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
项目概要
我们试图阐明控制转化生长因子激活的生物力学机制
beta (TGFβ) 是胸主动脉瘤 (TAA) 进展的主要介质。在此 PPG 应用程序中
我们提出了一个具有挑战性的提议,即细胞使用潜在形式的 TGFβ,它存在于
细胞外基质(ECM),作为生物力学变化的传感器。当周围矩阵发生变化时
由于固有的结构突变或周围力量(例如血压)的变化,TGFβ
动员起来改造EMC。我们假设要了解控制潜在 TGFβ 的机制
动员之前,我们必须识别潜在 TGFβ 复合物的具体个体成分。我们将重点关注
TGFβ 在两种互补类型血管病变发展中的特性;一个涉及
患有马凡氏综合症 (MFS) 并死于 TAA 的突变小鼠。另一个模型使用正常小鼠
其主动脉已被结扎以增加压力(缩窄模型),从而导致血管快速收缩
重塑,我们建议重复与压力相关的 TAA 促进的早期事件。因此,
第一个模型代表 ECM 成分发生改变的基质的遗传缺陷,而第二个模型
表示由于诱发应力而重塑的法线矩阵。我们将在目标 1 中鉴定以下亚型
TGFβ 参与 MFS 小鼠的 ECM 重塑和 TAA 生物合成(项目 1 以及核心 B 和 C)。在
目标 2,我们将表征参与 MFS 和高血压小鼠、基质重塑、
和动脉瘤形成(与项目 4 一起),并阐明 LTBP 是通过 TGFβ 还是通过其他途径发挥作用
结构功能(项目 1 和 4 以及核心 B 和 C)。在目标 3 中,我们将辨别 ECM 是否
MFS 细胞和动物更容易释放活性 TGFβ,比正常 ECM 更容易释放
机械应力(项目 3 和核心 C)以及阻止 TAA 形成的 ECM 变化是否也会影响
TGFβ 释放(与项目 1 和 4 以及核心 C)。从这些实验中获得的信息将
了解潜在的 TGFβ 如何促进 TAA,从而说明潜在的观点
药物治疗的发展。
!
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
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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
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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
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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.
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批准号:8678356
-
项目类别:
-
资助金额:$9.61万
-
财政年份:2013
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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
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项目类别:
-
资助金额:$34.45万
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财政年份:2013
-
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:8208224
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项目类别:
-
资助金额:$43.51万
-
财政年份:2009
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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:8021813
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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
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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
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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:7641413
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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:
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
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财政年份:2007
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负责人:DANIEL B RIFKIN
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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
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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: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
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批准号:6799538
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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
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批准号:7779682
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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
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批准号:8379270
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项目类别:
-
资助金额:$38.97万
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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: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
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依托单位:
海外基金