Dritan Agalliu
Visiting Assistant Professor, Developmental & Cell Biology
School of Biological Sciences
School of Biological Sciences
Assistant Professor, Developmental & Cell Biology
School of Biological Sciences
School of Biological Sciences
Ph.D., Columbia University, 2006, Genetics and Development
University of California, Irvine
4236 McGaugh Hall
Mail Code: 2300
Irvine, CA 92697
4236 McGaugh Hall
Mail Code: 2300
Irvine, CA 92697
Research Interests
blood-brain barrier, central nervous system, development, disease, stroke, CNS autoimmune diseases, multiple sclerosis, PANDAS/PANS
Appointments
Stanford University School of Medicine
Postdoctoral Scholar
Period: 8/2006 - 6/2011
Postdoctoral Scholar
Period: 8/2006 - 6/2011
Research Abstract
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; and 2) how structural components of the BBB are affected in diseases of the brain and spinal cord where barrier function is impaired; 3) the role of Wnt signaling in blood-brain barrier repair in CNS diseases associated with impaired BBB function.
Endothelial 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. This barrier breaks down during CNS insults such as trauma and stroke, or in CNS autoimmune disorders such as multiple sclerosis (MS) or Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus infections (PANDAS).
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. 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.
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 such as stroke, or CNS autoimmune diseases diseases such as multiple sclerosis or PANDAS. 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 these brain disorders. We have created a novel transgenic strain where tight junctions are labeled with GFP (Tie2p::eGFP::Claudin-5). 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 in stroke and Experimental Autoimmune Encephalitis (EAE), an animal model of human multiple sclerosis.
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/PANDAS). Recurrent GAS mucosal infections induce a strong antigen-specific Th17 cellular response in mice and humans. In multiple sclerosis, Th17 cells trigger inflammation and destruction of the BBB. 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 as well as some other brain regions where OB neurons send projections and eventually make synaptic connections. We are investigating the mechanisms of how these Th17 cells induce neuronal damage and BBB breakdown and the consequences for behavioral outcomes.
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; and 2) how structural components of the BBB are affected in diseases of the brain and spinal cord where barrier function is impaired; 3) the role of Wnt signaling in blood-brain barrier repair in CNS diseases associated with impaired BBB function.
Endothelial 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. This barrier breaks down during CNS insults such as trauma and stroke, or in CNS autoimmune disorders such as multiple sclerosis (MS) or Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus infections (PANDAS).
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. 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.
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 such as stroke, or CNS autoimmune diseases diseases such as multiple sclerosis or PANDAS. 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 these brain disorders. We have created a novel transgenic strain where tight junctions are labeled with GFP (Tie2p::eGFP::Claudin-5). 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 in stroke and Experimental Autoimmune Encephalitis (EAE), an animal model of human multiple sclerosis.
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/PANDAS). Recurrent GAS mucosal infections induce a strong antigen-specific Th17 cellular response in mice and humans. In multiple sclerosis, Th17 cells trigger inflammation and destruction of the BBB. 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 as well as some other brain regions where OB neurons send projections and eventually make synaptic connections. We are investigating the mechanisms of how these Th17 cells induce neuronal damage and BBB breakdown and the consequences for behavioral outcomes.
Publications
Mazzoni J., Cutforth T., and Agalliu D. (2015). Dissecting the role of smooth muscle cells versus pericytes in regulating cerebral blood flow using in vivo optical imaging. Neuron 87: 4-6. doi:10.1016/j.neuron.2015.06.024
Kurimoto S, Jung J, Tapadia M, Lengfeld J, Agalliu D, Waterman M, Mozaffar T, Gupta R. (2015). Activation of the Wnt/ß-catenin signaling cascade after traumatic nerve injury. Neuroscience 294:101-8. doi: 10.1016/j.neuroscience.2015.02.049.
Lengfeld J, Cutforth T, Agalliu D. (2014). The role of angiogenesis in the pathology of multiple sclerosis. Vascular Cell 28;6(1):23. doi: 10.1186/s13221-014-0023-6. eCollection 2014.
