While through efforts like the Surviving Sepsis Campaign, ARDSNet and others, supportive therapies have improved survival of the critically injured and/or septic patient, nonetheless, a substantial number still develop this morbid syndrome and die. Unfortunately, as no true medicinal/ molecular therapeutic agent is presently available to treat the developing immune/ organ dysfunction in these individuals or diagnose/ prognose their trajectory, the need remains to further clarify the complex pathobiology of traumatic shock and/or sepsis so as to identify such agents. In this regard, we have recently uncovered a novel role for a family of cell-associated co-inhibitory receptors, Programmed Cell Death Receptor-1 [PD-1] and B-/T-Lymphocyte Attenuator [BTLA] and their respective ligands, popularly referred to as checkpoint proteins. What our data and information developing in the field tell us is that a number of these receptors may have far more diverse cell/organ targets than those of us historically appreciated. While checkpoint protein expression on CD4/CD8 lymphoid cells has a role in these dysfunctional septic processes, one of the novel observations we have made is that they appear to have unanticipated effects on phagocyte as well as `innate regulatory lymphoid cell' functions that also seems to contribute to the increased susceptibility/ immune suppression in the critically ill injured and/or septic patient/ animal. With this in mind, we propose to examine the following general hypothesis in this MIRA: that the classic co-inhibitory receptor(s), PD-1, BTLA and/or their ligands, play a novel role(s) in regulating the development of shock/septic immune/ organ dysfunction via novel myeloid cell and/or select regulatory lymphoid subset interactions with other immune or non-immune cells present in a given tissue. In the 1st sub-project area we will determine how the select expression of PD-1 or BTLA, on myeloid as opposed to lymphoid cells alters the development of morbid events associated with sepsis; then, how the expression of ligands for these co-inhibitory molecules, on leukocytes and/or endothelial/ epithelial cells, contribute to the onset of septic liver, intestine and/or kidney dysfunction. In our 2nd sub-project area, we will utilize a novel murine model of indirect-acute lung injury (iALI)(dual insults of hemorrhage shock followed by CLP) to ask how checkpoint protein expression not only effect the patho-mechanisms driving the development of iALI, but how are these co-inhibitors altering cell `priming'/'innate immune memory'/function. Finally, (3rd) since the neonate possesses a unique/nave immune system and is more susceptible to morbid response in the face of infectious challenge; we ask if the expression of members of the PD-1 family and/or their ligands not only have a comparative impact on the response to septic insult, but how it might be mediated? To do this we will interrogate these 3 cogent models of sepsis, shock/sepsis and/or neonatal sepsis, by applying a combination genetic mouse models, adoptive transfer and/or chimeric mouse constructs to examine these questions/ hypotheses along with select observational clinical studies in the critical ill patient population.
Despite the use of specific antibiotics, aggressive operative intervention, state-of-the-art support care and variety of novel anti-inflammatory agents (all of which have failed clinically) in critically ill/injured patients, multiple organ failure continues to be a major cause of morbidity/ mortality in the surgical intensive care unit. This study is designed to determine what role a family of cell surface-associated co-inhibitory molecules, checkpoint proteins, expressed on immune (i.e., neutrophil, macrophage, lymphoid cells, etc.) and non- immune cell's (i.e., epithelial and endothelial cell), has in the develop of organ injury in the critically ill patient. The role of these checkpoint protein genes will be established using genetically altered mice as well as drug interventions directed at these molecules in the series of experimental models of shock and/or sepsis, along with comparative observational patient based studies. It is our firm belief that the results of these studies will provide information that not only should allow us to better understand the pathobiology of immune/organ injury seen in response traumatic shock and/or sepsis, but also its attenuation.
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