'ENDOSEPSIS': Aging-associated, specific pathomechanisms of endothelial dysfunction in sepsis: pathway analysis and experimental therapy
Description: Background: The outcome of sepsis in elderly patients is substantially worse than in younger patients. Vascular dysfunction importantly contributes to pathophysiology of sepsis. Recent studies by the applicant and other groups provide key evidence that pro-inflammatory stimuli and oxidative stressors induce a significantly more severe degree of endothelial dysfunction in blood vessels of aged rats and mice, when compared to the responses in young animals. Despite the evidence that aging sensitizes the vasculature to the deleterious effects of pro-inflammatory factors and oxidants, and despite the fact that circulatory shock primarily affects the aging population, and despite the fact that the age of the population continues to increase in developed countries, surprisingly, there are currently no studies specifically focusing on the mechanisms underlying the sepsis-associated impairment of endothelial function in aging animals.Goal: The central hypotheses of the present application are that (1) accelerated endothelial dysfunction is a key contributor to multiple organ failure and mortality in aging animals during sepsis and (2) in aging blood vessels, unique cellular and molecular mechanisms operate that render them extremely vulnerable to the oxidative stress-associated endothelial dysfunction during sepsis. Hypothesis: Based on novel preliminary data, we hypothesize that (a) impaired activation of Nrf2 (a master regulatory factor of the antioxidant response) is involved in the development of endothelial dysfunction in aging blood vessels during sepsis - at least in part through activation of the nuclear enzyme PARP, and, in other part, through acceleration of telomere loss and (b) the dysregulation of Nrf2 in aging is the consequence of age-associated down-regulation of circulating IGF1 levels. Furthermore (c) we hypothesize that non-biased proteomic and metabolomic analysis of aging blood vessels during sepsis will identify unique pathophysiological patterns and will yield potentially targetable novel pathways that are selectively perturbed in the aged vasculature in response to sepsis.Design: The experimental design follows standard laboratory practice in cell culture models and in experimental animals. It combines molecular (silencing, knockout) and pharmacological (donors, inhibitors) approaches and incorporates all standards and controls to address the aims of the application.Setting: University laboratory setting (preclinical studies in cells and mice)Patients: none (the current project is strictly preclinical)Methods: Cell-based experiments (combined pharmacology and molecular biology); mouse models of sepsis (cecal ligature and puncture) and endotoxemia (bacterial LPS); ex vivo measurements of vascular function; specific methods related to oxidative/nitrative stress, Nrf2 activation, PARP activation, telomere loss, cell dysfunction; proteomic and metabolomic analysis.Project relevance: The relevance of the proposed studies is highlighted by the fact that there are no effective pharmacological approaches for the therapy of circulatory shock. The applicant teams offer an ideal combination of expertise in the areas of vascular dysfunction, organ failure and sepsis, regulation of reactive species and oxidant/antioxidant defenses and metabolomic analysis and are well suited to undertake the project. If successful, the project will identify new experimental therapeutic targets, which are potentially translatable for the benefit of patients suffering from sepsis or septic shock.
Amount: CHF 587,400
Funding type: research
Funder scheme: Project funding
Start date: 2022-05-01
End date: 2026-04-30
Investigator: Szabo, Csaba
Institution: University of Fribourg – FR
Funded outputs count: 5
Funder award ID: 204371
OpenAlex ID: G6972564175