Animal and Clinical Core

动物和临床核心

基本信息

批准号：
10468114
负责人：
JEFFREY R FINEMAN
金额：
$ 66.18万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-20 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10468114
关键词：
Adult Anatomy Animal Model Animals Apoptosis Apoptotic Biochemical Bioenergetics Biological Biological Specimen database Biomechanics Blood Pressure Blood Vessels Blood flow Blood specimen Cardiac Cardiopulmonary Cardiopulmonary Bypass Cardiovascular system Cell Culture Techniques Cell Proliferation Cells Child Childhood Clinical Clinical Data Complex Congenital Heart Defects Coupled Data Data Analyses Databases Development Disease Progression Endothelium Ensure Equipment Evaluation Fetal Sheep Human Human Resources In Vitro Infant Laboratories Life Ligation Lung Measurement Metabolic Microfluidics Mitochondria Modeling Monitor Morphology Nitrogen Nitrogen Oxides Operative Surgical Procedures Oxygen Pathologic Pathway interactions Patients Pattern Peptides Periodicity Perioperative Peripheral Phenotype Physiological Post-Translational Protein Processing Postoperative Period Preparation Procedures Process Pulmonary artery structure Reproducibility Research Research Institute Research Personnel Resources Running Sampling Secure Services Shunt Device Smooth Muscle Myocytes Standardization Stretching Surgical Models System Techniques Tissues Training Tube Variant Vascular Endothelial Cell Work angiogenesis animal morbidity animal mortality base biobank clinical database clinically relevant congenital heart disorder cost efficient design disorder subtype experience experimental study fetal hemodynamics in utero in vivo in vivo imaging indexing innovation lung injury mechanical force mechanotransduction neonate novel postnatal pressure pulmonary vascular disorder pulmonary vascular remodeling repaired screening shear stress sheep model targeted treatment

项目摘要

ABSTRACT: With the use of fetal cardiac surgical techniques, Core C is designed to provide PPG investigators with rigorously defined and reproducible novel ovine models of congenital heart disease (CHD). To this end, Core C will comprehensively generate, manage and provide all animal-related experiments, resources, and expertise. In addition, Core C will obtain peri-operative blood samples from neonates, infants, children, and adults with a wide range of differing congenital heart defects, to be utilized by PPG investigators. A secure database is already established that contains banked samples and clinical data on >300 patients. In this context, Core C will be defined by providing six services: 1) Ovine models of CHD. This will include our well-established Shunt model and our newly created LPA ligation model. Tissues (peripheral lung and isolated vessels) and primary pulmonary artery endothelial and smooth muscle cells (both proximal and microvascular) will be available to PPG investigators. 2) Acquisition and analysis of data. This will include the evaluation of cardiopulmonary hemodynamics, pulmonary vascular reactivity (both in vivo and in vitro), the assessment of pulmonary vascular remodeling, advanced in vivo imaging, the effect of cardiopulmonary bypass on hemodynamics and vascular function, and the effect of different therapies. 3) Biochemical, proliferation, apoptosis, and angiogenesis determinations. This will include the measurement of various reactive oxygen and nitrogen species of oxygen or nitrogen oxide in vascular cells and tissues, indices of cell proliferation, apoptosis, and tube formation. 4) The in vitro assessment of differing biomechanical forces. This includes the utilization of a novel microfluidic chamber (UCSD) that allows the simultaneous and independent variation of pressure, cyclic stretch, and flow-induced shear stresses on the vascular endothelial cells. 5) Use of the CAR peptide to target therapeutics to the damaged pulmonary endothelium. To reduce the potential of off-target effects, we will utilize IV co-delivery of our therapies with the CARSKNKDC (CAR) peptide. 6) A bio-repository and corresponding clinical database of neonates, infants, children, and adults with CHD. Blood samples from patients with CHD will be obtained before and after surgical repair for human confirmation of aberrant pathways initially identified in animals and for metabolic screening. Correlation between the identified aberrations, with the type of CHD (+/- flow; +/- pressure), and degree of pre-operative and post-operative pulmonary vascular disease will be sought. Core C will enhance the scientific work for all three projects by assuring that all animal models are standardized and performed in a uniform manner by highly experienced and trained personnel. Investigators who have had many years of experience using these techniques run Core C. They have developed or adapted several of the techniques and applied them to perform physiological studies in in vitro and in vivo systems. As a central dedicated analytical resource Core C will ensure these analyses are also carried out in a cost-efficient manner with minimal animal morbidity and mortality.

摘要：使用胎儿心脏手术技术，Core C旨在提供PPG研究者具有严格定义和可重现的先天性心脏病（CHD）的新型卵巢模型。为此，核心C将全面生成，管理和提供所有与动物有关的实验，资源和专业知识。此外，核心C将从新生儿，婴儿，儿童和 PPG研究人员将使用各种不同先天性心脏缺陷的成年人。安全已经建立了数据库，其中包含> 300名患者的库存样本和临床数据。在这种情况下， Core C将通过提供六个服务来定义：1）CHD的烤箱模型。这将包括我们已建立的分流模型和我们新创建的LPA连接模型。组织（周围肺和孤立的血管）和原发性肺动脉内皮和平滑肌细胞（近端和微血管）将是可用于PPG调查人员。 2）数据获取和分析。这将包括评估心肺血液动力学，肺血管反应性（体内和体外），评估肺血管重塑，高级体内成像，心肺旁路的影响血液动力学和血管功能，以及不同疗法的作用。 3）生化，增殖，细胞凋亡和血管生成确定。这将包括测量各种活性氧和血管细胞和组织中氧气或氧化氮的氮种，细胞增殖指标，凋亡，凋亡，和管形成。 4）对不同生物力学力的体外评估。这包括利用一个新型的微流体室（UCSD），允许同时且独立的压力变化伸展和流动诱导的剪切应力在血管内皮细胞上。 5）使用汽车肽靶向对受损的肺部内皮的治疗学。为了降低脱靶效应的潜力，我们将利用静脉注射我们的疗法与汽车（CAR）肽的疗法。 6）生物叛逆者和相应的新生儿，婴儿，儿童和成年人的临床数据库。冠心病患者的血液样本将在手术修复之前和之后获得人类确认最初鉴定的异常途径的在动物和代谢筛查中。确定的畸变与冠心病类型之间的相关性（+/- 流动; +/-压力）以及术前和术后肺血管疾病的程度。 Core C将通过确保所有动物模型都标准化，从而增强所有三个项目的科学工作并由经验丰富训练的人员以统一的方式表演。曾经的调查人员使用这些技术运行核心的多年经验。他们已经开发或改编了几个技术并将其应用于体外和体内系统中的生理研究。作为中央专用的分析资源核心C将确保以经济高效的方式进行这些分析具有最小的动物发病率和死亡率。