Multiple sclerosis (MS) is a chronic debilitating autoimmune disease involving inflammation and damage to the central nervous system (CNS). A variety of autoantigens, including myelin oligodendrocyte glycoprotein (MOG), proteolipid protein (PLP), and myelin basic protein (MBP) have been implicated in the pathogenesis of MS. The T cells reactive against these antigens access the CNS through the blood-brain barrier and cause inflammation and tissue damage. Two of the main challenges for researchers working in the field of MS are - 1) to define the underlying mechanisms that render the CNS highly prone to an autoimmune attack, and 2) to devise novel ways to direct the orally-administered or injected drugs primarily into the CNS to enhance their efficacy while minimizing adverse effects. We hypothesize that the vascular endothelium of the CNS is characterized by unique molecular markers that facilitate both selective migration of the pathogenic T cells into the target organ (the CNS) as well as cellular interaction with the inducers/mediators of inflammation and tissue damage. In collaboration with Dr. Erkki Ruoslahti (Sanford-Burnham Institute at La Jolla, CA), we recently completed and published (PNAS 2011, 108: 12857) study of the synovial vasculature in the rat adjuvant arthritis model. The objective of that study was to identify unique joint-specific vascular markers using an innovative approach of in vivo enrichment of clones from a phage peptide-display library. The advantage of the phage system for detection of tissue-specific markers is that there is no a priori bias in predicting the ligand in the vascular endothelium. In addition, unlike antibodies, the phage-displayed peptides interact with the functional domain of the target molecule. This approach has been pioneered by Dr. Ruoslahti, who has developed the concept of vascular 'address molecules'or 'zip codes'. His group and other investigators have examined several organs in this regard except the inflamed CNS. We hypothesize that the vascular endothelium of the brain and the spinal cord in EAE is characterized by unique molecular markers, and that the targeting of drugs via one or more of these markers would downregulate inflammation and tissue damage in the CNS without undue adverse reactions or systemic toxicity.
The aims of our study based on MOG-EAE and PLP-EAE models (and in collaboration with Dr. Ruoslahti, and EAE experts- Drs. Scott and Lees) are as follows:
Aim 1, to identify unique 'address molecules'for vascular endothelium of the inflamed CNS in mice with EAE using the in vivo screening of phage peptide-display library method.
Aim 2, to use CNS-homing peptides for vasculature-targeted drug delivery into sites of CNS inflammation and tissue damage. We believe that the results of this study would advance our understanding of the pathogenesis of EAE/MS, and pave the way for designing novel peptide-directed therapeutics for MS through translational research. .

Public Health Relevance

Multiple sclerosis (MS) is an autoimmune disease of the brain and the spinal cord. Uncontrolled disease results in paralysis and disability. Immune cells pass from the bloodstream into the brain to induced disease. The inner lining (vascular endothelium) of the blood vessels plays a critical role in controlling the trafficking of immune cells into the brain as well as in interacting with mediators of inflammation and tissue damage. Therefore, defining the characteristics of the vascular endothelium is of paramount importance not only in fully understanding the disease process in MS, but also in developing novel therapeutic approaches for drug delivery selectively into the inflamed brain. In this proposal, we have outlined a novel strategy using phage peptide-display library to study the vascular endothelium of the brain and the spinal cord in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We plan to use the peptides thus identified for targeted drug delivery into inflamed brain and spinal cord using liposomes encapsulating a drug (e.g., interferon-b) used for EAE/MS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS082918-01A1
Application #
8638421
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
2013-09-30
Project End
2015-08-31
Budget Start
2013-09-30
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$230,250
Indirect Cost
$80,250
Name
University of Maryland Baltimore
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201