Molecular Basis of Blood-Brain Barrier Breach in Lupus
Abstract
Cognitive Impairment Is Common in Lupus: The prevalence of neuropsychiatric systemic lupus erythematosus (NPSLE) varies from 40.3% to 91%, and NPSLE represents a major source of morbidity in systemic lupus erythematosus (SLE), and the second leading cause of mortality after lupus nephritis. Cognitive impairment is the most common manifestation of NPSLE, affecting 10%-80% of SLE patients. Although NPSLE and cognitive impairment are common in lupus patients, we have no way of monitoring these manifestations in the clinic and we do not understand their molecular basis. Breach in Blood Brain Barrier (BBBB) in SLE: In all individuals, a physical barrier exists between the circulating blood and the brain, called the blood brain barrier (BBB). Recent observations show that ~25% of all SLE patients have extensive BBBB (based on neuroimaging), associated with brain grey matter shrinkage and cognitive impairment. This could contribute to disease since blood proteins can readily gain access to the brain if this barrier is breached. Again, our understanding of this barrier breach in lupus is a black box. Knowledge Gap: We are now faced with several unanswered questions. What proteins are responsible for BBBB in lupus? What proteins are associated with cognitive impairment in SLE? Can these proteins actually cause BBBB or cognitive impairment? Can tracking these proteins help monitor the progression of disease in NPSLE? Can these proteins lead to novel therapeutics for managing NPSLE patients? To sum, we do not have a good understanding of the molecular basis of cognitive impairment and BBBB in NPSLE. Here, we propose to identify serum proteins/autoantibodies that are indicative of extensive BBB breach and/or cognitive impairment in SLE, using two unique patient cohorts characterized for BBBB using brain imaging, with concurrent serum samples, representing the largest such cohorts in the world. FY22 LRP Focus Areas Addressed (1) Understanding the biological mechanisms of lupus disease including, but not limited to, studies of informative/rare patients (2) Determining the pathobiology of end organ injury related to lupus disease in target human tissues We hypothesize that selected serum proteins may be associated with BBBB, and actively breach the BBB. The objective of this proposal is to test this hypothesis through two Aims. Exploratory serum proteomics will be carried out in a Test cohort, followed by validation in a Validation cohort in Aim 1. Mechanistic studies are proposed in Aim 2. Impact: These studies could have a significant impact on the management of NPSLE in several respects: (1) They could uncover novel serum proteins for the diagnosis and/or follow up of NPSLE (since such proteins are currently non-existent). In a patient diagnosed to have SLE, the emergence of these novel serum proteins or autoantibodies in circulation may signal the onset of NPSLE. Future studies are warranted to examine if fluctuations in the levels of these proteins are indicative of active NP disease, using serially collected samples. (2) They may identify potential outcome measures for NPSLE trials, for which biomarkers are lacking. (3) They may shed light on the pathogenesis of BBBB and cognitive decline in NPSLE, which is currently a black box. (4) They may pave the path toward more selective therapies for NPSLE patients with cognitive deficits. For example, if a particular protein is associated with cognitive deficits in NPSLE patients (based on Aim 1) and is also shown to induce neuronal injury in pre-clinical models (based on Aim 2), these proteins can potentially be therapeutically targeted. Of importance, we do not currently have any therapeutics that are specifically targeted toward disease manifestations associated with NPSLE.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310408
Entities
People
- Chandra Mohan
Organizations
- United States Army
- University of Houston