The long-term objective of this training award is to acquire the skills and experience necessary to become an innovative, productive, and independent physician-scientist in the field of chronic kidney disease (CKD)-related atherosclerosis. CKD is a known accelerant of atherosclerosis. Indeed, cardiovascular disease is the leading cause of mortality in patients with CKD. After accounting for frequently comorbid conditions, such as diabetes and hypertension, renal disease emerges as an independent risk factor for cardiovascular disease. The CKD-specific mechanisms responsible have not bet fully elucidated. This proposal aims to advance the understanding of CKD-related atherosclerosis by examining the mechanisms by which renal disease may interfere with the regression of atherosclerosis. Atherosclerotic plaques are dynamic: the net result of progressive and regressive forces. Pilot data suggests that decreased renal function impairs regression of atherosclerosis. ApoE-/- mice are used to generate atherosclerotic aortic lesions. Aortae are then transplanted into wild-type mice with or without kidney disease (remnant kidney model) to investigate how renal impairment affects regression of the atherosclerotic lesions. The hypotheses to be tested are: 1) kidney disease prevents the regression of atherosclerosis 2) the impairment is a result of defective chemokine receptor 7 (CCR7) signaling. Experiments will utilize immunohistochemistry, ELISA, laser-capture microdissection, real-time PCR, microarray analysis and in vitro migration assays. Conventional therapy does not fully mitigate the excess cardiovascular risk afflicting the large and growing population of patients with CKD. Investigating novel pathomechanisms of renal disease, such as impaired atherosclerosis regression, is a desirable goal.
Chronic kidney disease affects millions of Americans. Many of those affected will die prematurely from heart disease. Understanding how kidney disease can worsen heart disease is an important goal.
|Ponda, Manish P; Breslow, Jan L (2016) Serum stimulation of CCR7 chemotaxis due to coagulation factor XIIa-dependent production of high-molecular-weight kininogen domain 5. Proc Natl Acad Sci U S A 113:E7059-E7068|