In human beings, the blood levels of high-density lipoprotein (HDL) are inversely correlated with the risk of cardiovascular diseases.  In general, the higher your HDL (or good cholesterol) level, the lower your risk for heart disease later in life.  These diseases are currently the #1 killer in this country, claiming nearly 1 million lives per year (about one person dead every 32 seconds).  In addition, these diseases are becoming increasingly prevalent in developing countries as they consume higher fat diets common to Western lifestyles. 

    A major cause of cardiovascular disease is the accumulation of cholesterol in the blood vessels such as those that supply oxygen to the heart or brain.  Unresolved cycles of inflammatory response result in the accumulation of fatty plaques in the artery wall - a condition called atherosclerosis.  These plaques can constrict blood flow through the artery or even rupture to produce a blood clot or thrombus. If this happens in the coronary arteries supplying the heart, one has a heart attack.  In the brain, this can cause a stroke.  Although we know that HDL levels are inversely related to atherosclerosis, the detailed mechanisms for its protective role are not well understood.

    To make things even more complicated, HDL isn't just one 'thing'. Our work and others shows that the family is made up of numberous subclasses of particles and each can contain combinations of cargo selected from a palette of up to 100 different proteins. Some of these are known to play roles in lipid transport, but many have intriguing roles in innate immunity, blood clotting, protease inhibition, and even metal and vitamin transport.  We beleive that these particles mediate a huge amount of unknown biology, not only with respect to cardiovascular disease, but also many other chronic metabolic and immunological disorders.  Unfortunately, little work has been done to isolate and define the structure and function of these HDL subspecies and thier relation to human disease.  That's where we come in!

    The mission of our laboratory is to determine the molecular basis underlying the roles of HDL in human metabolic and inflammatory diseases.  Our laboratory uses a wide range of techniques spanning biophysical chemistry, molecular biology, cell biology and mass spectrometry to understand:

      1) the structural organization of the major apolipoproteins in HDL and their conformational transitions in response to lipid and lipid metabolism,

      2) the molecular details of HDL protein interactions with cell surface receptors and transporters,

      3) the protein and lipid compositions of various HDL subspecies and their altered distribution in the setting of cardiovascular disease, obesity and diabetes, and

      4) the specific functions of the many HDL associated proteins and how they interact on the particle surface to alter function.

The overarching goal is to use this understanding to design new therapies aimed at enhancing the protective effects of HDL against human disease. The projects in our lab are well suited for graduate students and Physician Scientist Training Program (M.D./Ph.D.) students because they are highly focused, mechanistic studies on highly relevant human diseases.


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