- PROJECT 1 This project will further our studies of the contribution of cross-reactive anti-DNA anti-N- methyl-D-aspartate receptor (NMDAR) antibodies, denoted DNRAbs, to neuropsychiatric lupus (NPSLE). NPSLE affects approximately 80% of lupus patients and substantially diminishes quality of life. We previously pioneered models for DNRAb-mediated fixed cognitive or behavioral impairment;we will now develop a model of DNRAb-mediated transient impairment. Based on our observation of variable DNRAb concentration in cerebrospinal fluid of lupus patients, we will explore the concentration of tissue-penetrating antibody in reversible and irreversible damage. We will explore the contribution of NMDAR subunit composition to reversible and irreversible damage and will determine whether there can be irreversible injury in the absence of neuronal death. We propose the highly novel hypothesis that microglia are altered in NPSLE as a consequence of ingesting apoptotic neurons and microglial activation functions to sustain neuronal damage. Finally, we will explore therapeutic strategies for preventing irreversible brain injury. These studies will develop new paradigms for antibody-mediated brain disease. We will utilize standard methodologies such as electrophysiology in hippocampal slice preparation, behavioral and cognitive testing and immunocytochemistry. We will pioneer the use of in vivo electrophysiology, microPET studies in a mouse model of NPSLE and RNA-seq of microglial cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
2P01AI073693-06A1
Application #
8741187
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-07-03
Budget End
2015-06-30
Support Year
6
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:
Honig, Gerard; Mader, Simone; Chen, Huiyi et al. (2016) Blood-Brain Barrier Deterioration and Hippocampal Gene Expression in Polymicrobial Sepsis: An Evaluation of Endothelial MyD88 and the Vagus Nerve. PLoS One 11:e0144215
Vingtdeux, Valérie; Chang, Eric H; Frattini, Stephen A et al. (2016) CALHM1 deficiency impairs cerebral neuron activity and memory flexibility in mice. Sci Rep 6:24250
Dhawan, Vijay; Robeson, William; Bjelke, David et al. (2015) Human Radiation Dosimetry for the N-Methyl-D-Aspartate Receptor Radioligand 11C-CNS5161. J Nucl Med 56:869-72
Huerta, Patricio T; Gibson, Elizabeth L; Rey, Carson et al. (2015) Integrative neuroscience approach to neuropsychiatric lupus. Immunol Res 63:11-7
Kowal, Czeslawa; Athanassiou, Andrew; Chen, Huiyi et al. (2015) Maternal antibodies and developing blood-brain barrier. Immunol Res 63:18-25
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
Mackay, Meggan; Tang, Chris C; Volpe, Bruce T et al. (2015) Brain metabolism and autoantibody titres predict functional impairment in systemic lupus erythematosus. Lupus Sci Med 2:e000074
Jeganathan, Venkatesh; Peeva, Elena; Diamond, Betty (2014) Hormonal milieu at time of B cell activation controls duration of autoantibody response. J Autoimmun 53:46-54
Braniste, Viorica; Al-Asmakh, Maha; Kowal, Czeslawa et al. (2014) The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med 6:263ra158

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