Browsing by Department "Veterinary - Physiology & Pharmacology"

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Exercise Training-Enhanced Reactive Oxygen Species as Protective Mechanisms in the Coronary Microcirculation
Veterinary - Physiology & Pharmacology; TAMU; https://hdl.handle.net/20.500.14641/207; DHHS-NIH-National Heart, Lung, and Blood Institute
Project Summary Regular exercise is a proven, powerful and cost-effective intervention for the treatment and secondary prevention of coronary artery disease. However, a detailed understanding of the fundamental cellular and molecular mechanisms that underlie exercise-induced cardioprotection are lacking, limiting the development of effective new therapeutic strategies for diseased patients. Despite recent advances in the appreciation of reactive oxygen species (ROS) as critical regulators of cell signaling, the details of the specific contributions of these molecules to physiologic signaling and functional adaptions in the vascular system remain to be elucidated. This is particularly true in the coronary microcirculation where studies determining the contributions of ROS in the control of blood flow are sparse. The proposed studies will utilize a combination of in vitro and in vivo approaches to determine how exercise-induced adaptations in ROS signaling affect vascular reactivity and coronary blood flow into both control and ischemic myocardium, an area that has been largely unexplored in the coronary circulation. The overarching hypothesis is that ROS play a critical and protective role in the exercise training-induced restoration of vasodilation responses in the coronary microcirculation and thereby enhances perfusion and contractile function of the at-risk myocardium. Aim 1 will determine exercise training- induced adaptations in ROS production in hearts subjected to chronic coronary artery occlusion. Aim 2 will determine the effects of exercise training on the expression and subcellular localization of candidate sources of ROS production and associated regulatory subunit proteins in microvascular endothelium of hearts subjected to chronic coronary artery occlusion. Aim 3 will identify the adaptations by which exercise training promotes downstream signaling pathway(s) for ROS-mediated dilation in arterioles isolated from hearts subjected to chronic coronary artery occlusion. Aim 4 will identify the signaling mechanisms by which exercise training enhances regional perfusion and myocardial contractile function at rest and during dobutamine-induced myocardial stress in hearts subjected to chronic coronary occlusion. These studies are of high impact since the knowledge gained will provide novel insight into the protective role of ROS in the cardiovascular system. The proposed studies will provide important new information with significant mechanistic insight into human ischemic heart disease and identify the role of ROS signaling in the control of coronary blood flow in health, disease, and exercise adaptation.
Exercise Training-Enhanced Reactive Oxygen Species as Protective Mechanisms in the Coronary Microcirculation
Veterinary - Physiology & Pharmacology; TAMU; https://hdl.handle.net/20.500.14641/207; DHHS-NIH-National Heart, Lung, and Blood Institute
Project Summary Regular exercise is a proven, powerful and cost-effective intervention for the treatment and secondary prevention of coronary artery disease. However, a detailed understanding of the fundamental cellular and molecular mechanisms that underlie exercise-induced cardioprotection are lacking, limiting the development of effective new therapeutic strategies for diseased patients. Despite recent advances in the appreciation of reactive oxygen species (ROS) as critical regulators of cell signaling, the details of the specific contributions of these molecules to physiologic signaling and functional adaptions in the vascular system remain to be elucidated. This is particularly true in the coronary microcirculation where studies determining the contributions of ROS in the control of blood flow are sparse. The proposed studies will utilize a combination of in vitro and in vivo approaches to determine how exercise-induced adaptations in ROS signaling affect vascular reactivity and coronary blood flow into both control and ischemic myocardium, an area that has been largely unexplored in the coronary circulation. The overarching hypothesis is that ROS play a critical and protective role in the exercise training-induced restoration of vasodilation responses in the coronary microcirculation and thereby enhances perfusion and contractile function of the at-risk myocardium. Aim 1 will determine exercise training- induced adaptations in ROS production in hearts subjected to chronic coronary artery occlusion. Aim 2 will determine the effects of exercise training on the expression and subcellular localization of candidate sources of ROS production and associated regulatory subunit proteins in microvascular endothelium of hearts subjected to chronic coronary artery occlusion. Aim 3 will identify the adaptations by which exercise training promotes downstream signaling pathway(s) for ROS-mediated dilation in arterioles isolated from hearts subjected to chronic coronary artery occlusion. Aim 4 will identify the signaling mechanisms by which exercise training enhances regional perfusion and myocardial contractile function at rest and during dobutamine-induced myocardial stress in hearts subjected to chronic coronary occlusion. These studies are of high impact since the knowledge gained will provide novel insight into the protective role of ROS in the cardiovascular system. The proposed studies will provide important new information with significant mechanistic insight into human ischemic heart disease and identify the role of ROS signaling in the control of coronary blood flow in health, disease, and exercise adaptation.
IHSFC Voucher YR 3: Investigating Sertoli and Peritubular Myoid Cell Behavior in In Vitro Tubular 3D Hydrogel Cultures
Veterinary - Physiology & Pharmacology; TAMU; https://hdl.handle.net/20.500.14641/561; DHHS-NIH-National Institute of Environmental Health Sciences
This project aimed to progress development of a novel organoid model of the seminiferous epithelium. Among the utility of such a functional organoid model would be application for studies of chemical toxicity testing that may replace animal model use in safety/hazard screening as a NAM for regulatory science. The goal in this proposal was to extend the tissue chip explant model previously developed in our lab, by further establishing a novel tubular organoid.
IHSFC Voucher YR 4: Development of tissue specific lncRNA MALA Tl and AhR double null mouse models for analysis of toxic responses to environmental chemicals
Veterinary - Physiology & Pharmacology; TAMU; https://hdl.handle.net/20.500.14641/614; DHHS-NIH-National Institute of Environmental Health Sciences
Project description: To investigate the function of the MALAT1 in ? cells and to study the effects of PCB126 on the b cell population in the absence of MALAT1 in vivo, we will utilize the service of the core to establish conditional MALAT1 knockout mouse model by CRISPR/Cas9 technology in murine embryonic stem (ES) cells. The complete 6,982 bp long Malat1 sequence will be deleted, including 250 nucleotides upstream of the transcriptional start site and 321 nucleotides following the 3?-end of the Malat1 transcript. A schematic presentation of the targeted Malat1 locus, its construction by in ES cells as well as Cre- and FloxP-mediated deletions in mice are shown in the Figure. Verification of correct MALAT1 targeting in ES cells and mice will be performed by PCR and Southern Blot analysis The floxP mice once generated will then be bred with the ins1-Cre mouse to produce the pancreatic ? cell specific null mice for further investigation for the toxic responses to dosing of PCB126.
Yr. 2 IHSFC Voucher - Development of pancreatic cell specific lncRNA MALA Tl null mouse model for analysis diabetogenic environmental chemicals.
Veterinary - Physiology & Pharmacology; TAMU; https://hdl.handle.net/20.500.14641/614; DHHS-NIH-National Institute of Environmental Health Sciences
Project description: To investigate the function of the MALAT1 in cells and to study the effects of PCB126 and other “dioxin like” xenobiotics on the cell population in the absence of MALAT1 in vivo, we planned to develop the tissue/organ specific targeting at pancreatic cells as well as other organs. MALAT1 knockout mouse model by CRISPR/Cas9 technology with insertion of loxP franking the Malat1-201 which is the longest the transcripts of 4 known transcripts of the Malat1 mouse gene.