Blood Brain Barrier I Laboratory

RESEARCH FOCUS

This laboratory investigates how cytokines modulate central nervous system functions by way of the BBB, as well as the regulation of cerebral blood flow and metabolism by neuroinflammation. It also investigates the role of the BBB endothelia and astrocytes in neuroendocrine control, particularly related to peptides/polypeptides involved in feeding behavior.
The Blood Brain Barrier I Laboratory's primary objective is to identify mechanisms, regulation, and clinical applications of cytokine transport across the blood-brain and blood-spinal cord barrier (BBB).

Several decades ago, we pioneered the concept that peptides in the periphery have central nervous system (CNS) effects, and we are still leading the way in describing the mechanisms involved. In recent years, we showed that these small proteins not only cross the BBB, but also elicit signaling transduction in the cerebral endothelial cells composing the BBB. The significance of these studies lies in the concept that the BBB is a dynamic interface between the body and brain that is actively engaged in regulatory functions while protecting the brain from harmful substances. Lately, we have been focusing on the role of astrocytes, another component of the BBB, in obesity, neuroinflammation, and autoimmune diseases.  

  1. Role of leptin signaling on astrocyte functions. We have shown that the leptin receptor is upregulated in mice with diet-induced obesity and experimental autoimmune encephalomyelitis. To elucidate the functions of the astrocytic leptin receptor, our cell culture approaches test the expression of inflammatory markers and determine the production of gliotransmitters. In addition, hypoxic and excitotoxic challenges have shown that leptin signaling modulates astrocytic activities. Our in vivo studies use behavioral, electrophysiological, immunohistological, and biochemical methods to characterize the phenotype of astrocyte-specific leptin receptor knockout mice generated in our lab.
  2. How do obesity and other challenges to the CNS upregulate astrocytic leptin receptors? Are the changes in the astrocytic leptin system selective or nonspecific as a result of reactive astrogliosis? We are conducting BBB transport studies and cellular assays to determine the metabolic factors and intracellular signaling mechanisms responsible for the translational regulation in astrocytes. 
  3. Effects of astrocytic activity or the astrocytic leptin receptor on neuronal leptin signaling and behavioral outcome, including feeding, metabolism, and cognition. This will be achieved by the use of selective astrocyte activity inhibitors and the astrocyte-specific leptin receptor knockout mice. 
  4. What is the role of endothelial leptin signaling in the development of obesity and the autoimmune response? We will determine the outcome of a high-fat diet or experimental autoimmune encephalomyelitis in endothelial-specific leptin receptor knockout mice generated in our lab.
  5. How does TNF modulate endogenous IL15 trafficking in cerebral endothelia? We have shown that TNF is a strong positive regulator of IL15 production in endothelia and a facilitator of cerebral IL15 signaling. Cellular trafficking studies will further determine the compartmentalization and fate of IL15 in response to a TNF challenge. This illustrates an important principle of signaling modification by the BBB in the event of neuroinflammatory signals from the periphery.

Research in the BBB Group is supported by the National Institutes of Health. 

FACULTY

Weihong Pan, M.D., Ph.D.