HomeFacultyDritan Agalliu

Dritan Agalliu

Dritan Agalliu, Ph.D.
Assistant Professor

4236 McGaugh Hall
University of California Irvine
Irvine, CA 92697

Tel:   (949) 824-6847
Fax: (949) 824-4709
Email: dagalliu@uci.edu
Website: Lab Homepage

Molecular, cellular and genetic analysis of mammalian blood-brain barrier development and the role of the barrier in disease pathogenesis – My laboratory is investigating three fundamental issues in the biology of the mammalian blood-brain barrier (BBB): 1) the mechanisms governing development and maintenance of the barrier; 2) how structural components of the BBB are affected in diseases of the brain and spinal cord where barrier function is impaired; and 3) the role of Wnt/beta-catenin signaling in repairing the damaged BBB in CNS diseases.

Agalliu ResearchEndothelial cells that line the blood vessels of the mammalian central nervous system (CNS) form a unique, tight barrier that maintains the homeostasis necessary for neuronal and glial function, and protects the CNS from pathological agents and immune cell invasion. Barrier properties of CNS endothelial cells (ECs) are mediated by three distinct cell biological mechanisms: a) extremely tight junctions that prevent diffusion of small molecules between endothelial cells (paracellular pathway); b) very few endocytotic vesicles (caveolae) that transcytose slowly and thereby reduce transport of large molecules across the brain endothelium (transcellular pathway); and c) transporters that shuttle only selected molecules between the blood and the brain (Figure 1). This barrier breaks down during CNS insults such as stroke, or in CNS autoimmune disorders such as multiple sclerosis (MS).

What are the cellular and molecular mechanisms that govern development and maintenance of the BBB?
We are interested in identifying key signaling pathways that regulate formation of the BBB, because the molecular mechanisms that control this process are poorly understood and have obvious implications for repairing BBB function for CNS diseases in which the barrier breaks down. We have found that the Wnt/beta-catenin pathway plays an important role in regulating both CNS angiogenesis and some properties of the barrier. We have identified a novel inhibitor of this pathway named Apcdd1 that is expressed in CNS endothelial cells when they acquire their barrier properties during development. We are currently investigating the roles of Apcdd1 in CNS angiogenesis and blood-brain barrier development. In addition, we are also interested in understanding how tight junctions between endothelial cells in the CNS develop and mature during BBB formation. We have developed proteomic discovery platforms for: a) identifying novel junctional proteins important for barrier development and function; and b) potential BBB structural modifications that underlie CNS diseases exhibiting reduced barrier function.

How are structural components of the BBB affected in diseases of the brain and spinal cord, where barrier function is impaired?
Remarkably little is known about how the BBB breaks down in CNS diseases that have various pathological origins such as stroke, or in CNS autoimmune diseases such as multiple sclerosis. In particular, the roles of BBB structural components such as tight junctions and transcytosis vesicles (caveolae) that allow small or large molecules, respectively, to cross the BBB are poorly defined for the pathogenesis of brain disorders. We have created a novel transgenic strain where tight junctions are labeled with GFP. This strain allows real-time analysis of tight junction dynamics and changes in EC transcytosis rates for a variety of CNS disease models where the BBB is compromised. We are using these novel transgenic mice to image tight junctions in brain capillaries using two-photon microscopy in vivo, combined with quantitative analysis of fluorescent tracer leakage across the BBB. We are currently investigating this question in stroke and Experimental Autoimmune Encephalitis (EAE), a mouse model for multiple sclerosis (MS).

How does repeated Streptococcus pyogenes infection induce rapid onset of neuropsychiatric symptoms in children?
Despite emerging evidence that inflammatory molecules alter synapse formation, neuronal connectivity and behavior, the molecular mechanisms underlying impairment of brain development and function by infections that induce an aberrant immune response remain poorly understood. Group A Streptococci (S. pyogenes; GAS), the primary agent for acute pharyngitis in children, is associated with several autoimmune diseases, including the central nervous system (CNS) autoimmune motor and behavioral disorders Sydenham’s chorea and Pediatric Acute-onset Neuropsychiatric Syndrome (PANS). Recurrent GAS mucosal infections induce a strong antigen-specific Th17 cellular response in mice and humans. Th17 cells have been implicated in triggering inflammation and destruction of the blood-brain barrier (BBB) in MS. The dominant response to intranasal infection is expansion of GAS-specific Th17 cells that populate the Nasal-Associated Lymphoid Tissue (NALT) and other lymphoid tissues. Our preliminary experiments show that these T cells specifically home to the brain, localizing primarily in the olfactory bulb (OB) and along the olfactory nerve. We are investigating the mechanisms of how these T cells induce neuronal damage and BBB breakdown and the consequences for behavioral outcomes.

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