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Research Projects

  1. Berk_FIG The mechanisms by which the biomechanical force generated by blood flow (shear stress) contributes to CVD. Specifically when blood flow is turbulent or disturbed (d-flow) there is a predilection for atherosclerosis and endothelial dysfunction. In contrast, steady flow (s-flow) stimulates a canonical atheroprotective pathway. We have discovered that a family of proteins that contain the protein binding motif termed (PB1 domain) are regulated both by expression and activity depending on blood flow pattern. PB1 domain proteins are dramatically overexpressed in the biomechanical transduction pathway. Of the 13 PB1 domain proteins in the human genome, 7 play a role in this pathway. S-flow stimulates an atheroprotective pathway that involves MEKK3 (PB1)-MEK5(PB1)-ERK5-KLF2 transcription factor. We showed that PKCz inhibited the pathway by phosphorylating ERK5. Using an antibody to the specific ERK5 phospho-serine we showed increased phosphorylation in d-flow regions. Furthermore, we have shown an absolute requirement for another PB1 protein, p62 that regulates PKCz activity and location. Recently we developed mouse models with altered levels of PKCz and p62 in a tissue specific manner that exhibit important phenotypes such as atherosclerosis and hypertension. We are currently studying the downstream mechanisms responsible for these phenotypes and developing reagents to inhibit the function of these proteins.
  2. The role of Cyclophilin A (CypA) in pulmonary arterial hypertension (PAH). We have previously established that CypA is secreted from all cell types present in vessels; and participates in a positive feedback loop in Smooth Muscle Cells (SMC) generating reactive oxygen species (ROS) by binding p47phox and translocating it to the membrane. Most importantly, we used several mouse models of CypA deletion and over-expression to demonstrate a pathogenic role for CypA in atherosclerosis and aneurysm formation. Likely pathogenic mechanisms include our data which demonstrated that CypA had pro-inflammatory and pro-apoptotic effects on endothelial cells (EC) and stimulated SMC proliferation, MMP activation, and migration. Based on our previous work it is logical that CypA would be a potential pathogenic mediator of PAH. Therefore, we first measured plasma CypA in PAH patients. There was a 2-fold increase in circulating CypA. Expression of CypA assayed by immunohistochemistry was also enhanced in lungs of PAH patients, as well as in the rat PAH model of pneumonectomy and monocrotaline (pMCT) treatment. To strengthen our hypothesis that CypA is a novel mediator of PAH, we generated cell-specific CypA over-expressing transgenic mice (ecCypA-tg and smcCypA-tg). The exciting result was the EC specific ecCypA-tg mice developed pulmonary hypertension at 3 months of age. Based on these findings, we will investigate the role of extracellular (eCypA) as a novel mediator of PAH based on two mechanisms: vascular remodeling (EC apoptosis, EC-transdifferentiation, SMC proliferation and migration) and inflammation.
  3. The genetic basis for vascular intima inflammation, a predictor of cardiovascular mortality. A long-term goal in treating atherosclerosis and hypertension is to understand the mechanisms that regulate the structure of blood vessels, a process termed “vascular remodeling.” An important predictive phenotype for human cardiovascular disease is vascular remodeling in the carotid artery, represented by the measurement termed intima-media thickening (IMT). Clinical studies of atherosclerosis and coronary artery disease have yet to identify single gene candidates that could be targeted to treat IMT. In this project we will gain insight into the genetic mechanisms responsible for IMT by a systems biology approach that involves genome wide association studies combined with congenic mouse strains, which differ in vascular remodeling phenotypes. Previously we performed a quantitative trail locus (QTL) analysis of vascular remodeling alleles in a backcross of C3HeB/FeJ (C3H/F) and SJL/J (SJL) mouse strains and identified three QTLs, termed Intima modifier loci (lm1 on chromosome 2, lm2 on chromosome 11 and Im3 on chromosome 18, that regulate intimal thickening. We found using congenic mice that genomic material on Im1 and Im3 from SJL on the C3H/F background promoted intimal thickening in response to carotid injury (low flow). Our major hypothesis is that genetic elements within these two loci, Im1 and Im3, work via a cooperative mechanism (trans-acting) to regulate intimal thickening. Based on our preliminary data our goal is to employ an integrative genomic approach to identify elements critical to the regulatory network between Im1 and Im3 loci. Using a combination of analyses including congenic fine mapping, genome-wide association with the Hybrid Mouse Diversity Panel (HMDP), RNA sequencing, biological pathway and network we will identify the cooperative regulation of these genomic regions. We will map the intimal regulatory locus using Im1/Im3 double congenic mouse lines; perform genome-wide association mapping of the intima trait using the HMDP combined with SJLxC3H/F backcross; and establish intima regulatory networks based on deep sequencing data in the Im1/Im3 congenic mouse lines.