Knowland D., Arac A., Sekiguchi K.J., Hsu M., Lutz S.E., Perrino J., Steinberg G.K., Barres B.A., Nimmerjahn A., and Agalliu D (2014). Stepwise recruitment of transcellular and paracellular pathways underlies blood-brain barrier breakdown in stroke. Neuron 82: 603-617.
Lutz S.E., Lengfeld J., and Agalliu D (2014). Stem cell-based therapies for multiple sclerosis: recent advances in animal models and human clinical trials. Regenerative Medicine 9 (2): 129-132.
Liu L, Eckert MA, Riazifar H, Kang DK, Agalliu D, Zhao W (2013). From blood to the brain: can systemically transplanted mesenchymal stem cells cross the blood-brain barrier? Stem Cells Int. 2013;2013:435093. doi: 10.1155/2013/435093. Epub 2013 Aug 12.
Liu S, Agalliu D, Yu C, Fisher M (2012). The role of pericytes in blood-brain barrier function and stroke. Current Pharmaceutical Design 18: 3653-62.
Shimomura Y*, Agalliu D*, Vonica A*, Luria V*, Wajid M, Baumer A, Belli S, Petukhova L, Schinzel A, Brivanlou AH, Barres BA and Christiano AM (2010). APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex. Nature 464: 1043-1047.
Daneman R, Rumah KR, Zhou L, Agalliu D, Cahoy JD, Kaushal A and Barres BA (2010). The mouse blood-brain barrier transcriptome: a new resource for understanding the development and function of brain endothelial cells. PLoS One 5: e13741.
Daneman R, Agalliu D, Zhou L, Kuhnert F, Kuo CJ and Barres BA (2009). Wnt/beta-catenin signaling is required for CNS, but not non-CNS, angiogenesis. Proc. Natl. Acad. Sci. USA 106: 641-646.
Emery B, Agalliu D, Cahoy JD, Watkins TA, Dugas JC, Mulinyawe SB, Ibrahim A, Ligon KL, Rowitch DH and Barres BA (2009). Identification of myelin-gene regulatory factor as a critical transcriptional regulator required for CNS myelination. Cell 138: 172-85.
Agalliu D, Takada S, Agalliu I, McMahon AP and Jessell TM (2009). Motor neurons with axial muscle projections specified by Wnt4/5 signaling. Neuron 61: 708-720.
Agalliu D and Schieren I (2009). Heterogeneity in the developmental potential of motor neuron progenitors revealed by clonal analysis of single cells in vitro. Neural Development 4: 2.
Masckauchan, NTH, Agalliu D, Vorontchikhina M, Ahn A, Parmalee NL, Li C, Khoo A, Tycko B, Brown AM and Kitajewski J (2006). Wnt5a signaling induces proliferation and survival of endothelial cells and expression of MMP-1 and Tie-2. Molecular Biology of the Cell 17: 5163-72.
Lieberam I*, Agalliu D*, Nagasawa T, Ericson J and Jessell TM (2005). A Cxcl12-Cxcr4 chemokine signaling pathway defines the initial trajectory of mammalian motor axons. Neuron 47: 667-679.
*equal authorship
*equal authorship
Grants
American Heart Association
National Multiple Sclerosis Society
NIH NHLBI R01
Professional Societies
American Heart Association
International Brain Barriers Society
Society for Neuroscience
North American Vascular Biology Organization
Graduate Programs
Cell Biology
Cellular and Molecular Biosciences
Developmental Biology and Genetics
Interdepartmental Neuroscience Program
Neurobiology
Stem Cell Biology
Research Centers
UCI MS Research Center http://www.ucimsrc.org/faculty/
Institute for Immunology
Link to this profile
https://faculty.uci.edu/profile/?facultyId=5892
https://faculty.uci.edu/profile/?facultyId=5892
Last updated
07/02/2015
07/02/2015