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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
91

EFFECTS OF VOLUNTARY EXERCISE PRECONDITIONING ON LEFT VENTRICULAR SYSTOLIC FUNCTION AND CARDIAC AUTOPHAGY IN ANGIOTENSIN II-INDUCED HYPERTENSIVE MICE

Wilson, Brittany Elizabeth January 2016 (has links)
Purpose/Hypothesis: Hypertension is a clinical condition with persistent elevation or raised blood pressure and accounts for approximately 9.4 million deaths every year. Exercise is one of the most effective non-pharmacological interventions and is emphasized in the current treatment guidelines for Hypertension from the World Health Organization. Currently, there is no consensus on whether autophagy is compensatory or causative in the transition from adaptive left ventricular hypertrophy to maladaptive left ventricular remodeling. It also remains unclear whether exercise preconditioning is sufficient to target autophagy for therapeutic benefits in Angiotensin II-induced hypertensive mice. The purpose of this study was to examine the effect of voluntary running exercise preconditioning on systolic function and autophagy in the heart in angiotensin II-induced hypertensive mice. Methods: Forty C57BL6/J mice were divided into 4 groups; Sedentary Sham (Sed), Sedentary Angiotensin II (SAII), Exercise Sham (Ex), Exercise Angiotensin II (ExAII). Animals in the exercise group were singly-housed and familiarized with a running wheel for 3 days prior to the study commencing. Exercise mice had access to a voluntary running wheel for 7 weeks. Ang II was infused at a constant rate using an implantable osmotic pump for the last two weeks of the experimental period. Results: Heart weight was greater in SAII, Ex and ExAII groups compared to Sed mice. Mice in Ex and ExAII groups had no significant differences in running distance or running speed. Ang II infusion caused a significantly higher thickness in the left ventricular posterior wall in diastole (LVPWd) in SAII mice which was further exacerbated in ExAII mice, creating a greater hypertrophy effect. Exercise training significantly raised systolic function as measured by ejection fraction (EF%) and fractional shortening (FS%), and exercise training prevented a significant percent reduction of EF% that was observed in SAII mice. SAII mice had significant elevations in fibrosis when compared to Sed and Ex mice, while ExAII mice had significant elevation in fibrosis when compared to Ex mice. In response to exercise training, DRP1 mRNA expression was significantly reduced, and in SAII mice protein expression of LC3II/I ratio was significantly higher which was attenuated in ExAII mice. Conclusion: Ang II resulted in a greater cardiac hypertrophy, and exercise training prevented the significant reduction in pre-post AII infusion in ejection fraction, preserving LV systolic function in ExAII mice. Ang II significantly raised the formation of autophagic machinery in SAII mice, which was attenuated in ExAII mice. This was not accompanied by a reduction in p62, indicating a possible impairment in autophagic flux in the left ventricle. Voluntary running did not alter basal autophagy, but did reduce LC3 autophagosome formation in ExAII mice and was able to attenuate the reduction in systolic function seen in SAII mice. / Kinesiology
92

Domain-based Bioinformatics Analysis and Molecular Insights for the Autoregulatory Mechanism of Phafin2

