The Lau Lab uses a combination of computational and experimental approaches to study the atomic and molecular details governing the function of protein complexes involved in intercellular communication. We study ionotropic glutamate receptors (iGluRs), which are ligand-gated ion channels that mediate the majority of excitatory synaptic transmission in the central nervous system. iGluRs are important in synaptic plasticity, which underlies learning and memory. Receptor dysfunction has been implicated in a number of neurological disorders.

Researchers in the Adam Sapirstein Lab focus on the roles played by phospholipases A2 and their lipid metabolites in brain injury. Using in vivo and in vitro models of stroke and excitotoxicity, the team is examining the roles of the cytosolic, Group V, and Group X PLA2s as well as the function of PLA2s in cerebrovascular regulation. Investigators have discovered that cPLA2 is necessary for the early electrophysiologic changes that happen in hippocampal CA1 neurons after exposure to N-methyl-d-aspartate (NMDA). This finding has critical ramifications in terms of the possible uses of selective cPLA2 inhibitors after acute neurologic injuries.

The research activities of the Neuroimmunopathology Laboratory focus on studies of immunological and molecular mechanisms involved in the pathogenesis of neurological disorders. Our main areas of research include studies of neurological complications of HIV infection and AIDS, multiple sclerosis, transverse myelitis, autism and epilepsy. We seek to explore and identify immunopathological mechanisms associated with neurological disease that may be the target of potential therapeutic interventions. The laboratory collaborates with other researchers and laboratories at Johns Hopkins and other institutions in projects related with studies of the interaction between the immune and central nervous systems in pathological processes leading to neurological dysfunction.

Malfunction and malformation of blood vessels are associated with a broad range of medical conditions, including cancer, cardiovascular diseases, and neurological disorders. The ultimate goal of the Komatsu lab is to find a way to reverse the process of abnormal vessel formation and restore normal function to these vessels. In cancer, normalization of tumor blood vessels facilitates lymphocyte infiltration, potentiating anti-tumor immunity, and enhances the efficacy of immunotherapies as well as conventional cancer treatments. Normalization of regenerating blood vessels is also necessary for reestablishing blood flow to ischemic hearts and limbs, and preventing blindness caused by diabetic retinopathy or macular degeneration. Komatsu lab’s research is uncovering key molecular pathways important for the normalization of pathological vasculature.

In the Lee Martin Laboratory, we are testing the hypothesis that selective vulnerability--the phenomenon in which only certain groups of neurons degenerate in adult onset neurological disorders like amyotrophic lateral sclerosis and Alzheimer's disease--is dictated by brain regional connectivity, mitochondrial function and oxidative stress. We believe it is mediated by excitotoxic cell death resulting from abnormalities in excitatory glutamatergic signal transduction pathways, including glutamate transporters and glutamate receptors as well as their downstream intracellular signaling molecules. We are also investigating the contribution of neuronal/glial apoptosis and necrosis as cell death pathways in animal (including transgenic mice) models of acute and progressive neurodegeneration. We use a variety of anatomical and molecular neurobiological approaches, including neuronal tract-tracing techniques, immunocytochemistry, immunoblotting, antipeptide antibody production, transmission electron microscopy and DNA analysis to determine the precise regional and cellular vulnerabilities and the synaptic and molecular mechanisms that result in selective neuronal degeneration.

Our research is focused on understanding the basic mechanisms of programmed cell death in disease pathogenesis. Billions of cells die per day in the human body. Like cell division and differentiation, cell death is also critical for normal development and maintenance of healthy tissues. Apoptosis and other forms of cell death are required for trimming excess, expired and damaged cells. Therefore, many genetically programmed cell suicide pathways have evolved to promote long-term survival of species from yeast to humans. Defective cell death programs cause disease states. Insufficient cell death underlies human cancer and autoimmune disease, while excessive cell death underlies human neurological disorders and aging. Of particular interest to our group are the mechanisms by which Bcl-2 family proteins and other factors regulate programmed cell death, particularly in the nervous system, in cancer and in virus infections. Interestingly, cell death regulators also regulate many other cellular processes prior to a death stimulus, including neuronal activity, mitochondrial dynamics and energetics. We study these unknown mechanisms. We have reported that many insults can trigger cells to activate a cellular death pathway (Nature, 361:739-742, 1993), that several viruses encode proteins to block attempted cell suicide (Proc. Natl. Acad. Sci. 94: 690-694, 1997), that cellular anti-death genes can alter the pathogenesis of virus infections (Nature Med. 5:832-835, 1999) and of genetic diseases (PNAS. 97:13312-7, 2000) reflective of many human disorders. We have shown that anti-apoptotic Bcl-2 family proteins can be converted into killer molecules (Science 278:1966-8, 1997), that Bcl-2 family proteins interact with regulators of caspases and regulators of cell cycle check point activation (Molecular Cell 6:31-40, 2000). In addition, Bcl-2 family proteins have normal physiological roles in regulating mitochondrial fission/fusion and mitochondrial energetics to facilitate neuronal activity in healthy brains.