Clinical data suggest an association between elevated levels of Hcy, also known as hyperhomocysteine-mia (HHcy) and stroke. HHcy is generated due to increase in de-methylation of methionine by S-adenosine- homocysteine hydrolase (SAHH) and a decrease in methyltetrahydrofolate reductase (MTHFR) and cystathionine-y-lyase (CSE, an enzyme responsible for Hcy metabolism to H2S, a most potent vasodilator, antioxidant and anti-hypertensive agent) contribute to mitochondria dysfunction (mitophagy) and ischemic stroke. Cytochrome-C transports electrons and facilitates mitochondrial bioenergetics. Interestingly, during HHcy, cytochrome-C becomes homocysteinylated (N-Hcy-cyt-c). However, it's consequence to mitophagy and stroke is unclear. The long-term goal of this project is to understand the mechanism of mitophagy, mitochondrial repair and permeability in brain vasculature during I/R injury. Our preliminary studies suggest that during I/R ,total Hcy levels increases, causes N-Hcy-cyt-C , increases mitochondrial matrix metalloproteinase-9 (mtMMP-9), in-part degradation of mt-matrix (connexin and tight junction protein, TJP) which led to mitophagy and permeability in brain vasculature. Interestingly, THC decreases Hcy level and mitigates brain damage. Tetra hydro-curcumin (THC), a major herbal antioxidant and anti-inflammatory agent, has shown to protect brain against I/R injury. The central hypothesis of this proposal is that HHcy contributes to mitophagy mediated brain damage through N-Hcy-cyt-C in part, by increasing oxidative stress, mtMMP-9, degrades connexin-43 and TJP (Figure 1). The treatment with THC, CSE gene and SAHH shRNA gene transfer attenuates mitophagy and permeability. We will test this hypothesis by following three specific aims:
Specific Aim #1 : To determine whether the Hcy contributes to mitophagy, in part by inducing oxidative stress, exacerbating homocysteinylation of cytochrome-c in ischemia reperfusion and if THC, CSE and SAHH shRNA gene therapy mitigates these changes.
Specific Aim #2 : To determine whether the homocysteinylation of cytochrome-c activates mt-MMP-9, disruption of collagen/elastin ratio, mtCxn43 and mt-tight junction proteins in ischemia reperfusion and if THC, CSE and SAHH shRNA gene therapy ameliorate.
Specific Aim #3 : To determine whether Hcy alters mitochondrial (mt) bioenergetics and cerebro-vascular remodeling in ischemia reperfusion and if THC, CSE and SAHH shRNA gene therapy alleviate. These studies will demonstrate the novel mechanism of cerebrovascular remodeling and have therapeutic ramifications for mitochondrial repair in cerebral ischemic stroke.
These studies will delineate the mechanisms of mitophagy and cerebrovascular remodeling in brain vasculature. The treatment with dietary herbal antioxidant tetrahydrocurcumin, naked CSE DNA and SAHH shRNA gene therapy mediated stabilization of mitochondrial membrane potential by inhibition of mitochondrial DNA methylation;oxidant and proteolysis stress via novel mechanistic pathways will be powerful therapeutic strategy for preventing ischemic stroke.
|Behera, Jyotirmaya; Kelly, Kimberly E; Voor, Michael J et al. (2018) Hydrogen Sulfide Promotes Bone Homeostasis by Balancing Inflammatory Cytokine Signaling in CBS-Deficient Mice through an Epigenetic Mechanism. Sci Rep 8:15226|
|Behera, Jyotirmaya; George, Akash K; Voor, Michael J et al. (2018) Hydrogen sulfide epigenetically mitigates bone loss through OPG/RANKL regulation during hyperhomocysteinemia in mice. Bone 114:90-108|
|George, Akash K; Behera, Jyotirmaya; Kelly, Kimberly E et al. (2018) Exercise Mitigates Alcohol Induced Endoplasmic Reticulum Stress Mediated Cognitive Impairment through ATF6-Herp Signaling. Sci Rep 8:5158|
|Behera, Jyotirmaya; Tyagi, Neetu (2018) Exosomes: mediators of bone diseases, protection, and therapeutics potential. Oncoscience 5:181-195|
|Vacek, Jonathan C; Behera, Jyotirmaya; George, Akash K et al. (2018) Tetrahydrocurcumin ameliorates homocysteine-mediated mitochondrial remodeling in brain endothelial cells. J Cell Physiol 233:3080-3092|
|Zhai, Yuankun; Tyagi, Suresh C; Tyagi, Neetu (2017) Cross-talk of MicroRNA and hydrogen sulfide: A novel therapeutic approach for bone diseases. Biomed Pharmacother 92:1073-1084|
|Kalani, Anuradha; Chaturvedi, Pankaj; Maldonado, Claudio et al. (2017) Dementia-like pathology in type-2 diabetes: A novel microRNA mechanism. Mol Cell Neurosci 80:58-65|
|Muradashvili, Nino; Tyagi, Suresh C; Lominadze, David (2017) Localization of Fibrinogen in the Vasculo-Astrocyte Interface after Cortical Contusion Injury in Mice. Brain Sci 7:|
|George, Akash K; Behera, Jyotirmaya; Kelly, Kimberly E et al. (2017) Hydrogen sulfide, endoplasmic reticulum stress and alcohol mediated neurotoxicity. Brain Res Bull 130:251-256|
|Behera, Jyotirmaya; Bala, Jyoti; Nuru, Mohammed et al. (2017) Homocysteine as a Pathological Biomarker for Bone Disease. J Cell Physiol 232:2704-2709|
Showing the most recent 10 out of 34 publications