Hasan, Mahmudul 19 August 2024 (has links)
Phafin2, an adaptor protein, is involved in various cellular processes, such as apoptosis, autophagy, endosomal cargo transportation, and macropinocytosis. Two domains, namely, PH and FYVE, contribute to Phafin2's cell membrane binding. Phafin2 also contains a poly aspartic acid (polyD) motif in its C-terminal region that can specifically autoinhibit the PH domain binding to membrane phosphatidylinositol 3-phosphate (PtdIns3P). Firstly, the study investigated the domain-based evolutionary pattern of PH, FYVE, and polyD motif of Phafin2 among its orthologs and Phafin2- like proteins. Using different bioinformatics tools and resources, it was concluded that the polyD motif only evolved in Phafin2 and PH- or both PH-FYVE-containing proteins of animals, highlighting the association in cellular functions that might have evolved uniquely in animals. Moreover, PH domain-free FYVE-containing proteins lack polyD motifs. Secondly, intramolecular autoregulatory and membrane binding properties of Phafin2 were studied by employing liposome co-sedimentation assay, isothermal titration calorimetry, and nuclear magnetic resonance spectroscopy. The residues Gly38, Lys45, Leu45, Lys51, Ala52, and Arg53 of the PH domain form a positively charged binding pocket that can bind the negatively charged polyD motif. The mutated Phafin2 PH domain (K51A/R53C and R53C) was unable to bind to synthetic polyD peptides, establishing the significance of those residues for the interaction between the PH domain and polyD motif. Moreover, the study also concluded that Phafin2-mediated membrane binding is not curvature-dependent. / Master of Science / Phafin2 is a protein that plays a crucial role in several important cellular functions, including cell death, recycling of cellular components, and transporting materials within cells. The protein's ability to attach to cell membranes is mainly due to two of its specific regions, the PH and FYVE domains. Additionally, Phafin2 has a section called the polyD motif that can block the PH domain from binding to specific cell membrane molecules. This study explored how these regions of Phafin2 have evolved across different species, focusing on the PH, FYVE, and polyD motifs. The findings suggest that the polyD motif is unique to Phafin2 and similar animal proteins, potentially indicating a unique role in animal cell functions. Further experiments examined how Phafin2 regulates itself and binds to cell membranes. The study identified specific amino acids in the PH domain crucial for interacting with the polyD motif. When these amino acids were altered, Phafin2 could no longer bind to synthetic polyD peptides, highlighting their importance. Finally, the research determined that Phafin2's ability to bind to membranes does not depend on the shape or curvature of the membrane.
93

Exploring the Significance of Autophagy in Host Defense in an Enteric Parasitic Infection

Mowna, Sadrina Afrin January 2024 (has links)
Autophagy is a conserved cellular process that is responsible for degrading and recycling cytoplasmic constituents and has also emerged as a significant factor in modulating immune responses during enteric infections. This study investigates the role of autophagy in host defense during enteric parasitic infection, Trichuris muris, by focusing on the host defense, expulsion of worms, infection pathogenesis, and gut microbiota composition. Using C57BL/6 mice that are resistant and AKR mice that are susceptible to T. muris infection, we confirmed that when infected with T. muris, C57BL/6 mice can clear the infection almost completely by day 21 post-infection (p.i.). In contrast, AKR mice cannot, and therefore harbor a chronic infection within. Moreover, autophagy gene 7 floxed mice (Atg7fl/fl) and mice that are deficient in the autophagy protein, autophagy 7, in their intestinal epithelial cells (Atg7ΔIEC), were infected with T. muris and sacrificed on different time points. We observed that the Atg7fl/fl mice were able to almost clear the infection by day 21 p.i. but the Atg7ΔIEC mice were unable to clear infection by day 21 p.i. In vitro experiments consisted of exposing intestinal epithelial (HT-29) cell lines to T. muris excretory secretory products (ESPs) at different concentrations and also for different time-points, however, autophagy protein levels remained unchanged in those concentrations and time-points. Microbiota from uninfected and infected Atg7fl/fl and Atg7ΔIEC, analyzed by 16s rRNA sequencing revealed no significant differences in microbial composition among uninfected mice and minor differences in microbiota composition among T. muris infected mice. / Thesis / Master of Science in Medical Sciences (MSMS)
94

Structural Study of Proteins Involved in Autophagy / オートファジーに関与するタンパク質の構造生物学的研究

Walinda, Erik 24 September 2015 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第19315号 / 工博第4112号 / 新制||工||1634(附属図書館) / 32317 / 京都大学大学院工学研究科分子工学専攻 / (主査)教授 白川 昌宏, 教授 跡見 晴幸, 教授 梶 弘典 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM
95

