Executive Summary : | Acute-on-Chronic Liver Failure (ACLF) is a liver dysfunction caused by dysfunctional immune activation, leading to multiple organ failure and approximately 50% short-term mortality. The research aims to understand and limit systemic inflammation sources that can lead to mortality. Studies have shown that elevated neutrophil-to-lymphocyte ratio (NLR) is associated with 28-day mortality, along with overexpression of neutrophil-specific genes and surface markers. Neutrophils are important mediators of ACLF pathogenesis, and a neutrophil sub-population characterized by surface expression of CD177 in ACLF patients has been identified. CD177 is a GPI-anchored glycoprotein involved in neutrophil migration, longevity, elevated NETosis, reactive oxygen species generation, and lower inflammatory cytokine production.
Metabolic regulation and autophagy are also key regulators of neutrophil function. However, metabolic phenotypes and autophagy have not been studied in pathogenic neutrophil subsets, including CD177+ neutrophils. Understanding the metabolic pathways linked to CD177+ neutrophil subsets can reveal enzyme targets that can be modulated using small molecules or re-purposed drugs. The study aims to understand the signaling pathway of CD177 in neutrophils using siRNA and small molecule inhibitor approaches, the link between CD177 expression and metabolic regulation of neutrophils using untargeted metabolomics, the correlation between CD177 expression, metabolic profiles, Atg7 mediated autophagy, and mTOR activity with ACLF patient 28-day mortality, and evaluate the potential of modulators of mTORC1, glycolysis, pentose phosphate pathway, and TCA cycle in correcting neutrophil dysfunction in ACLF neutrophils. |
Co-PI: | Dr. Shalimar, All India Institute Of Medical Sciences (AIIMS), New Delhi-110029, Dr. Jayanth Kumar Palanichamy, All India Institute Of Medical Sciences (AIIMS), New Delhi-110029, Dr. Archna Singh, All India Institute Of Medical Sciences (AIIMS), New Delhi-110029, Dr. Yashwant Kumar, Translational Health Science And Technology Institute, Faridabad, Haryana-121001 |