Experimental approaches to improve our understanding and treatment of major diabetic complications have focused on single mechanisms or pathways and resulted in the identification of specific mechanisms that drive diabetic damage. With the recent emergence of genome-wide profiling capatiilities and comprehensive data integration strategies, biomedical research is at a point where it can move toward a more holistic view of tissue responses to complex chronic diseases. This is of particular relevance to diabetic end-organ damage since multiple mechanisms converge to slowly alter the cellular milieu in target tissues in diabetes, mandating the integration of separate pathways to elucidate the complex pattern of responses in the treatment or prevention of diabetic complications. Indeed, therapies that have worked best to prevent progression of diabetic nephropathy (DN) and polyneuropathy (DPN) affect multiple pathways and mechanisms, whereas those that target a single, """"""""critical"""""""" pathway have often yielded disappointing results. Our team of scientists will use a systems biology approach to achieve 3 goals, to: 1) efficiently identify the essential cellular responses that lead to DN and DPN, 2) identify those responses that are most amenable to conventional and novel therapies, and 3) discover biomarkers for the critical cellular alterations that lead to complications and respond to effective therapies. Our strategy relies on information-rich sequential and reciprocal transcriptomic, protein and metabolite comparisons between humans with DN and DPN and the best extant murine models of these complications. Our hypothesis is that a complex network of responses, including but not limited to those altered by oxidant stress, leads to the onset and progression of diabetic microvascular complications. These critical responses will be identified by performing genome-wide RNA and metabolite profiles from kidney and nerve of humans with DN and DPN. The expression data sets of human end-organ damage from untreated and treated animals will be compared to data sets obtained from kidney and nerve from murine models with DN and DPN. Three different treatment paradigms known to ameliorate DN and DPN will be used as independent tools in the mouse models to identify new critical responses that lead to complications and are responsible for effective treatment in humans. This reciprocal cross-species approach will identify candidate pathways and molecules whose regulation alters disease progression. Finally, we will return to the murine models of DN and DPN to discover new biomarkers that will be useful in the diagnosis and therapeutic management of human DN and DPN.
Two of the most devastating complications of diabetes are kidney disease and nerve disease which both result in increased illness and death. The multifactorial causes of these complications remain poorly understood and treatments are limited. Therefore, we have devised a team approach to use """"""""systems biology"""""""" to study diabetic humans with these complications, with the help of mouse models, and to identify the critical molecular responses that cause kidney and nerve damage and that can be reversed by therapy.
|O'Brien, Phillipe D; Hinder, Lucy M; Parlee, Sebastian D et al. (2017) Dual CCR2/CCR5 antagonist treatment attenuates adipose inflammation, but not microvascular complications in ob/ob mice. Diabetes Obes Metab 19:1468-1472|
|Abcouwer, Steven F (2017) Müller Cell-Microglia Cross Talk Drives Neuroinflammation in Diabetic Retinopathy. Diabetes 66:261-263|
|O'Brien, Phillipe D; Hinder, Lucy M; Callaghan, Brian C et al. (2017) Neurological consequences of obesity. Lancet Neurol 16:465-477|
|Afshinnia, Farsad; Zeng, Lixia; Byun, Jaeman et al. (2017) Myeloperoxidase Levels and Its Product 3-Chlorotyrosine Predict Chronic Kidney Disease Severity and Associated Coronary Artery Disease. Am J Nephrol 46:73-81|
|Shah, Anjali R; Gardner, Thomas W (2017) Diabetic retinopathy: research to clinical practice. Clin Diabetes Endocrinol 3:9|
|Niewczas, Monika A; Mathew, Anna V; Croall, Stephanie et al. (2017) Circulating Modified Metabolites and a Risk of ESRD in Patients With Type 1 Diabetes and Chronic Kidney Disease. Diabetes Care 40:383-390|
|Wall, Valerie Z; Barnhart, Shelley; Kramer, Farah et al. (2017) Inflammatory stimuli induce acyl-CoA thioesterase 7 and remodeling of phospholipids containing unsaturated long (?C20)-acyl chains in macrophages. J Lipid Res 58:1174-1185|
|Zhang, Hongyu; Nair, Viji; Saha, Jharna et al. (2017) Podocyte-specific JAK2 overexpression worsens diabetic kidney disease in mice. Kidney Int 92:909-921|
|Feldman, Eva L; Nave, Klaus-Armin; Jensen, Troels S et al. (2017) New Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain. Neuron 93:1296-1313|
|Scerbo, Diego; Son, Ni-Huiping; Sirwi, Alaa et al. (2017) Kidney triglyceride accumulation in the fasted mouse is dependent upon serum free fatty acids. J Lipid Res 58:1132-1142|
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