Cerebrovascular Diseases & Aging

Richard Kraig MD PhD focusses his research on deciphering how the brain can protect itself against neurological disease. The brain is unique among organ structures. It can alter its regional, cellular and molecular structure in response to activity. This classically is evidenced by Hebbian synaptic plasticity but it also extends to environmental enrichment (i.e., increased intellectual, social, and physical activity), which protects the brain against neurodegeneration. The mechanisms by which naturally increased brain activity strengthens brain are largely unknown. Deciphering the bases by which increased brain from environmental enrichment alters both the form and function of brain has immense clinical value since environmental enrichment reduces subsequent neurological disease by half without negative sequelae.

Dr. Kraig's work, and that of others, shows that learning involves increased production of tumor necrosis factor alpha (TNF-a), one a group of innate cytokines, typically recognized for their involvement as early responders to disease. Furthermore, his work shows that neuroprotection from activity depends on intrinsic production of TNF-a. This is an adaptive change that requires time to develop and extinguishes if not maintained by activity. Cytokines, including TNF-a, alter tissue structure and function by altering gene expression of related transcription factors, growth factors and anti-apoptotic genes.

TNF-a and the other innate cytokines are highly pleiotropic and interactive. Accordingly, Dr. Kraig's lab has developed cell-specific genomic and proteomic techniques to acquire the “vocabulary” needed to understand the “syntax” of activity-dependent neuroprotection via the application of computational analysis strategies.

Dr. Kraig uses in vitro and in vivo animal models of epilepsy, stroke, aging, and migraine as our exemplary diseases for study. They use cellular and molecular imaging strategies as well as genomic and proteomic techniques and computational analyses of data from these approaches to search for the “signaling syntax” by which natural neural activity makes brain more resilient to disease. Their tools include real-time cellular imaging, laser dissection microscopy, real-time RT-PCR, semi-quantitative cellular cytological and immunohistochemical imaging, all proteomic tools (including bead-based, multiplexed ELISAs), and nanoparticle gene delivery systems now in development.

Specific Research Projects:

  1. The mechanisms and consequences of spreading depression
  2. The mechanisms by which brain activity results in neuroprotection
  3. How sleep modulates activity-dependent neuroprotection
  4. How cold generates neuroprotection
  5. Development and use of nanoparticle-based gene delivery for epilepsy treatment
  6. Development and use of macrophage-nanoparticle gene delivery systems for treatment of brain disease