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Altered Mechanotransduction as a Therapeutic Target for Thoracic Aortic Aneurysm

改变机械传导作为胸主动脉瘤的治疗靶点

基本信息

批准号：
10378120
负责人：
DANIEL B RIFKIN
金额：
$ 239.37万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10378120
关键词：
Affect Aneurysm Angiotensin II Angiotensin II Receptor Angiotensinogen Antihypertensive Agents Aorta Applications Grants Area Binding Proteins Biochemical Bioinformatics Biological Biomechanics Blood Vessels Blood flow Cells Characteristics Chest Clinical Complement Complex Cytokine Receptors Data Development Disease Elastic Fiber Endothelial Cells Extracellular Matrix FBN1 Failure Genes Genetic Goals Homeostasis Human ITGA5 gene In Situ In Vitro Individual Inflammatory Infusion procedures Institution Lead Life Ligands Marfan Syndrome Measures Mechanical Stress Mediator of activation protein Medical Modeling Molecular Mus Mutation Operative Surgical Procedures Pathogenesis Pathology Pathway interactions Pattern Pharmacology Pharmacotherapy Physiological Program Research Project Grants Property Protein Isoforms Receptor Cell Receptor Signaling Regulation Relaxation Role Signal Transduction Signaling Molecule Smooth Muscle Myocytes Specific qualifier value Specimen Stimulus Stretching TGFBR1 gene Techniques Testing Thoracic Aortic Aneurysm Thoracic aorta Tissues Transforming Growth Factor beta Vasoconstrictor Agents biomechanical test blood pressure elevation cadherin 5 cell type data integration differential expression experimental study hemodynamics improved outcome in vivo insight interdisciplinary approach mechanical force mechanical load mechanical signal mechanotransduction mouse model mutant novel novel therapeutics postnatal pressure prevent prophylactic protective effect protein activation receptor response shear stress therapeutic target transcriptome sequencing

项目摘要

Overall - Project Summary Thoracic aortic aneurysms (TAA) are a group of life threatening conditions for which there is no good therapy. We have proposed that specific genetic defects and environmental insults that alter distinct aspects of the physiological interactions amongst cells and ECM lead to TAAs. As such, we view TAA as a disease of altered vascular mechanobiology. In this Program Project Grant application, we will focus on the biological responses of aortic cells, namely smooth muscle cells (SMC) and endothelial cells (EC) to the two major physical determinants of disease, namely decreased ECM integrity and increased hemodynamic loads. We will examine responses of ECs and SMCs during aneurysm development in mice with normal or compromised ECM while focusing on signaling through angiotensin II and transforming growth factor beta in response to increased hemodynamic loads. We will examine responses of the multiple mouse models to changes in flow, pressure, and additional genetic perturbations focusing on AT1r, TGFBR1/2, TGFβ, and flow-dependent signaling and activation (e.g., VECAD and PECAM). Consequences of cellular and tissue changes will be analyzed with our Computational and Experimental Biomechanical Assessment and Bioinformatics and Modeling Cores. For example, a subset of mice from all mouse models will be tested in the Computational and Experimental Biomechanical Assessment core for biomechanical parameters and all differentially expressed gene data from RNAseq experiments will be analyzed in the Bioinformatics and Modeling core. In this way the information from all four projects can be applied en mass yielding considerably more significance. Our intent is to develop novel interpretations from the changes in biomechanics and cell signaling to yield new testable hypothesis concerning ECM modulation in addition to the revelation of important signaling nodes and novel potential drug therapies. We propose that a consistent, integrated approach, using unique but complementary mouse models for aneurysm genesis and progression, studied under several conditions will yield unique insights in a synergistic manner.

总体--项目摘要胸主动脉瘤(TAA)是一组危及生命的疾病，目前还没有很好的治疗方法。我们已经提出，特定的遗传缺陷和环境侮辱改变了细胞与细胞外基质之间的生理相互作用导致TAAs。因此，我们认为TAA是一种改变了血管机械生物学。在本计划的项目资助申请中，我们将重点关注生物血管平滑肌细胞(SMC)和内皮细胞(EC)对两种主要成分的反应疾病的物理决定因素，即ECM完整性降低和血流动力学负荷增加。我们会检测正常或受损小鼠动脉瘤形成过程中内皮细胞和平滑肌细胞的反应 ECM，同时专注于通过血管紧张素II和转化生长因子β反应信号血流动力学负荷增加。我们将检查多个鼠标模型对流量变化的反应，压力和其他遗传扰动，集中在AT1r、TGFBR1/2、转化生长因子β和依赖于流的信令和激活(例如，VECAD和PECAM)。细胞和组织变化的后果将是分析了我们的计算和实验生物力学评估和生物信息学模特核心。例如，来自所有小鼠模型的小鼠的子集将在计算和实验生物力学评价指标与各参数的差异性表达来自RNAseq实验的基因数据将在生物信息学和建模核心中进行分析。通过这种方式，来自所有四个项目的信息都可以批量应用，产生的意义要大得多。我们的意图是从生物力学和细胞信号的变化中开发新的解释以产生新的可测试性关于ECM调制的假设--兼论重要信令节点的揭示和新颖潜在的药物疗法。我们建议采用一致、综合的方法，使用独特但互补的方法在几种条件下研究动脉瘤发生和发展的小鼠模型将产生独特的以协同的方式获得洞察力。

项目成果

期刊论文数量（38）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Excessive adventitial stress drives inflammation-mediated fibrosis in hypertensive aortic remodelling in mice.

DOI：
10.1098/rsif.2021.0336
发表时间：
2021-07
期刊：
Journal of the Royal Society, Interface
影响因子：
0
作者：
Spronck B;Latorre M;Wang M;Mehta S;Caulk AW;Ren P;Ramachandra AB;Murtada SI;Rojas A;He CS;Jiang B;Bersi MR;Tellides G;Humphrey JD
通讯作者：
Humphrey JD

A fast, robust method for quantitative assessment of collagen fibril architecture from transmission electron micrographs.

一种通过透射电子显微照片定量评估胶原原纤维结构的快速、稳健的方法。

DOI：
10.1101/2023.02.06.527383
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Rego,BrunoV;Weiss,Dar;Humphrey,JayD
通讯作者：
Humphrey,JayD

Quantitative not qualitative histology differentiates aneurysmal from nondilated ascending aortas and reveals a net gain of medial components.

DOI：
10.1038/s41598-021-92659-1
发表时间：
2021-06-23
期刊：
Scientific reports
影响因子：
4.6
作者：
Yousef S;Matsumoto N;Dabe I;Mori M;Landry AB;Lee SR;Kawamura Y;Yang C;Li G;Assi R;Vallabhajosyula P;Geirsson A;Moeckel G;Humphrey JD;Tellides G
通讯作者：
Tellides G

Diagnosis of Thoracic Aortic Aneurysms by Computed Tomography Without Allometric Scaling.

通过计算机断层扫描诊断胸动脉动脉瘤，而无需同形缩放。

DOI：
10.1001/jamanetworkopen.2020.23689
发表时间：
2020-11-02
期刊：
JAMA network open
影响因子：
13.8
作者：
Yousef S;Mori M;Bin Mahmood SU;Assi R;Vallabhajosyula P;Geirsson A;Tellides G
通讯作者：
Tellides G

Intracellular signaling control of mechanical homeostasis in the aorta.

主动脉中机械稳态的细胞内信号控制。