Atherosclerosis is the leading cause of cardiovascular deaths, accounting for ~30% of all deaths in Australia in 2018. Atherosclerotic plaque rupture leads to heart failure and stroke. Decades of clinical research indicates that features of plaque rupture is thinning of the fibrous cap due to loss of cap smooth muscle cells (SMCs) and accumulation of inflamed bone marrow derived macrophages. Treatments for atherosclerosis are limited to lipid lowering and reducing inflammation in plaques and have failed to target plaque regression. In this project we are using colchicine as an anti-inflammatory drug to combat plaque rupture.
Results from this work is spearheading a nested trial within the NHMRC-funded clinical trial for use of colchicine in persistently-inflamed survivors of acute coronary syndrome. To characterize the pathways involved, and strengthen its use clinically, we will interrogate colchicine's plaque stabilizing effects using in vitro and in vivo models of atherosclerosis.
Significance: Ultimately, this novel project will uncover novel pathways and genes involving in plaque cap thickness this will have important implications for cardiovascular therapeutics. Also, the studies described are likely to uncover novel anti-inflammatory mechanisms that could be relevant more broadly, and potentially developed for use in other chronic inflammatory diseases such as chronic kidney disease, diabetes and rheumatoid arthritis, itself are risk factors for CVD
For decades, there have been enormous efforts to identify and develop an effective therapy to treat unstable atherosclerotic plaque. However, despite major advancements in our understanding of plaque biology, clinical practice has no improved outcomes for treatment of unstable plaques. These results are not surprising, considering the complexity of plaque biology. In this project, using advanced genetic and molecular biology techniques on atheroprone mice, we will investigate if anti-inflammatory drug colchicine can regress plaque progression and stabilize atherosclerotic plaques.
Impact of Diabetes of hematopoietic cells linked to atherosclerosis
Obesity and diabetes are major risk factors for a broad range of cardiovascular diseases. With three-times as many people in the world estimated to die from over-nutrition than from starvation or malnutrition in today's society, the health implications of this "diabesity" epidemic are enormous. Based on current trends, this scenario will get worse, leading to a tsunami of cardiovascular diseases that could overwhelm a healthcare system already struggling to deal with an ageing population. Thus, there is an urgent need to uncover the fundamental mechanisms underlying the development of diabetes, including how cardiovascular risk factors affect atherosclerosis - in order to develop rationale strategies for minimizing the impact of these risk factors on our health and economy.
Bone-marrow derived stem cells (BMDSCs) and progenitor cells are integral to tissue homeostasis and repair and contribute to health through their ability to self-renew and commit to specialized effector cells. Importantly, defects in a variety of progenitor cell populations have been described in both preclinical and human diabetes. The general perception is that diabetes drives defects in bone marrow derived stem cells (BMDSCs) which accrue damage over time, disrupting tissue homeostasis and increasing risk of morbidity. However, the mechanisms by which defective BMDSCs can influence the pathology of individual plaque cells in atherosclerosis, and the subsequent impact this has on diabetes and obesity remains unknown.
In this study, we will be characterizing effects of these BMDSCs on atherosclerotic plaque burden using state-of-the-art of the art transgenic mouse models and cardiovascular genetics. We will be using Cre-LoxP system, genetic knockouts, lineage tracing, clonal analysis, Single-cell RNA sequencing, bone marrow transplant and culturing BMDSCs,histology of mouse and human patient samples and general cell and molecular biology techniques.
The opportunity ID for this research opportunity is 2914