Pharmacological Interventions Leading to the Reduction of Inflammation
We currently study the role of Dendritic Cell-Specific Intercellular Adhesion Molecule-3-Grabbing Non-Integrin (DC-SIGN) ligand 1 (DCSL1) that binds DC-SIGN on monocytes and dendritic cells. In our recent in vivo study, we determined that DCSL1 reduces the number of TNF-α+ macrophages in treated females but not male mice. The reduction of this particular macrophage subset was also accompanied by a reduced deposition of collagen in the matrix. The interaction between fibroblasts and leukocytes and resultant fibrosis has been a subject of our previous studies.
Determine the Mechanism by which Fibroblasts Contribute to Interstitial Fibrosis in the Aging Heart
We have defined that although fibroblasts in the old heart have reduced responsiveness to its canonical activator, TGF-β, they synthesize and deposit higher levels of matrix components, which leads to fibrosis. The mechanism by which they became activated with aging, as well as their increased phenotypic heterogeneity, is a subject of this project.
The myofibroblast is a specialized fibroblast that expresses α-smooth muscle actin (α-SMA) and participates in wound contraction and fibrosis. The fibroblast to myofibroblast transition depends on chemical and mechanical signals. A fibroblast senses the changes in the extracellular matrix and transduces these changes to the cytoskeleton and the nucleus resulting in activation or inhibition of α-SMA transcription in a process called mechanosensing. The fibroblasts in the old heart have a reduced ability to transition into myofibroblasts. We are currently investigating the mechanosensing pathway in the old fibroblasts.