Diseases of the aorta, including aneurysms and dissections, are common causes of morbidity and mortality. Aortic aneurysms and dissections are difficult to diagnose and are typically treated with expensive and complex surgical/interventional procedures, all of which have significant complication rates. Other than blood pressure control, which is of limited efficacy, there are currently no effective medical therapies for aortic aneurysms and dissections. The absence of effective therapies is due to our limited understanding of the pathogenesis of aortic disease. More specifically, we do not understand the molecular and cellular mechanisms that preserve aortic health nor do we understand why and how these mechanisms fail, resulting in aneurysms, dissections, and often in sudden death. The broad, long-term objective of this project is to define the mechanisms that preserve aortic health and to manipulate these pathways to prevent aortic disease. There are 3 specific aims, all carried out in mice.
The aims are focused on defining the role of intracellular signals initiated by transforming growth factor beta (TGF-?) in maintaining the health of smooth muscle cells (SMC) in the aorta, thereby preserving aortic structure and function. Dysfunction and destruction of SMC are common features of aortic diseases. Accordingly, strategies that prevent SMC dysfunction and destruction will likely preserve aortic health.
The aims make use of a novel mouse model, in which genetic disruption of a critical TGF-? receptor specifically in SMC eliminates physiological TGF-? signaling. Preliminary data suggest that TGF-? signaling has beneficial effects in aortic SMC, that eliminating TGF-? signaling in SMC damages the aorta, and that preserving SMC TGF-? signaling will prevent aortic disease.
Aim 1 will continue to define the consequences on aortic health of eliminating SMC TGF-? signaling in normal adult mice.
Aim 2 will test whether loss of SMC TGF-? signaling in a mouse model of Marfan syndrome will prevent (as predicted by one current model) or-more likely-accelerate their aortic aneurysmal disease.
Aim 3 will test the hypothesis that loss of SMC TGF-? signaling in a mouse model of acquired aortic aneurysm formation (chronic angiotensin II infusion) will accelerate SMC damage and aneurysm growth. Experiments in all aims are designed to identify pathways through which TGF-? acts to maintain SMC health and preserve aortic structure and function. Accomplishment of these 3 aims will clarify whether physiologic TGF-? signaling in SMC is critical for maintaining postnatal aortic homeostasis and will also reveal whether TGF-? signaling in SMC protects against the development of both genetically based and environmentally induced aortic aneurysms. Application of the knowledge acquired here will illuminate pathways that could be exploited to develop novel therapies that preserve aortic health and prevent or stabilize aortic dissections and aneurysms.

Public Health Relevance

Aortic diseases including aneurysms (abnormal widening of the aorta) and dissections (disruption of the aortic wall with abnormal entry of blood into the wall) are common causes of human morbidity and mortality, including sudden death. These diseases are typically treated with expensive, complex surgical and interventional procedures, all of which have significant complication rates. This project aims to identify biological mechanisms that preserve aortic health and prevent aortic disease with the expectation that knowledge of these mechanisms will spur development of medical therapies that preserve aortic health and prevent or stabilize aortic dissections and aneurysms.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL116612-02
Application #
8717714
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Tolunay, Eser
Project Start
2013-08-15
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$378,525
Indirect Cost
$133,525
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195