The Discovery of Novel 14-3-3 Binding Proteins ATG9A and PTOV1 and Their Role in Regulating Cancer Mechanisms

McEwan, Colten Mitchell 03 August 2022 (has links)
14-3-3 proteins are among a family of phospho-binding proteins that are known to regulate many essential cellular mechanisms. By binding to sites of phosphorylation, 14-3-3s are integrated into multiple signaling pathways that govern critical processes, such as apoptosis, cell cycle progression, autophagy, glucose metabolism, and cell motility. These processes are crucial for tumorigenesis and 14-3-3 proteins are known to play a central role in facilitating cancer progression. In this study, my colleagues and I discover two novel 14-3-3 interacting proteins, ATG9A and PTOV1, that are both vital to essential cellular functions and describe various mechanisms that these two proteins regulate. ATG9A is a multi-pass transmembrane lipid scramblase that is found primarily as a homotrimer in the ER or small ATG9A vesicles. It is essential in the cellular recycling process called autophagy and is believed to act at the earliest stages of autophagy by providing the seed for the growth of the double membrane vesicle called an autophagosome. Previous work in our lab demonstrated that upon hypoxic stress, AMPK, the master nutrient-sensing kinase, phosphorylates S761 on the C-terminus of ATG9A. This triggers the binding of 14-3-3ζ to contribute to ATG9A function in hypoxia induced autophagy. Despite this revelation, the exact function of ATG9A is still poorly understood, especially in unstimulated conditions where autophagy functions at a basal level and AMPK is inactive. In this study, we sought to understand ATG9A function more broadly by identifying novel interactors of ATG9A and the role ATG9A plays in basal autophagy. To do this, we employed BioID mass spectrometry and various biochemical approaches to identify LRBA as a bona fide ATG9A interactor and autophagy regulator. Furthermore, using deuterium labeling and quantitative whole proteome mass spectrometry, and various other biochemical techniques, we show that ATG9A regulates the basal degradation of p62 and is recruited to sites of basal autophagy by active poly-ubiquitination to initiate basal autophagy. PTOV1 is an oncogenic protein that is poorly understood. Our current understanding of PTOV1 is limited to a few studies, which demonstrate that PTOV1 is highly expressed in primary prostate tumor samples and is correlated with metastasis, drug resistance, and poor clinical outcomes. In this study, we identify a mechanism by which SGK2, a poorly understood kinase, phosphorylates PTOV1 at S36 to trigger 14-3-3 binding at that site to increase PTOV1 stability in the cytosol and increase c-Jun expression. Upon SGK2 inhibition, 14-3-3 releases PTOV1 and PTOV1 is shuttled into the nucleus where HUWE1, an E3 ubiquitin ligase, ubiquitinates PTOV1 and initiates PTOV1 degradation by the proteasome. This is the first detailed mechanism of regulation identified for the poorly understood oncogene, PTOV1, and sheds light on potential therapeutic targets for cancer treatments.
96

The Role of Autophagy in Flower Senescence and Abiotic Stress Responses of <i>Petunia × hybrida</i> 'Mitchell Diploid'

Quijia Pillajo, Juan Oswaldo January 2017 (has links)
No description available.
97

The Role of c-FLIP in the Regulation of Apoptosis, Necroptosis and Autophagy in T Lymphocytes

