Cardiovascular disease is a major cause of morbidity and mortality in patients with Type 1 diabetes (T1D). In addition, cerebrovascular dysfunction contributes to the pathogenesis of stroke and cognitive impairment observed in humans with T1D. These consequences of T1D may be related to alterations in cellular networks that increase oxidative stress, and impair nitric oxide synthase (NOS) and potassium (K+) channel- dependent reactivity of cerebral vessels. We suggest that T1D impairs reactivity of cerebral vessels by altering the balance between key cellular networks responsible for governing oxidative stress, and thus reducing nitric oxide (NO) bioavailability and produce K+ channel dysfunction. We also have evidence suggesting that exercise training (ExT) may restore this balance. Our central hypothesis is that T1D alters the contribution of oxidative cellular networks governing cerebrovascular reactivity, and that ExT will alleviate cerebrovascular dysfunction during T1D via effects on these cellular networks. To test this hypothesis, the following aims are proposed.
In Specific Aim #1, we will test the hypothesis that the contribution of NOS and K+ channels in the regulation of cerebrovascular function is impaired in T1D and that ExT will alleviate/prevent this impairment.
In Specific Aim #2, we will test the hypothesis that T1D impairs NOS- and K+ channel-dependent responses of cerebral vessels via activation of cellular networks that lead to an increase in oxidative stress and that ExT can alleviate cerebrovascular dysfunction by influencing these critical networks.
In Specific Aim #3, we will test the hypothesis that alterations/manipulations in antioxidant pathways may contribute to impaired responses of cerebral vessels during T1D and that ExT can alleviate this impairment by influencing these antioxidant pathways.
In Specific Aim #4, we will test the hypothesis that ExT can reduce cerebral ischemic brain damage during T1D mainly via its influence on oxidative stress. Our studies will be the first comprehensive and integrative attempt to examine mechanisms that contribute to impaired reactivity of cerebral vessels during T1D and the therapeutic benefits of ExT on cerebral vessels and brain damage during T1D. We will use established techniques to examine in vivo reactivity of cerebral vessels coupled with new innovative molecular and biochemical approaches to determine the effects of T1D and ExT on the brain.

Public Health Relevance

While T1D contributes to many disorders of the brain, including stroke, cellular mechanisms that account for the effects of T1D on the brain remain virtually unknown. ExT may be a valid therapeutic approach for the treatment of brain dysfunction during T1D, however, no studies have examined this approach for the treatment of cerebrovascular dysfunction during T1D. Our studies will be the first to examine the potential therapeutic benefits of ExT on brain function during T1D.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL090657-04
Application #
8269055
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Charette, Marc F
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$356,400
Indirect Cost
$108,900
Name
Louisiana State University Hsc Shreveport
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
095439774
City
Shreveport
State
LA
Country
United States
Zip Code
71103
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Arrick, Denise M; Sun, Hong; Patel, Kaushik P et al. (2011) Chronic resveratrol treatment restores vascular responsiveness of cerebral arterioles in type 1 diabetic rats. Am J Physiol Heart Circ Physiol 301:H696-703
Zhao, Honggang; Mayhan, William G; Arrick, Denise M et al. (2011) Dose-related influence of chronic alcohol consumption on cerebral ischemia/reperfusion injury. Alcohol Clin Exp Res 35:1265-9
Shao, Chun Hong; Capek, Haley L; Patel, Kaushik P et al. (2011) Carbonylation contributes to SERCA2a activity loss and diastolic dysfunction in a rat model of type 1 diabetes. Diabetes 60:947-59
Shao, Chun-Hong; Rozanski, George J; Nagai, Ryoji et al. (2010) Carbonylation of myosin heavy chains in rat heart during diabetes. Biochem Pharmacol 80:205-17
Zhao, Honggang; Mayhan, William G; Arrick, Denise M et al. (2010) Alcohol-induced exacerbation of ischemic brain injury: role of NAD(P)H oxidase. Alcohol Clin Exp Res 34:1948-55
Mayhan, William G; Arrick, Denise M; Sun, Hong et al. (2010) Exercise training restores impaired dilator responses of cerebral arterioles during chronic exposure to nicotine. J Appl Physiol 109:1109-14
Arrick, Denise M; Mayhan, William G (2010) Inhibition of endothelin-1 receptors improves impaired nitric oxide synthase-dependent dilation of cerebral arterioles in type-1 diabetic rats. Microcirculation 17:439-46
Arrick, Denise M; Sharpe, Glenda M; Sun, Hong et al. (2008) Losartan improves impaired nitric oxide synthase-dependent dilatation of cerebral arterioles in type 1 diabetic rats. Brain Res 1209:128-35