Premature aging syndromes are the result of several identified rare mutations leading to the dysfunction of multiple organ systems characterized by features of normal aging such as osteoporosis, alopecia and skin wrinkling. Patients with Hutchinson-Gilford Progeria Syndrome (HGPS) and Werner's Syndrome (WS) for example, are affected by accelerated, premature atherosclerosis leading to heart attacks and strokes. Just as monogenic diseases such as familial hypercholesterolemia and familial defective apoB-100 have provided powerful molecular insights into the pathogenesis of atherosclerosis, premature aging syndromes may offer an opportunity to expose new critical pathways involved in atherogenesis. While several lines of investigation have begun to probe the vascular defects associated with these syndromes, the involvement of vascular endothelium in the pathogenesis of the vascular disease associated with HGPS and WS remains unexplored. Our laboratory and others have shown that endothelial dysfunction, which constitutes a multi- faceted impairment of the vital functions of the lining of the heart and blood vessels, is an early critical event in the development of vascular disease. We have shown that this dysfunction can be caused by the presence or absence of biomechanical stimuli. Biomechanical forces are important players in endothelial function, particularly in evoking atherosclerosis-resistant or atherosclerosis-susceptible phenotypes depending on the specific biomechanical stimulus. These distinct cellular phenotypes are the result genetic programs activated by specific mechanosensitive signaling pathways in response to atheroprotective or atheroprone shear stress present in the human arterial tree. Based on these observations, biomechanical forces can be considered """"""""local risk factors"""""""" in atherogenesis. Here, it is my working hypothesis that the early appearance of atherosclerosis in premature aging syndromes is a consequence of dysfunctional endothelial cell responsiveness to atheroprotective shear stress. To test this hypothesis, in Specific Aim 1, we will first create induced pluripotent stem (iPS) cells from fibroblasts that have been harvested from normal, HGPS and WS human patients.
In Specific Aim 2, we will differentiate these iPS cells into endothelium. We will rigorously characterize this endothelium both structurally and functionally to ensure it has a mature, arterial identity. Assured of this, in Specific Aim 3, we will subject the normal and premature aging model iPS cell-derived endothelium to shear stress waveforms present in the adult human vasculature and assess the resulting endothelial phenotype. This will indicate whether the premature aging model endothelium is predisposed atherosclerosis due to dysfunctional mechanotransduction.

Public Health Relevance

We will study the mechanism responsible for the increased risk of vascular disease during aging. To approach this, we will work with cells modeling two premature aging diseases, namely Hutchinson-Gilford Progeria Syndrome and Werner's Syndrome and research their ability to respond to fluid flow as in human arteries. Studying the early onset of vascular disease in premature aging syndromes may shed light on the age-related causes of vascular diseases in general.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AG037249-02
Application #
8072079
Study Section
Special Emphasis Panel (ZRG1-F10A-S (20))
Program Officer
Kohanski, Ronald A
Project Start
2010-05-01
Project End
2013-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
2
Fiscal Year
2011
Total Cost
$40,592
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Adams, William J; Zhang, Yuzhi; Cloutier, Jennifer et al. (2013) Functional vascular endothelium derived from human induced pluripotent stem cells. Stem Cell Reports 1:105-13
Adams, William J; Garcia-Cardena, Guillermo (2012) Novel stem cell-based drug discovery platforms for cardiovascular disease. J Biomol Screen 17:1117-27