Biomedical subjects

Kelli A Sullivan

Publications and source records attributed to Kelli A Sullivan.

5 recordsLinked to original sources

PubMed2006

Receptor for advanced glycation end products activation injures primary sensory neurons via oxidative stress.

The receptor for advanced glycation end products (RAGE) may promote diabetic vascular and renal disease through the activation of intracellular signaling pathways that promote oxidative stress. Oxidative stress is a mediator of hyperglycemia-induced cell injury and a unifying theme for all mechanisms of diabetic complications, but there are few studies on the expression and potential contribution of RAGE in diabetic neuropathy. The current study demonstrates that dorsal root ganglia neurons express functional RAGE and respond to the RAGE ligand S100 with similar downstream signaling, oxidative stress, and cellular injury as other diabetic complication-prone tissues. RAGE-induced phosphatidylinositol-3 kinase activity is associated with formation of reactive oxygen species, caspase-3 activation, and nuclear DNA degradation. These events are prevented by treatment with the antioxidant alpha-lipoic acid. Our data indicate that therapies aimed at decreasing RAGE ligands, blocking RAGE signaling, or preventing oxidative stress could significantly decrease the development of neuropathy in diabetic patients.

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PubMed2006

Reduction in podocyte density as a pathologic feature in early diabetic nephropathy in rodents: prevention by lipoic acid treatment.

BACKGROUND: A reduction in the number of podocytes and podocyte density has been documented in the kidneys of patients with diabetes mellitus. Additional studies have shown that podocyte injury and loss occurs in both diabetic animals and humans. However, most studies in animals have examined relatively long-term changes in podocyte number and density and have not examined effects early after initiation of diabetes. We hypothesized that streptozotocin diabetes in rats and mice would result in an early reduction in podocyte density and that this reduction would be prevented by antioxidants. METHODS: The number of podocytes per glomerular section and the podocyte density in glomeruli from rats and mice with streptozotocin (STZ)-diabetes mellitus was determined at several time points based on detection of the glomerular podocyte specific antigens, WT-1 and GLEPP1. The effect of insulin administration or treatment with the antioxidant, alpha-lipoic acid, on podocyte number was assessed. RESULTS: Experimental diabetes resulted in a rapid decline in apparent podocyte number and podocyte density. A significant reduction in podocytes/glomerular cross-section was found in STZ diabetes in rats at 2 weeks (14%), 6 weeks (18%) and 8 weeks (34%) following STZ injection. Similar declines in apparent podocyte number were found in STZ diabetes in C57BL/6 mice at 2 weeks, but not at 3 days after injection. Treatment with alpha-lipoic acid substantially prevented podocyte loss in diabetic rats but treatment with insulin had only a modest effect. CONCLUSION: STZ diabetes results in reduction in apparent podocyte number and in podocyte density within 2 weeks after onset of hyperglycemia. Prevention of these effects with antioxidant therapy suggests that this early reduction in podocyte density is due in part to increased levels of reactive oxygen species as well as hyperglycemia.

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PubMed2005

New developments in diabetic neuropathy.

PURPOSE OF REVIEW: Diabetic neuropathy is a debilitating consequence of type 1 and 2 diabetes. Hyperglycemia disrupts the normal function of neurons and their supporting glia at multiple levels. The complexity of this complication, combined with difficulties of delivering therapy to sensory, sympathetic and parasympathetic neurons, contributes to the intractability of this serious diabetic complication. This review summarizes recent reviews examining the state of research on and treatment of diabetic neuropathy and highlights areas of clinical and basic research that may yield new diagnostic and treatment options. RECENT FINDINGS: Recent reviews summarize the effects of hyperglycemia on the peripheral nervous system as well as diagnosis and treatment of patients with diabetic neuropathy. Advances in the analysis of intraepidermal fiber densities could shorten the time course of clinical trials and extend data analyses to include sympathetic as well as sensory information. Unchecked glucose-mediated oxidative stress and advanced glycation endproduct signaling through receptors for advanced glycation endproducts are implicated in diabetic neuropathy and may serve as new therapeutic targets. SUMMARY: The best efforts of countless investigators have yet to find effective treatments either to stop the progression of axonal degeneration and cell death or regrow damaged axons. Basic research into the prevention of oxidative stress caused by excess glucose as well as the prevention of advanced glycation endproduct/receptor for advanced glycation endproduct signaling may offer new therapeutic targets. The use of skin biopsies may aid in early detection of both sensory and autonomic neuropathy, and perhaps in the case of patients with type 2 diabetes, diagnose neuropathy prior to the onset of symptoms.

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PubMed2004

In situ imaging of mitochondrial outer-membrane pores using atomic force microscopy.

Here we describe a technique for imaging of the outer contours of the mitochondrial membrane using atomic force microscopy, subsequent to or during a toxic or metabolic challenge. Pore formation in both glucose-challenged and 1,3-dinitrobenzene (DNB)-challenged mitochondria was observed using this technique. Our approach enables quantification of individual mitochondrial membrane pore formations. With this work, we have produced some of the highest resolution images of the outer contours of the in situ mitochondrial membrane published to date. These are potentially the first images of the component protein clusters at the time of formation of the mitochondrial membrane transition pore in situ. With the current work, we have extended the application of atomic force microscopy of mitochondrial membranes to fluid imaging. We have also begun to correlate 3-D surface features of mitochondria dotted with open membrane pores with features previously viewed with electron microscopy (EM) of fixed sections.

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PubMed2003

Applying database technology to clinical and basic research bioinformatics projects.

This paper describes the application of database technology to medical information with the goal of providing medical and clinical researchers with the tools necessary to plan bioinformatics projects. Commercial database management systems were utilized, standard database design practices were applied, a user interface was created, data entered, and the development of analysis tools, including data mining technologies is underway. Databases were constructed based on animal and cell culture models of diabetes and clinical data. Bioinformatics is a useful tool in both basic research and clinical settings. The advantages of relational databases and an approach to managing bioinformatics projects are discussed.

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