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In Vitro Human Tissue-Engineered Blood Vessel Disease Model of Progeria

早衰症体外人体组织工程血管疾病模型

基本信息

批准号：
9759965
负责人：
George A Truskey
金额：
$ 46.21万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9759965
关键词：
20 year old Address Aging Alternative Splicing Animal Model Animals Antisense Oligonucleotides Apoptosis Arterial Fatty Streak Arteries Atherosclerosis Autophagocytosis Bacterial Artificial Chromosomes Biological Markers Blood Vessels CCI-779 Cardiovascular Diseases Cardiovascular system Cause of Death Cell Aging Cell Count Cell Differentiation process Cell Nucleus Cells Cellularity Cessation of life Clinical Research Combined Modality Therapy Coronary artery Cultured Cells Development Disease Disease Progression Disease model Drug Combinations Drug effect disorder Effectiveness Endothelium Ensure Environment Epigenetic Process Exhibits Farnesyl Transferase Inhibitor Fibroblasts Fibrosis Gene Expression Gene Mutation Genes Hour Human Human Engineering Impairment In Vitro Individual Inflammation Inflammation Mediators Inflammatory Knock-in Lamin Type A Lamins Lesion Lipids Lonafarnib Measurement Medial Mediating Methylene blue Mitochondria Mitosis Modeling Mus Myocardial Infarction Nuclear Nuclear Protein Oxidative Stress Parents Patients Perfusion Pharmaceutical Preparations Pharmacotherapy Phenotype Physiological Point Mutation Pravastatin Preparation Process Production Progeria Proteins RNA Splicing Rare Diseases Running Rupture Shapes Signal Pathway Signal Transduction Site Smooth Muscle Myocytes Stroke Structure Syndrome System Testing Therapeutic Thick Tissue Engineering Treatment Effectiveness Vascular Diseases Zoledronic Acid aged biomarker identification calcification carbene clinical candidate drug candidate histone methylation human tissue improved in vivo in vivo Model induced pluripotent stem cell microphysiology system mouse model normal aging novel novel therapeutics osteogenic protein degradation response

项目摘要

Abstract Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare autosomal dominant disease of accelerated aging which leads to death between 7 and 20 years of age. The disease arises from point mutations that produce an alternately spliced form of the nuclear protein lamin A, known as progerin, that accumulates in the cell nucleus. Mouse models of HGPS exhibit many phenotypical similarities with the HGPS lamin gene mutation, but atherosclerosis does not develop, suggesting a limit to the suitability of animal models. Since cardiovascular disease represents the primary cause of death among those with HGPS, we propose to use a novel tissue engineered blood vessel microphysiological system to develop biomarkers for the disease and assess the effectiveness of treatment against relevant physiological measurements. We have developed arteriolar-scale endothelialized tissue-engineered blood vessels (TEBVs) using smooth muscle cells (SMCs) derived from induced pluripotent stem cells (iPSCs) using healthy and HGPS cells. The TEBVs can be produced and perfused at physiological flow conditions within a few hours of preparation and exhibit endothelial-mediated vasoactivity and respond to inflammatory mediators. We can perform standard functional tests and examine the effects of inflammatory signals, thus tracking the progression of the disease in the same vessel. The HGPS-TEBVs provide a more realistic in vitro environment than cells cultured on plastic and can help advance the process of discovering novel therapeutics and identification of biomarkers. In this project, we will test the hypotheses that tissue-engineered blood vessels made with cells derived from individuals with HGPS recapitulate in vitro the structure and activity found in vivo and can aid in assessing the effectiveness and mode of action suitable drug candidates for clinical studies. In Aim 1, we will test the hypothesis that TEBVs with cells derived from HGPS patients have the same phenotype as a mouse model of HGPS. We will assess (1) the relative contribution of reduced cell number and oxidative stress on the altered function of HGPS- TEBVs, (2) the effect of flow on EC NRF2 activity and oxidative genes it regulates, and (3) compare TEBV structure and function with the mouse model for HGPS. Control conditions will consist of TEBVs prepared with cells derived from a parent of one of the HGPS patients. In Aim 2, we will modify our system to run multiple TEBVs simultaneously and test the hypothesis that combination therapies have been ineffective because they have not restored SMC number, differentiation, and vasoactivity. In Aim 3, we will assess the suitability of novel treatments for progeria to alter the HGPS phenotype in the TEBVs. We will examine the effect of agents which improve mitochondrial function and or protein degradation, alone or in combination with lonafarnib and anti-sense oligonucleotides that inhibit progerin production. Corresponding studies in mice will be performed to assess whether the HGPS-TEBV model reproduces changes to vessels found in mouse model of HGPS.

摘要