Top
Research

Mechanism of Neutrophil Extracellular Trap (NET) Formation: A recently identified paradigm in neutrophil activation is the formation of extracellular traps (Neutrophil Extracellular Traps, NETs), which are DNA fibrils expelled by these cells that are decorated with granular contents such as various proteases. NET formation has been shown to be largely dependent upon reactive oxygen species (ROS) generation and autophagy. However, factors governing autophagy activation and the extent to which ROS and autophagy cross-talk during NET formation remain unknown. In this regard, our paradigm-shifting and novel observations implicate innate immune C-type lectin receptor Mincle, a ROS sensor calcium channel protein TRPM2 and PARP-1 as central regulators of ROS-independent, and -dependent NET formation respectively, by integrating multiple intracellular signaling pathways, NLRP3 inflammasome and autophagy machinery, which we are currently investigating in the context of pneumonic sepsis, septic peritonitis, breast cancer and chronic granulomatous disease, In this regard, we have identified novel Mincle/Autophagy/ ROS axis, ROS/Trpm2/autophagy axis and PARP-1/NLRP3/p38 MAPK axis of NET formation which we are currently investigating for mechanistic underpinnings.
Diagnostic and Therapeutic Targeting of NETs: NETs have been reported to play protective roles in infectious diseases by trapping, neutralizing and killing extracellular microbes. On the flip side, an exuberant NET formation has been linked to development of many inflammatory diseases or disorders by promoting hyper activated immune response. More recently, NETs have also been shown to promote cancer proliferation and metastasis. Several projects in our lab are focused on diagnostic and therapeutic targeting of NETs in these diseases. These include:quantitative and structural variations in circulating NETs for diagnostic and prognostic purposes in oncologic and infectious diseases
effect of long-term tamoxifen treatment on NET formation causing drug resistance and cancer metastasis in women with HR+ breast cancer
use of PARP-1 inhibitors as adjuvant therapy to control NET formation
identification and characterization of novel helminth parasitic factors as NET inhibitors

Mechanism of Efferocytosis and neutrophil homeostasis in pneumonic sepsis: Once the neutrophils complete their task of clearing the pathological insult, clearance of infiltrating immune cells and host cell debris is achieved by a process called efferocytosis which not only prevents the potential tissue damage caused by alarmins released from dead/dying cells but also promotes tissue repair. The mechanisms regulating efferocytosis of neutrophils in acute and chronic lung diseases not well understood. We have identified protective role of C-type lectin receptors Clec4d and MGL-1 in resolution of inflammation in pneumonic sepsis by modulation of neutrophil cell-death pathway which impacts efferocytic clearance of these cells during bacterial infection. We are elucidating the enzymes and molecular signaling pathways controlling the expression of specific “eat-me” signals as well as cell death machinery involved in these processes.
Mechanisms of Helminth induced immune modulation: An overwhelming inflammatory response, termed “cytokine storm” or hypercytokinemia is thought to be responsible for shock, multiple-organ failure and eventual death in septic patients. However, anti-inflammatory interventions have not been a successful treatment option for sepsis. This highlights the need to take into account, not only the initiation of inflammation, but also the resolution thereof, which favors tissue repair. In this regard, studies in collaboration with Dr. Bibhuti B. Mishra have shown that secreted proteins from a helminth parasite modulate host inflammatory response via regulation of Ca2+ influx in macrophages through interaction with calcium channels and by epigenetic modulations. We aim to utilize these helminth antigens as therapy for pneumonic sepsis as well as multiple other inflammatory diseases.
Research

Give Now

Research Areas

Subscribe
