Laboratory Focus: My laboratory, in the Division of Surgical Research, at R.I. Hospital is focused on developing a better understanding of what the pathophysiological/pre-dispositional mechanisms of shock, injury and/or sepsis are and what impact they may have on the individual that lead to increasing their susceptibility to subsequent infection as well as the development of multiple organ failure.
Overall Goal: To elucidate not only unique therapeutic targets for the treatment of the severely injured/ shocked and/or septic patient’s but uncover novel prognostic markers of their course.
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Project Area 1: Role of Checkpoint Proteins in the Development of Immune and/or Organ (liver, kidney, heart/ vasculature, intestines, etc.) Dysfunction in Response to Septic Challenge.
Questions:
- How does select expression of PD-1, BTLA and/or VISTA on myeloid vs. lymphocytes, alter the development of morbid septic events?
- Alternatively, how does expression of ligands for these co-inhibitory molecules on leukocytes vs. endothelial (EC)/ epithelial (EpiC) cells affect the onset of septic liver, intestine and/or kidney dysfunction?
Central hypothesis: The hypothesis being examined here is that classic adaptive/lymphoid co-inhibitory receptors, like PD-1, BTLA or VISTA and/or their ligands, contribute in distinct fashion(s) to the development of septic morbidity via their novel myeloid cell and/or select regulatory lymphoid subset interactions with other immune or non-immune (EC and/or EpiC) cells present in a given tissue.
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Project Area 2: Checkpoint Proteins and the Pathology of Neonatal Sepsis.
Questions:
- Since the neonate possesses a unique/naïve immune system (vs. our adult one) and is more susceptible to morbid outcome when faced with infectious insult, we ask if expression of B7-family member checkpoint proteins not only have a comparative impact on the response to septic insult as seen in the adult, but how is it mediated?
Central hypothesis: Here we are considering the hypothesis that neonates exhibit immune suppression mediated by selective checkpoint protein expression in response to septic insult; and that this insult is retained in the host innate immune memory going forward.
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Project 3: Co-Inhibitory Molecules and the Pathology of Indirect-Acute Lung Injury (iALI)/Acute Respiratory Distress Syndrome (ARDS).
Questions:
- How does severe injury (here as hypotensive shock) serve to predispose an individual to a much poorer pulmonary response, i.e., develops ARDS to an otherwise innocuous subsequent challenge (something encountered in the surgical theater in post-shock resuscitation [Rx])?
- What does shock driven predisposition/priming to ARDS of pulmonary immune and/or non-immune cells look like transcriptomically/ epigenomically and what regulates this?
- How is this response to shock/sepsis altered by the expression of VISTA, PD-1:PD-L1, etc.?
Central hypothesis: Here we hypothesize that VISTA plays a novel role relative to that of PD-1:PD-L1 in the regulation of mouse/ patient leukocytes and/or EC/EpiC pre-dispositional change(s) that develop during the response to hypotensive shock in our model of experimental iALI.
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Funded Research