He, Ming-Xiao January 2013 (has links)
<p>To maintain homeostasis, T lymphocytes die through caspase&ndash;dependent apoptosis. However, blockage of caspase activity in T lymphocytes does not increase cell survival. The loss of caspase 8 activity leads to programmed necrosis (necroptosis) upon T cell receptor (TCR) stimulation in T lymphocytes. Necroptosis is correlated with excessive macroautophagy, an intracellular catabolic process characterized by the sequestration of cytoplasmic compartments through double&ndash;membrane vacuoles. Meanwhile, the proper induction of macroautophagy is required for T lymphocyte survival and function. Cellular caspase 8 (FLICE)&ndash;like inhibitory protein (c&ndash;FLIP) promotes survival in T lymphocytes. c&ndash;FLIP suppresses death receptor&ndash;induced apoptosis by modulating caspase 8 activation. Whether this modulation plays a role in the regulation of necroptosis has yet to be studied. Additionally, overexpression of c&ndash;FLIP reduces autophagy induction and promotes cell survival in cell lines. It remains unclear whether c&ndash;FLIP protects primary T lymphocytes by regulating the threshold at which autophagy occurs. In this study, c&ndash;FLIP isoform&ndash;specific conditional deletion models were used to study the role of c&ndash;FLIP in necroptosis and autophagy in primary T lymphocytes.</p><p>Our results showed that the long isoform of c&ndash;FLIP (c&ndash; FLIP<sub>L</sub>) regulates necroptosis by inhibiting receptor interacting protein 1 (RIP&ndash;1). Upon TCR stimulation, c&ndash;FLIP<sub>L</sub>&ndash;deficient T cells underwent RIP&ndash;1&ndash;dependent necroptosis. Interestingly, though previous studies have generally described necroptosis in the absence of caspase 8 activity and apoptosis, pro&ndash;apoptotic caspase 8 activity and the rate of apoptosis were also increased in c&ndash;FLIPL&ndash;deficient T lymphocytes. Moreover, c&ndash; FLIP<sub>L</sub>&ndash;deficient T cells exhibited enhanced autophagy, which served a cytoprotective function. </p><p>Apoptosis can be induced by either death receptors on the plasma membrane (extrinsic pathway), or the damage of the genome and/or cellular organelles (intrinsic pathway). Previous studies in c&ndash;FLIP&ndash;deficient T lymphocytes suggested that c&ndash;FLIP promotes cell survival in the absence of death receptor signals. Independent of death receptor signaling, mitochondria sense apoptotic stimuli and mediate the activation of caspases. Whether c&ndash;FLIP regulates mitochondrion&ndash;dependent apoptotic signaling remains unknown. Here, by deleting the <italic>c&ndash;Flip <italic> gene in mature T lymphocytes, we showed a role for c&ndash;FLIP in the intrinsic apoptosis pathway. In naïve T cells stimulated with the apoptosis inducer, c&ndash;FLIP suppressed cytochrome c release from mitochondria. Bim&ndash;deletion rescued the enhanced apoptosis in c&ndash;FLIP&ndash;deficient T cells, while inhibition of caspase 8 did not. Different from activated T cells, there were no signs of necroptosis in c&ndash;FLIP&ndash;deficient naïve T cells. Together, our findings indicate that c&ndash;FLIP is a key regulator of apoptosis, necroptosis and autophagy in T lymphocytes.</p> / Dissertation
98

