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Development of hypothermia in systemic inflammation: the signaling hypothesis cryogenic

Grant number: 20/00631-4
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): March 01, 2020
Effective date (End): February 28, 2023
Field of knowledge:Biological Sciences - Immunology - Applied Immunology
Principal researcher:Alexandre Alarcon Steiner
Grantee:Caroline Martins de Matos
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:18/03418-0 - Hypothermia in Sepsis: causes and consequences, AP.TEM

Abstract

A change in body temperature is a hallmark of systemic inflammation. The fever (rise in body temperature) is the most prevalent and studied response, however, hypothermia (reduction in body temperature) occurs in the most severe cases. Recent studies from our group indicate that hypothermia does not result from thermoregulatory failure. Furon the contrary, this appears to be a regulated response with biological value when the costs of fever outweigh its benefits. However, the mechanisms governing the turn of fever to hypothermia remain unclear. Here, we propose to unravel the mechanisms by which COX constitutive isoform (COX-1) transmits hypothermic inducing signals cryogenic agents) in systemic inflammation. We propose that the role of COX-1 in this process involves two mechanistically distinct phases: (i) a first phase preceding induction cytokines and may involve activation of COX-1 in platelets; and (ii) a second phasein which COX-1 activation in spleen cells (possibly macrophages or mast cells) amplifies the production of a cryogenic cytokine, TNF-±. CRE-loxP technology will be phenotype-specific exclusion of the gene encoding COX-1, ie Ptgs1. To this end, transgenic mice expressing CRE recombinase on platelets, macrophages will be crossed with mice in which the Ptgs1 gene is flanked with loxP sequences. The lineages of mice resulting from the crosses will be evaluated for hypothermic response LPS, as well as the production of pro- and anti-inflammatory cytokines. Thes plenectomy will be employed to evaluate the role of the spleen in these strains. Besides that, a lipid analysis will be employed to identify which prostaglandin (PG) is the most phenotype-specific absence of COX-1 in systemic inflammation induced by LPS. This strategy will be complemented by experiments involving downstream enzymes to COX, as well as PGs, which will be tested for their effects on LPS-induced hypothermia and on cytokine production. (AU)

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