Research Projects

Rationale: Cardiac fibrosis is a central pathological feature of many cardiovascular diseases and a key contributor to progressive heart failure. It is driven not only by fibroblast activation but also by sustained inflammatory signaling. Myeloid Differentiation Protein 2 (MD2), a co-receptor of Toll-like Receptor 4 (TLR4), is a novel therapeutic target for inflammation associated cardiac fibrosis. It plays a crucial upstream role in sensing damage-associated molecular patterns (DAMPs) and triggering NF-κB-mediated pro-inflammatory cascades. Its overactivation is implicated in myocardial inflammation and subsequent fibrotic remodelling. Current pharmacologic inhibitors of MD2 lack tissue specificity and can affect systemic immune function. Therefore, developing a targeted delivery system that suppresses MD2 activity specifically in diseased cardiac tissue could provide a novel and safer therapeutic strategy. Hypothesis: We hypothesize that cardiac homing peptide-functionalized polymeric nanoparticles of PLGA (poly-lactic-co-glycolic acid), functional PLGA or Lipid-Polymer Hybrid will selectively accumulate in fibrotic cardiac tissue, effectively deliver the MD2 inhibitor to the site of inflammation and fibrosis, suppress TLR4/MD2 signaling, reduce inflammatory cytokine production, and attenuate cardiac fibrosis more efficiently and safely than non-targeted therapies. Model System to Be Tested: In VITRO- RAW 264.7 cell line/ THP-1 macrophages/ Bone marrow derived macrophages. IN VIVO- Isoproterenol induced fibrosis in C57BL/6J male mice. Key Experiments: • Synthesis, surface modification, and physicochemical characterization of the CHP-functionalized nanoparticles. • Quantification of inflammatory markers and ROS levels in vitro. • Comparative evaluation of fibrosis attenuation across treatment groups in an animal model of fibrosis. Significance: This research study will provide a novel, targeted nanotherapeutic platform for treating inflammation-induced cardiac fibrosis. It will validate MD2 as a druggable upstream regulator of cardiac remodelling and demonstrate the feasibility of organ-targeted nanoparticle therapy using peptide ligands. Fundamentally, it will advance our understanding of TLR4/MD2’s role in fibrotic signaling in the heart.