Bench to Bedside and Back: Understanding Inflammation and Vascular Pathology through Collaborative Research

Temple researchers [left to right] Xiao-Feng Yang, MD, PhD, FAHA; Eric Choi, MD; and Hong Wang, MD, PhD are investigating the role of inflammation in accelerating atherosclerosis associated with chronic kidney disease.
Temple researchers [left to right] Xiao-Feng Yang, MD, PhD, FAHA; Eric Choi, MD; and Hong Wang, MD, PhD are investigating the role of inflammation in accelerating atherosclerosis associated with chronic kidney disease.
A team of researchers at Temple’s Center for Metabolic Disease Research (CMDR) has earned an NIH R01 multi-PI grant of more than $2 million to investigate the mechanism by which chronic kidney disease accelerates vascular diseases like atherosclerosis. Patients with chronic kidney disease (CKD) have extremely high rates of cardiovascular morbidity and mortality, 10 to 30 times higher than the general population, and are more likely to die of cardiovascular disease than renal failure.1 CKD, which affects up to 10 percent of the world’s population, causes hyperuremia, known to accelerate atherosclerosis, but the precise pathways are not well understood.

This issue is of particular concern to Temple because Philadelphia’s rate of kidney disease is higher than the national average, with 25 deaths from chronic kidney disease per 100,000 people2 (compared with a national average of 14.9 per 100,0003), according to the Centers for Disease Control. CKD is especially prevalent among residents of Temple Health’s catchment area, as is kidney failure.

Chronic kidney disease hastens the progress of atherosclerosis.
Chronic kidney disease hastens the progress of atherosclerosis.

Chronic inflammation (which may often be triggered or exacerbated by metabolic syndrome) likely plays a role in accelerating vascular diseases like atherosclerosis and arterial neointimal hyperplasia in patients with CKD. Researchers at CMDR have identified the caspase-1 enzyme as a potential therapeutic target, having demonstrated that suppression of caspase-1 mitigates neointimal hyperplasia in mice with CKD.4

The Temple research team employs a unique collaborative model that does away with the traditional information flow between bench and clinical researchers. The team is co-led by clinical and bench researchers, including Hong Wang, MD, PhD, director of the Center for Metabolic Disease Research; Eric Choi, MD, Chief of Vascular and Endovascular Surgery; and Xiao-Feng Yang, MD, PhD, FAHA, Professor of Pharmacology. This allows a constant interplay of perspectives.

“We are looking at newer collaborative models between basic and clinical researchers to optimize the translational clinical trial format from beginning to end,” says Dr. Choi.

“It can be difficult to establish a routine collaboration between clinical and basic scientists because we’re speaking different scientific and clinical languages,” says Dr. Wang. “But we believe that by taking the time to understand each other we can have a big impact on a large scale. This is the perfect model for collaboration between clinical and basic science research labs.”

Caspase-1 mediates several inflammatory processes in chronic kidney disease.
Caspase-1 mediates several inflammatory processes in chronic kidney disease.

Using a mouse model and clinical studies of patients with cardiovascular and kidney disease, the researchers will investigate whether preventing the activation of caspase-1 can slow or avert the progression of atherosclerosis, as it does with neointimal hyperplasia—and exactly how the process works. Any treatment that targets caspase-1 must also consider the vital functions in which this protein plays a role, including tissue repair and homeostatic responses to stress.5 Drs. Wang, Choi and Yang will also study in greater detail the major cellular changes CKD induces in blood vessels: activation of endothelial cells, migration and generation of vascular smooth muscle cells, and differentiation of inflammatory monocytes. They will bring all of this information to bear on developing new drug treatment methods for CKD-accelerated atherosclerosis.

Their work will be part of a larger initiative to examine inflammation, kidney disease and vascular pathology. A joint enterprise of researchers, industry and health administrators, the program is under the auspices of the NIH. “We believe that all this has to do with systemic inflammation,” says Dr. Choi. “Because blood vessels go everywhere, metabolic syndrome is manifested in the blood vessels as systemic inflammation. We’re trying to have an impact on systemic inflammation to treat vascular disease and treat metabolic syndrome.”

1 Sarnak, M.J., et al. (2003). AHA Scientific Statement: Kidney Disease as a Risk Factor for Development of Cardiovascular Disease: A Statement From the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 108 (17): 2154–2169.
2 Community Health Status Indicators. (2015). Chronic kidney disease deaths (rates per 100,000 persons). Centers for Disease Control and Prevention, U.S. Department of Health and Human Services.
3 National Center for Health Statistics. (2016). CDC FastStats: Kidney Disease. Centers for Disease Control and Prevention, U.S. Department of Health and Human Services.
4 Ferrer, L.M., et al. (2016). Caspase-1 Plays a Critical Role in Accelerating Chronic Kidney Disease-Promoted Neointimal Hyperplasia in the Carotid Artery. J Cardiovasc Transl Res. 9: 136–144.
5 Sun, Q., and Scott, M.J. (2016). Caspase-1 as a multifunctional inflammatory mediator: noncytokine maturation roles. J Leukoc Biol. 100 (5): 961–967.