This is a application to study the contribution of a particular autoantibody to aspects of neuropsychiatric lupus. Four proposed research projects derive from the observation that a subset of anti-DNA antibodies present in the serum of lupus patients cross-reacts with NMDA receptors (NMDARs) and is capable of mediating apoptotic death of neurons leading to hippocampal (cognitive) or amygdale (behavioral) impairment. The immediate goals of the Program are four-fold;each goal is addressed in a specific project: Project 1: to determine whether there is variability in the electrophysiologic signature of monoclonal antibodies to the NMDAR corresponding with functional variability;Project 2: to determine whether maternal antibodies to the NMDAR cause impairment in fetal brain development;Project 3: to determine if antibody-mediated impairment of the hippocampus or amygdala can be detected by functional magnetic resonance imaging in patients with lupus and Project 4: to determine whether we can develop therapeutic strategies for neuroprotection. The Program includes an Administrative Core with an Advisory Committee to facilitate the research agenda. There is a Behavior Core, a Histology Core and a Monoclonal Antibody Core to provide high quality, uniform quality immunohistology and behavioral analysis as well as standardized batches of monoclonal anti-NMDAR antibodies for Projects 1, 2 and 4. This Program represents a multidisciplinary approach to a perplexing and disabling problem in patients with systemic lupus. The investigators have track records of productivity and collaborative interactions that ensure the success of this endeavor.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI073693-05
Application #
8308312
Study Section
Special Emphasis Panel (ZAI1-KS-I (J1))
Program Officer
Johnson, David R
Project Start
2008-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$2,221,830
Indirect Cost
$883,378
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
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
Vo, An; Volpe, Bruce T; Tang, Chris C et al. (2014) Regional brain metabolism in a murine systemic lupus erythematosus model. J Cereb Blood Flow Metab 34:1315-20
Chang, Eric H; Frattini, Stephen A; Robbiati, Sergio et al. (2013) Construction of microdrive arrays for chronic neural recordings in awake behaving mice. J Vis Exp :e50470
Cohen-Solal, J F G; Diamond, B (2011) [Neuropsychiatric lupus and autoantibodies against ionotropic glutamate receptor (NMDAR)]. Rev Med Interne 32:130-2
Cohen-Solal, Joel; Diamond, Betty (2011) Lessons from an anti-DNA autoantibody. Mol Immunol 48:1328-31
Bloom, Ona; Cheng, Kai Fan; Cheng, Kai Fen et al. (2011) Generation of a unique small molecule peptidomimetic that neutralizes lupus autoantibody activity. Proc Natl Acad Sci U S A 108:10255-9
Diamond, B; Bloom, O; Al Abed, Y et al. (2011) Moving towards a cure: blocking pathogenic antibodies in systemic lupus erythematosus. J Intern Med 269:36-44
Aranow, Cynthia; Diamond, Betty; Mackay, Meggan (2010) Glutamate receptor biology and its clinical significance in neuropsychiatric systemic lupus erythematosus. Rheum Dis Clin North Am 36:187-201, x-xi
Faust, Thomas W; Chang, Eric H; Kowal, Czeslawa et al. (2010) Neurotoxic lupus autoantibodies alter brain function through two distinct mechanisms. Proc Natl Acad Sci U S A 107:18569-74
Diamond, Betty (2010) Antibodies and the Brain: Lessons from Lupus. J Immunol 185:2637-2640

Showing the most recent 10 out of 15 publications