function (with Projects 1 and 4 and Cores B and C). In Aim 3, we will discern whether the ECM of
the MFS cells and animals releases active TGFβ more readily that does normal ECM when placed under
mechanical stress (with Project 3 and Core C) and if changes in the ECM that block TAA formation also affect
TGFβ release (with Projects 1 and 4 and Core C). The information obtained from these experiments will
provide an understanding of how latent TGFβ contributes to TAA and thereby illustrate potential points for the
development of drug therapy.
!
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
2019 Elastin, Elastic Fibers and Microfibrils Gordon Research Conference and Seminar
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批准号:9760801
-
项目类别:
-
资助金额:$1.5万
-
财政年份:2019
-
负责人:DANIEL B RIFKIN
-
依托单位:
Core A-Administrative Core
-
批准号:10378121
-
项目类别:
-
资助金额:$19.16万
-
财政年份:2018
-
负责人:DANIEL B RIFKIN
-
依托单位:
Altered Mechanotransduction as a Therapeutic Target for Thoracic Aortic Aneurysm
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批准号:10378120
-
项目类别:
-
资助金额:$239.37万
-
财政年份:2018
-
负责人:DANIEL B RIFKIN
-
依托单位:
Altered Mechanotransduction as a Therapeutic Target for Thoracic Aortic Aneurysm
-
批准号:9883023
-
项目类别:
-
资助金额:$240.07万
-
财政年份:2018
-
负责人:DANIEL B RIFKIN
-
依托单位:
Graduate Program in Cellular and Molecular Biology.
-
批准号:8678356
-
项目类别:
-
资助金额:$9.61万
-
财政年份:2013
-
负责人:DANIEL B RIFKIN
-
依托单位:
Regulation of TGF-Beta Activity in the Lung by LTBP-4
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批准号:8761275
-
项目类别:
-
资助金额:$34.45万
-
财政年份:2013
-
负责人:DANIEL B RIFKIN
-
依托单位:
Mechanisms for Latent TGF-beta1 Activation In Vivo
-
批准号:8208224
-
项目类别:
-
资助金额:$43.51万
-
财政年份:2009
-
负责人:DANIEL B RIFKIN
-
依托单位:
Mechanisms for Latent TGF-beta1 Activation In Vivo
-
批准号:8021813
-
项目类别:
-
资助金额:$43.51万
-
财政年份:2009
-
负责人:DANIEL B RIFKIN
-
依托单位:
TGF-Beta and Inflammation in Gastric Cancer
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批准号:7786283
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项目类别:
-
资助金额:$18.65万
-
财政年份:2009
-
负责人:DANIEL B RIFKIN
-
依托单位:
Mechanisms for Latent TGF-beta1 Activation In Vivo
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批准号:7746445
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项目类别:
-
资助金额:$44.11万
-
财政年份:2009
-
负责人:DANIEL B RIFKIN
-
依托单位:
TGF-Beta and Inflammation in Gastric Cancer
-
批准号:7641413
-
项目类别:
-
资助金额:$18.65万
-
财政年份:2009
-
负责人:DANIEL B RIFKIN
-
依托单位:
Cell Signaling in Marfan Syndrome
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批准号:7460911
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项目类别:
-
资助金额:$26.75万
-
财政年份:2007
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负责人:DANIEL B RIFKIN
-
依托单位:
A Genetic Screen for Latent TGF-beta Activators
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批准号:6940806
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项目类别:
-
资助金额:$15.21万
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财政年份:2004
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负责人:DANIEL B RIFKIN
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依托单位:
Nodal Points in Marfan Syndrome Progression
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批准号:8527713
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项目类别:
-
资助金额:$36.8万
-
财政年份:2004
-
负责人:DANIEL B RIFKIN
-
依托单位:
Nodal Points in Marfan Syndrome Progression
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批准号:8122263
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项目类别:
-
资助金额:$35.47万
-
财政年份:2004
-
负责人:DANIEL B RIFKIN
-
依托单位:
A Genetic Screen for Latent TGF-beta Activators
-
批准号:6799538
-
项目类别:
-
资助金额:$15.21万
-
财政年份:2004
-
负责人:DANIEL B RIFKIN
-
依托单位:
PROJECT 3: Cell Signaling in Marfan Syndrome (Daniel Rifkin, Ph.D.)
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批准号:6852074
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项目类别:
-
资助金额:$26.11万
-
财政年份:2004
-
负责人:DANIEL B RIFKIN
-
依托单位:
Nodal Points in Marfan Syndrome Progression
-
批准号:7779682
-
项目类别:
-
资助金额:$36.54万
-
财政年份:2004
-
负责人:DANIEL B RIFKIN
-
依托单位:
Nodal Points in Marfan Syndrome Progression
-
批准号:8379270
-
项目类别:
-
资助金额:$38.97万
-
财政年份:2004
-
负责人:DANIEL B RIFKIN
-
依托单位:
Nodal Points in Marfan Syndrome Progression
-
批准号:8317955
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项目类别:
-
资助金额:$42.2万
-
财政年份:2004
-
负责人:DANIEL B RIFKIN
-
依托单位:
海外基金