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Research Emphasis Area on Neuroinflammation

Coordinator: Gwenn Garden, M.D., Ph.D.

The research emphasis area on neuroinflammation developed out of the common interest of faculty members studying the role of inflammatory cells in CNS injury and disease. Inflammation and cells involved in the innate immune response appear to modulate both pathogenesis and regeneration/recovery in a wide variety of disease and injury states including traumatic brain and spinal cord injury, ischemia, hemorrhage, epilepsy syndromes, CNS infections, autoimmune diseases of the CNS, and autism. In addition, recent findings demonstrate a strong role for inflammation in modulating the pathogenesis of a number of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Amyotrophic Lateral Sclerosis (ALS).

The Neuroinflammation REA’s focus on collaborative research is concerned with three overarching issues. The first concerns the key molecular regulators that control the features and timing of inflammatory responses in the CNS. Investigators are collaborating on a number of projects aimed at studying a variety of regulators of microglia activation, the primary cellular response in CNS inflammation. These include study of small molecules such as prostaglandins and endogenous cannabinoids in regulating the inflammatory response, evaluations of specific transcription factors including p53 and c-Maf that regulate the character of microglia activation and determining the role of micro RNA’s, recently described regulators of RNA stability and protein translation, in regulating inflammation. In addition, ex-vivo flow cytometry studies are being performed to isolate inflammatory cells from a variety of injury and disease models that involve CNS inflammation in order to perform genomic and proteomic experiments that will fully characterize the inflammatory response. These experiments are aimed at using discovery approaches to identify novel molecular regulators of disease specific inflammatory responses.

The second area focuses on the pharmacological manipulation of specific components of CNS inflammation and their influence on disease phenotype. These investigations have focused on collaborative interactions to study the impact of modulating prostaglandin, endogenous cannabinoids, or Notch signaling using agonists and antagonists of the appropriate receptors on microglia. These studies will be extended to a variety of in vivo and in vitro models of neurodegenerative disease or neuronal injury including CNS ischemia, Huntington’s disease, post-traumatic epilepsy, ALS, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, HIV associated neurocognitive disorders, and traumatic injury to the brain or spinal cord.
The third area is concerned with the extent to which the peripheral immune system modulates the characteristics of CNS inflammation in diseases that either do or do not involve loss of blood brain barrier integrity or show evidence for autoimmunity. In this area, investigators studying multiple sclerosis and the inflammatory response to CNS ischemia have been at the vanguard of efforts to determine what influences the transit of inflammatory cells across the blood brain barrier and what factors contribute to the specific anatomic localization of that transit. For example, in murine multiple sclerosis model, specific T-cell subsets that make a specific interleukin appear to preferentially transit into the spinal cord rather than the brain. In addition, in a murine Huntington’s disease model (as well as in patients with Huntington’s disease), cytokine expression is observed specifically in regions of the brain associated with early neurodegeneration, and investigators are attempting to determine whether signals from the peripheral immune system regulate the anatomic location of the inflammatory response. These efforts involve the use of ex-vivo flow cytometry as well as novel methods of tracking the CNS transit of labeled cells introduced into the peripheral blood by MRI methodologies.

Finally, our REA is also involved in methodological and resource development. Goals include the following: (1) to develop state-of- the-art methodologies aimed at characterizing the process of neuroinflammation using both in vivo animal imaging and ex vivo cell separation techniques to identify molecular and cellular changes associated with the inflammatory process of specific disease or injury models in rodents; (2) to establish the facilities and services needed to evaluate the impact of therapeutic interventions aimed at modulating the innate immune response in a variety of rodent CNS disease and injury models; and (3) to develop and make available molecularly tagged animals (such as transgenic mice expressing GFP specifically in brain macrophages) that will be useful for multiple investigators studying the role of neuroinflammation in CNS disease or injury.

Faculty Investigators

• Gwenn Garden, M.D., Ph.D., Associate Professor, Neurological Surgery, Coordinator
• Raimondo D’Ambrosio, Ph.D., Associate Professor, Neurological Surgery
• Joan Goverman, Ph.D., Associate Professor, Immunology
• Phillip Horner, Ph.D., Assistant Professor, Neurological Surgery
• Suman Jayadev, M.D., Acting Assistant Professor, Neurology
• Satoshi Minoshima, M.D., Ph.D., Professor, Radiology
• Thomas Moeller, Ph.D., Research Associate Professor, Neurology
• Thomas Montine, M.D., Ph.D., Professor, Pathology
• Sean Murphy, Ph.D., Professor, Neurological Surgery
• Nephi Stella, Ph.D., Associate Professor, Pharmacology
• Jonathan Weinstein, M.D., Ph.D., Assistant Professor, Neurology
• Jing Zhang, M.D., Ph.D., Associate Professor, Pathology