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DelloStritto Dissertation (Final).pdf (3.18 MB)

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TRPing up the Balance of Oxidative Stress - Transient Receptor Potential Vanilloid 1’s Role in Diabetic Microvascular Disease

DelloStritto, Daniel Justin
http://orcid.org/0000-0001-8495-5231
http://rave.ohiolink.edu/etdc/view?acc_num=ne2mh1469567446

Abstract Details

2016, Doctor of Philosophy, Northeast Ohio Medical University, Integrated Pharmaceutical Medicine.
Diabetes is a growing epidemic worldwide leading to an increase in cardiovascular morbidity and mortality. The maintenance of coronary blood flow (CBF) is crucial to supplying energy and oxygen to the working myocardium and this has been demonstrated to be disrupted in diabetes. Specifically, our lab has illustrated the ion channel Transient Receptor Potential Vanilloid subtype 1 (TRPV1) is a key regulator in CBF control, but it’s contribution to CBF regulation is attenuated in diabetes. A crucial mechanism behind pathologies seen in diabetes is the imbalance in oxidative stress (OS). Herein, we determined the role for oxidative stress, specifically H2O2, to regulate TRPV1-mediated CBF—demonstrating H2O2 differentially regulates TRPV1. Acutely, H2O2 increases CBF through a TRPV1-dependent signaling; however, exposure to prolonged OS blunts TRPV1-mediated endothelial signaling resulting in uncoupling of CBF. Similarly, this altered OS environment is known to lead to an increase lipid peroxidation (LPO). The LPO product 4-hydroxynonenal (4-HNE) increases oxidative post translational modification (PTM) resulting in altered protein function. As such, we established the ability of 4-HNE to modify TRPV1 resulting in blunting of TRPV1-dependent CBF regulation. Further elucidation determined this process occurs via a carbonylation reaction on Cysteine 621 of TRPV1. Overall, this dissertation demonstrated a role for TRPV1 to sense the oxidative environment and subsequently regulate CBF; however, in diabetes this perfusion is perturbed through the oxidative modification of TRPV1 leading to potential avenues for future therapeutic targeting.
Ian Bratz, Ph.D. (Advisor)
Altaf Darvesh , Ph.D. (Committee Member)
William Chilian , Ph.D. (Committee Member)
Marc Penn , M.D., Ph.D. (Committee Member)
Derek Damron , Ph.D. (Committee Member)
147 p.
Biology; Physiology
TRPV1, Diabetes, ROS, 4-HNE, Hydrogen Peroxide, Differential Regulation

Recommended Citations

Citations

  • DelloStritto, D. J. (2016). TRPing up the Balance of Oxidative Stress - Transient Receptor Potential Vanilloid 1’s Role in Diabetic Microvascular Disease [Doctoral dissertation, Northeast Ohio Medical University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ne2mh1469567446

    APA Style (7th edition)

  • DelloStritto, Daniel. TRPing up the Balance of Oxidative Stress - Transient Receptor Potential Vanilloid 1’s Role in Diabetic Microvascular Disease. 2016. Northeast Ohio Medical University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ne2mh1469567446.

    MLA Style (8th edition)

  • DelloStritto, Daniel. "TRPing up the Balance of Oxidative Stress - Transient Receptor Potential Vanilloid 1’s Role in Diabetic Microvascular Disease." Doctoral dissertation, Northeast Ohio Medical University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ne2mh1469567446

    Chicago Manual of Style (17th edition)

ne2mh1469567446
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© 2016, all rights reserved.
This open access ETD is published by NEOMED Integrated Pharmaceutical Medicine and OhioLINK.