Research Projects

Rationale of the research: Cognitive impairment and dementia are highly prevalent in chronic kidney disease (CKD), affecting up to 70% of individuals undergoing haemodialysis. Although mast cell overactivation and heightened neutrophil activity are well-documented in CKD patients, their specific roles in the progression of CKD-associated cognitive impairment remain largely unexplored. Our preliminary data demonstrate that pharmacological inhibition of mast cells significantly preserves cognitive function in a murine model of CKD. Using our well-characterized mouse model of CKD-associated cognitive impairment (Ghosh A., ACS Chem Neurosci, 2025), we observed increased brain infiltration of CD45⁺ leukocytes, neutrophils, macrophages, and mast cells (Fig 1.1 and Fig 1.2). Elevated expression of mast cell proteases (tryptase, chymase) was detected (Fig 1.2), which was reduced by sodium cromoglycate (a mast cell stabilizer), accompanied by improved cognitive function and increased expression of neuroplasticity markers (BDNF, PSD95, p-CREB) (Fig 1.3). Given these findings, a dual-targeted approach that addresses both mast cells and neutrophils may offer enhanced therapeutic benefits. Dipeptidyl peptidase-1 (DPP-1) is a critical enzyme responsible for the activation of neutrophil serine proteases (NSPs) as well as mast cell-derived proteases such as chymase and tryptase. Therefore, targeting DPP-1 represents a promising strategy to simultaneously modulate both immune cell types implicated in CKD-related neurocognitive decline. Hypothesis: We hypothesize that dual targeting of mast cells and neutrophils through inhibition of dipeptidyl peptidase-1 (DPP-1) will mitigate neuroinflammation, preserve cognitive function, and potentially slow the progression of chronic kidney disease Objectives: a. To design and synthesize novel, brain-permeable allosteric DPP-1 inhibitors using structure- and ligand-based drug design. b. To profile the expression of chymase, tryptase, and neutrophil elastase in CKD mice and correlate their levels with renal and neurocognitive outcomes. c. To evaluate the preclinical efficacy of novel DPP-1 inhibitors in mitigating renal dysfunction and neurocognitive impairment in a murine model of chronic kidney disease (CKD). Methods: We will employ a high-throughput screening approach, combined with in silico screening and molecular docking techniques, to design novel small-molecule inhibitors targeting DPP-1. These compounds will undergo a comprehensive evaluation process, including biochemical and cellular assays to assess binding affinity, selectivity, and degradation efficiency. The pharmacokinetic analysis of the potent inhibitors will be carried out in mice before proceeding with the efficacy studies. In vivo efficacy will be tested in an adenine-induced CKD mouse model to evaluate their potential to mitigate both CKD progression and associated cognitive impairment. Novelty: Currently there are no therapies indicated for the treating cognitive impairment associated with CKD. The cognitive impairment associated with CKD is managed clinically using anti-coagulant, antihypertensive, and administration of intestinal chelators to remove uremic toxins. Developing novel therapies or the preclinical proof of concept for the treatment of MCI secondary to CKD is necessary to improve the overall quality of life of the patients.