Mechanisms of morbidity after correcting aortic coarctations of varying severity

纠正不同严重程度的主动脉缩窄后的发病机制

基本信息

批准号：
10455296
负责人：
John Frank LaDisa
金额：
$ 26.53万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
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：
2018-07-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10455296
关键词：
Actins Adolescent Affect Aftercare Age Animal Model Aorta Aortic coarctation Arteries Binding Birth Blinded Blood Blood Pressure Blood Vessels Candidate Disease Gene Cardiovascular Abnormalities Cardiovascular Diseases Cardiovascular system Cell Culture Techniques Cell Proliferation Cell membrane Cells Child Clinical Congenital Cardiovascular Abnormality Cytoskeleton Data Disease Distal Down-Regulation Eligibility Determination Endothelial Cells Endothelium Exposure to Functional disorder Gene Expression Genes Genetic Goals Grant Health Heart Human Hydrolysis Hypertension Impairment Individual Ion Channel Lead Life Expectancy Liquid substance Longevity MARCKS gene Mechanics Medial Mediating Methods Mission Modeling Molecular Morbidity - disease rate NOS3 gene National Heart, Lung, and Blood Institute Natriuretic Peptides Neonatal Newly Diagnosed Nitric Oxide Operative Surgical Procedures Oryctolagus cuniculus Oxidative Stress Pathologic Pathway interactions Patients Peptide Receptor Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phospholipase C Phospholipids Play Population Prevention Production Protocols documentation Quality of life Records Refractory Regulation Relaxation Research Research Personnel Role Scientist Screening procedure Second Messenger Systems Severities Signal Pathway Stenosis Stimulus Structure Surgical sutures Testing Therapeutic Therapeutic Agents Thoracic aorta Time Tissues Translating Upper Extremity arterial remodeling arterial stiffness base clinical translation constriction endothelial dysfunction experience follow-up human tissue in vivo in vivo Model mechanical force new therapeutic target next generation novel protein expression receptor targeted agent transcriptome sequencing treatment duration treatment guidelines treatment optimization

项目摘要

Project Summary/Abstract Coarctation of the aorta (CoA) is a congenital cardiovascular (CV) disease characterized by a severe stenosis of the main artery delivering blood from the heart to the body. CoA affects 5,000 to 8,000 births annually in the U.S. Treatments exist, but treated CoA patients often have a reduced life expectancy from morbidity, most notably hypertension (HTN). Identifying the cause of morbidity is difficult because of confounding factors such as differences in patient age, time to follow-up, severity before treatment, and the presence of other CV abnormalities. It is also difficult to separate causal genetic contributions that create the initial stenosis from changes in gene expression due to mechanical consequences after its creation. To remove these barriers we used RNA sequencing to identify a candidate gene from humans with CoA that had upper extremity systolic blood pressure (BP) >99th percentile, thereby focusing on mechanical consequences. Natriuretic peptide receptor 3 (NPR3), a gene known to be associated with BP and cellular proliferation, was downregulated in sections of the aorta subjected to high BP when compared to normal BP regions. A novel animal model of CoA was then developed to control for the variability in humans (severity, duration & age), and to study mechanisms of arterial dysfunction by simulating treatment via absorbable suture. Changes in NPR3 seen in humans with CoA were replicated with this model. Preliminary data also showed that the current treatment guideline for CoA permits adverse arterial changes that do not revert after treatment without augmenting NPR3. Evidence is also provided for new severity and duration treatment thresholds that avoid adverse arterial changes. The current study uses this model with computational fluid dynamics and associated cell culture analysis to quantify detailed mechanical stimuli we hypothesize are responsible for arterial remodeling and endothelial dysfunction in CoA, and eventually lead to HTN. Stimuli are classified according to the structural, functional and cellular changes they impose using state-of-the-art approaches and specialized agents targeting NPR3. Aim 1 will confirm the mechanical stimuli that avoids adverse arterial changes by extracting HTN status from clinical records of CoA patients exposed to the same range of stimuli. Aim 2 will correlate adverse vascular changes from CoA with NPR3 expression via established pathways with intent to apply existing therapeutics. Aim 3 will test a novel mechanism for coarctation-induced arterial dysfunction via NPR3 involving myristoylated alanine- rich C kinase substrate (MARCKS) regulation of phosphoinositide-dependent ion channel and receptor control. The collective results have the potential for clinical translation in short order by suggesting revised criteria for when treatment of CoA should be implemented, and identifying targets for management of arterial changes. Translating results from the current proposal in these ways is aligned with NHLBI's mission of prevention and treatment of CV disease, enhancing the health of all individuals so that they can live longer and more fulfilling lives, and educating the next generation of scientists in the methods applied for this purpose.

