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.

Public Health Relevance

This project involves using engineered human tissue created with induced pluripotent stem cells as a model for disease processes and development of new therapies. Such an approach can be extremely useful for rare diseases for which developing new therapies is extremely challenging.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Vascular Cell and Molecular Biology Study Section (VCMB)
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Lundberg, Martha
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Duke University
Biomedical Engineering
Biomed Engr/Col Engr/Engr Sta
United States
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