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Research at Rush > Research Funding > 2012 Research Awardees > 2012 Pilot Awardees
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Congratulations to our 2012 Pilot Project Awardees!

Xiulong Xu, PhD
Kristin J Al-Ghoul, PhD
Elena N. Dedkova, PhD

Title: Insulin Receptor Sensitization by Targeting p70 S6 Kinase (S6K1)
PI: Xiulong Xu, PhD, Associate Professor, Department of General Surgery
Abstract: During long history of our ancestry evolution, human body has developed dominant genetic mechanisms to overcome the harsh conditions of food shortage and constant threat of hunger.  However, in modern time, increase in food availability has exposed the weakness of these dominant genetic traits, with obesity emerging as a prevalent metabolic disorder. One important pathogenic consequence of obesity is insulin resistance.  It plays a central role in the development of type 2 diabetes and cardiovascular disease, major causes of morbidity and rising health care costs in western societies.

The insulin receptor is a protein tyrosine kinase that phosphorylates several adaptor proteins and activates multiple signaling pathways such as the PI-3 kinase-PDK-AKT pathway.  p70 S6 kinase 1 (S6K1) is a member of the AGC family in the PI-3 kinase pathway that can be activated by nutrient overloads.  S6K1 phosphorylates insulin receptor substrates (IRS) and desensitizes insulin receptor signaling.  S6K1 is a key molecular element in driving insulin resistance under conditions of nutrient overload.  S6K1-/- mice are resistant to obesity and more tolerant to glucose challenges, compared to wild-type mice.

Leflunomide (Lef) is a novel immunomodulatory drug for treating rheumatoid arthritis (RA).  Interestingly, limited evidence indicates that blood glucose levels and body weights in rheumatoid arthritis patients treated with leflunomide are significantly lower than those treated with other drugs.  These observations cannot be explained by its inhibitory effect on protein tyrosine kinases and dihydrooratate dehydrogenase (DHO-DHase), a rate-limiting enzyme involved in pyrimidine nucleotide synthesis.  Recent study by Dr. Xu and his colleagues leads to the identification of S6K1 as a new molecular target of leflunomide.  They hypothesize that inhibition of S6K1 activity by leflunomide will lead to the sensitization of the insulin receptor and an increased glucose and lipid metabolism.  Dr. Xu proposes to determine whether lefunomide can sensitize insulin receptor in vitro and in vivo; and whether leflunomide treatment can control hyperglycemia and obesity in an obesity mouse model.   If the efficacy of leflunomide to sensitize insulin receptor and to overcome insulin resistance is proven, leflunomide can be added as a new class of glycemia control drug.

Title: The Role of Cytokines in the Initiation of Diabetic Cataracts
PI: Kristin J Al-Ghoul, PhD, Associate Professor, Department of Anatomy and Cell Biology
Abstract: Diabetes mellitus is a major cause of posterior subcapsular cataract (PSC) formation, and if untreated, can result in total opacification of the ocular lens and subsequent blindness. It is generally accepted that inflammation plays a central role in many of the pathological process/changes that take place during both type 1 and type 2 diabetes. Our recent studies have indicated that: 1) abnormal fiber end migration underlies PSC formation in an animal model of type 1 diabetes, and 2) pro-inflammatory cytokines are elevated in the vitreous humor just prior to and during the development of some types of PSCs, including PSC following diabetic induction. Here, we propose two hypotheses that address the role of inflammatory cytokines in the initiation of lenticular changes culminating in cataracts during type 1 diabetes. These studies will pinpoint which cytokines are altered (aim 1) as well as examine the direct effects of elevated cytokines on fiber end migration and morphology (aim 2). The proposed studies represent a logical extension of our previous work and will advance the field by elucidating the linkages between inflammation and cataractogenesis in type 1 diabetes. The long term goal is to identify factors capable of limiting or preventing the aberrant fiber migration, thus precluding PSC formation and the resultant visual compromise during diabetes.

Title: ß-hydroxybutyrate and its polymers in diabetic hearts: implications in cardiomyopathy
PI: Elena N. Dedkova, PhD, Assistant Professor, Department of Molecular Biophysics and Physiology
Award: $25,000
Abstract: Cardiovascular disease is a well-known complication of diabetes. Diabetes increases the risk of mortality from heart disease by 4.0 to 6.6-fold and 6.2- to 17.1-fold in men and women, respectively. It also significantly worsens the prognosis after heart failure, however mechanisms responsible for myocardial damage in diabetic hearts are not fully understood. The global population of diabetes-affected individuals is estimated to reach 300 million by the year 2025, making it a huge health problem and an enormous financial burden in USA. Recent studies demonstrated that diabetic animals and human patients have dramatically increased levels of poly-ß-hydroxybutyrate (PHB), a polymerized form of the ketone body ß-hydroxybutyrate (HB). We propose the existence of a link between elevation of PHB levels in diabetes and diabetes-mediated cardiomyopathy. The central goal of current proposal is to investigate the molecular mechanisms which underlie the process of PHB-induced cell damage. Specifically, we will test the central hypothesis that PHB causes cardiac cell death through activation of the mitochondrial Permeability Transition Pore (mPTP) channel. The mPTP is a large, non-selective channel in the inner mitochondrial membrane, and its opening leads to the dissipation of mitochondrial membrane potential, disruption of ATP production, release of pro-apoptotic factors, and ultimately cell death. Understanding the effect of mitochondrial PHB accumulation and metabolism on the performance of the heart will allow us to uncover previously unrecognized signaling pathways that are critical for cell survival and protection in diabetes.


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