项目摘要/摘要主动脉（COA）的缩合是一种先天性心血管（CV）疾病，其特征是严重狭窄主要动脉将血从心脏传递到身体。 COA每年在美国存在，但是接受治疗的COA患者通常会因发病率而降低预期寿命，大多数特别是高血压（HTN）。由于混杂因素，确定发病率的原因很困难随着患者年龄的差异，随访时间，治疗前的严重程度以及其他CV的存在异常。也很难分开因果遗传贡献，从而产生最初的狭窄基因表达因其创建后的机械后果而导致的变化。为了消除这些障碍使用RNA测序来鉴定具有上肢收缩期的COA的人类的候选基因血压（BP）>第99个百分位数，从而着重于机械后果。亚钠肽受体3（NPR3）是一种已知与BP和细胞增殖相关的基因，在与正常的BP区域相比，主动脉的截面具有高BP。 COA的新型动物模型然后开发以控制人类的变异性（严重程度，持续时间和年龄），并研究机制通过可吸收缝合线模拟治疗，动脉功能障碍。在人类中看到的NPR3的变化使用此模型复制了COA。初步数据还表明，当前的COA治疗指南允许在不增加NPR3的情况下在治疗后无法恢复的不良动脉变化。证据也是提供了新的严重性和持续时间治疗阈值，以避免动脉变化。电流研究使用该模型与计算流体动力学和相关的细胞培养分析来量化我们假设的详细的机械刺激负责动脉重塑和内皮功能障碍在COA，最终导致HTN。根据结构，功能和细胞对刺激进行分类他们使用针对NPR3的最先进的方法和专门的代理来实施的更改。目标1意志通过从临床中提取HTN状态来确认避免动脉变化的机械刺激 COA患者的记录暴露于相同的刺激范围。 AIM 2将使不良血管变化相关从具有NPR3表达的COA通过建立的途径，目的是应用现有的治疗剂。目标3意志测试一种通过NPR3涉及肉豆蔻酰胺 - 富含C磷酸肌醇依赖性离子通道和受体控制的富C激酶底物（MARCKS）调节。通过建议修订的标准当应实施COA的处理并确定用于管理动脉变化的目标时。以这些方式将当前提案的结果转换为NHLBI的预防任务和治疗简历疾病，增强所有人的健康，使他们能够更长，更充实生活，并在为此目的的方法中教育下一代科学家。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Molecular and Mechanical Mechanisms of Calcification Pathology Induced by Bicuspid Aortic Valve Abnormalities.

DOI：
10.3389/fcvm.2021.677977
发表时间：
2021
期刊：
Frontiers in cardiovascular medicine
影响因子：
3.6
作者：
Kazik HB;Kandail HS;LaDisa JF Jr;Lincoln J
通讯作者：
Lincoln J

Aortic Remodeling Kinetics in Response to Coarctation-Induced Mechanical Perturbations.

DOI：
10.3390/biomedicines11071817
发表时间：
2023-06-25
期刊：
Biomedicines
影响因子：
4.7
作者：
通讯作者：

C Type Natriuretic Peptide Receptor Activation Inhibits Sodium Channel Activity in Human Aortic Endothelial Cells by Activating the Diacylglycerol-Protein Kinase C Pathway.

DOI：
10.3390/ijms232213959
发表时间：
2022-11-12
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
通讯作者：

Coarctation duration and severity predict risk of hypertension precursors in a preclinical model and hypertensive status among patients.

缩窄持续时间和严重程度可以预测临床前模型中高血压先兆的风险和患者的高血压状态。

DOI：
10.1101/2023.10.30.23297766
发表时间：
2024
期刊：
medRxiv : the preprint server for health sciences
影响因子：
0
作者：
Ghorbannia,Arash;Jurkiewicz,Hilda;Nasif,Lith;Ahmed,Abdillahi;Co-Vu,Jennifer;Maadooliat,Mehdi;Woods,RonaldK;LaDisaJr,JohnF
通讯作者：
LaDisaJr,JohnF

Temporal evolution of mechanical stimuli from vascular remodeling in response to the severity and duration of aortic coarctation in a preclinical model.