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In a broad sense, my research involves the study of the nerve microenvironment in metabolic, toxic and immune-mediated neuropathies. However, a long-standing interest has been the pathogenesis of diabetic neuropathy. Collaborations with other Department of Pathology faculty foster a multidisciplinary approach that uses in vivo and in vitro studies, and variety of electrophysiological, morphological, behavioral, biochemical and molecular biological techniques to address relevant questions related to the etiologies of peripheral nerve diseases. An important focus is testing therapeutic options to alleviate nerve dysfunction in experimental studies in order to contribute pre-clinical data in support of clinical trials.

Early work characterized the biophysical properties of peripheral nerve edema in experimental diabetes. Key discoveries were that osmotic imbalances in experimental diabetes are ameliorated by aldose reductase inhibitors (ARIs), linking this abnormality with flux through AR, a polyol pathway enzyme implicated in diabetic complications, and that showed Schwann cells use flux through AR to accumulate polyols (i.e. non-perturbing osmolytes) to cope with osmotic stress. These and subsequent studies led to the recognition that Schwann cell injury is present in experimental diabetes, dependent on flux through AR, and comparable to that present in human diabetic neuropathy. Similar observations in nerve biopsies from cats with spontaneously occurring feline diabetes suggest that the Schwann cell is the initial focus of hyperglycemia-induced nerve injury, demonstrating that these abnormalities appear before significant axonal injury and revitalizing the notion that the site of the initial insult in human diabetic neuropathy is AR- linked Schwann cell injury.

The recognition of ARI-sensitive Schwann cell injury led us to consider that hyperglycemia- induced, exaggerated polyol-pathway activity hinders the production of neurotrophic factors, thereby disrupting nerve function and structure, and impairing the ability to respond to injury. Our report of neurotrophic factor depletion in experimental diabetes demonstrated that levels of CNTF, a peptide localized to Schwann cells, are reduced and a subsequent study revealed that expression of CNTF is ARI-sensitive. These reports and subsequent work have contributed to a growing literature recognizing neurotrophic factor depletion as a potential mechanism in the pathogenesis of diabetic neuropathy and have prompted studies to assess the therapeutic potential of administration exogenous neurotrophic factors (e.g. BDNF, CNTF, NT-3 and TX14(A)). Experimental studies helped provide some of the pre-clinical data supporting a clinical trial of TX14(A) in the treatment of painful diabetic neuropathy. Ongoing collaborations with several pharmaceutical companies are examining the efficacy of novel neurotrophic factors and compounds that stimulate synthesis of neurotrophic factors in treating experimental diabetic neuropathy. Recent efforts have been directed at investigating a possible role for neurotrophic factors expressed in the nerve microenvironment prior to or immediately after injury in recruiting macrophages after injury. In vitro, CNTFRa/CNTF, NGF and NT-3 promote macrophage chemotaxis in a dose-dependent, receptor-mediated and phosphorylation-dependent manner. These observations point to an unexpected, novel and potentially important role for factors with functions usually described in the context of trophic support. The in vivo relevance of these in vitro observations is now being examined with the intent of establishing the impact of reduced expression of these select neurotrophic factors on impaired nerve regeneration in diabetes.

Track(s):
Molecular Pathology


BMS Focus Areas:
Neurobiology