Project 1 Survivors of sepsis often experience persistent cognitive impairment. Our preliminary data show that this can be ameliorated by reducing systemic inflammation at a time when acute, life-threatening immune activation has resolved. In this project, we will explore the brain inflammation that is triggered by an episode of sepsis and whether TNF, IL-1 or HMGBI, or some combination of these is 1) the critical cytokine in the circulation that initiates brain inflammation or 2) a key cytokine within the brain that contributes to histologic and functional damage. Further, we will explore how systemic inflammation is communicated to the brain: whether by neural circuitry or by activation of brain microvascular endothelial cells. These studies will identify pathways connecting brain inflammation to systemic inflammation and will dissect those components of brain inflammation that lead to a persistent cognitive deficit.

Public Health Relevance

Individuals surviving sepsis often experience persistent cognitive impairment. This study will explore how systemic inflammation causes brain dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
1P01AI102852-01A1
Application #
8667803
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2014-08-01
Project End
2019-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Huerta, Patricio T; Robbiati, Sergio; Huerta, Tomás Salvador et al. (2016) Preclinical models of overwhelming sepsis implicate the neural system that encodes contextual fear memory. Mol Med 22:
Chang, Eric H; Volpe, Bruce T; Mackay, Meggan et al. (2015) Selective Impairment of Spatial Cognition Caused by Autoantibodies to the N-Methyl-d-Aspartate Receptor. EBioMedicine 2:755-64
Brimberg, Lior; Mader, Simone; Fujieda, Yuichiro et al. (2015) Antibodies as Mediators of Brain Pathology. Trends Immunol 36:709-24
Volpe, Bruce T; Berlin, Rose Ann; Frankfurt, Maya (2015) The brain at risk: the sepsis syndrome and lessons from preclinical experiments. Immunol Res 63:70-4
Valdés-Ferrer, Sergio I; Papoin, Julien; Dancho, Meghan E et al. (2015) HMGB1 mediates anemia of inflammation in murine sepsis survivors. Mol Med :
Huerta, Patricio T; Gibson, Elizabeth L; Rey, Carson et al. (2015) Integrative neuroscience approach to neuropsychiatric lupus. Immunol Res 63:11-7