MnSOD AND AUTOPHAGY IN PREVENTION OF OXIDATIVE MITOCHONDRIAL INJURIES INDUCED BY UVB IN MURINE SKIN

Bakthavatchalu, Vasudevan 01 January 2012 (has links)
UVB radiation is a known environmental carcinogen that causes DNA damage and increase ROS generation in mitochondria. Accumulating evidence suggests that mtDNA damage and increased ROS generation trigger mitochondrial translocation of p53. Within mitochondria, p53 interacts with nucleoid macromolecular complexes such as mitochondrial antioxidant MnSOD, mitochondrial DNA polymerase Polγ, and mtDNA. Mitochondria are considered to be a potential source for damage-associated molecular patterns (DAMPs) such as mtDNA, cytochrome C, ATP, and formyl peptides. Intracytoplasmic release of DAMPs can trigger inflammasome formation and programmed cell death processes. Autophagic clearance of mitochondria with compromised integrity can inhibit inflammatory and cell death processes. In this study we investigated whether and how MnSOD plays a protective role in UVB-induced mitochondrial damage. The possibility of MnSOD participating in the mtDNA repair process was addressed in vivo using transgenic and pharmacological approaches. The results demonstrate that MnSOD functions as a fidelity protein that maintains the activity of Polγ by preventing UVB-induced nitration and inactivation of Polγ and that MnSOD coordinates with p53 to prevent mtDNA damage. We also investigated whether autophagy is an adaptive response mechanism by which skin cells respond to mitochondrial injury, using mouse keratinocytes (JB6 cells) and C57/BL6 mice as in vitro and in vivo models. The results demonstrate that UVB induces autophagy initiation in murine skin tissues and that down regulation of AKTmTOR levels triggers initiation of autophagy processes. These results suggest that autophagy may play a role in scavenging damaged mitochondria. Taken together, the results from these studies suggest that MnSOD plays a protective role against UVB-induced mitochondria injury beyond its known antioxidant function. Within the mitochondrial matrix, MnSOD acts as an antioxidant and fidelity protein by prevention of UVB-induced nitration of Polγ. The functions of MnSOD may be to enhance mitochondrial membrane integrity and to prevent the genesis of oxidatively damaged mitochondrial components and subsequent intracytoplasmic spillage. Activation of autophagy serves as an additional response that scavenges damaged mitochondria.
99

Arsenite Alters Lysosome-Mediated Degradation and the Autophagy Process Leading to Immunosuppression in Human B-Lymphoblastoid Cell Lines

Bolt, Alicia Marie January 2012 (has links)
The immune system is a target of arsenic toxicity. Epidemiological data have shown that arsenic exposure is associated with characteristics of immunosuppression. Human B-lymphoblastoid cell lines (LCL) were used as an in vitro model of immune cell targeting by arsenic to investigate the mechanism of arsenic-induced cytotoxicity, which could provided insight into the mechanism underlying arsenic-induced immunotoxicity leading to the immunosuppression observed in humans. In LCL arsenite-induced cytotoxicity was not associated with apoptosis, but associated with hallmarks of autophagy, a cell stress-responsive process that facilitates the removal of cellular components through lysosome-mediated degradation. At environmentally relevant concentrations, arsenite-induced toxicity resulted in a decrease in cell proliferation that was correlated with hallmarks of autophagy including expansion of acidic vesicles, global induction of lysosomal gene expression, increased flux of the autophagosome marker LC3-II, and increased enzymatic activity of the lysosomal hydrolase cathepsin D. Investigation of the upstream cellular damage leading to the induction of autophagy revealed that arsenite induces proteotoxic damage leading to an accumulation of protein aggregates that may be targeted to the lysosome for degradation. In addition, global gene expression data showed an enrichment of ER stress responsive genes after arsenite exposure. Further evaluation of global gene expression data indicated that the global induction of lysosomal genes occurs before the activation of ER stress genes, suggesting that the induction of autophagy may occur before the generation of ER stress. To investigate the effect of arsenite-induced proteotoxicity and autophagy on normal immune function, the ability of LCL to process and present exogenous antigens onto MHC class II molecules was evaluated. Arsenite decreased antigen presentation of the exogenous antigen HSA. This decrease was associated with decreased lysosomal degradation of the model substrate DQ-Ova, suggesting that arsenite is disrupting lysosome-mediated degradation. In addition, arsenite exposure was associated with an increase in MHC class II protein aggregates, which could render them unavailable to bind peptide fragments. Through the identification that arsenite induces proteotoxicity and autophagy in LCL, it provides novel insight into the mechanisms of arsenic-induced immunotoxicity that could lead to a better understanding of the mechanisms underlying arsenic-induced immunosuppression observed in humans.
100

The Role of the Nrf2-Keap1 Pathway in Autophagy and How it Contributes to Arsenic Carcinogenicity

Lau, Alexandria G. January 2012 (has links)
NF-E2-related factor 2 (Nrf2) is a transcription factor that is responsible for maintaining cellular homeostasis by controlling the fate of cells through transcriptional upregulation of antioxidant response element-bearing genes critical for eliminating toxicants and carcinogens. Under quiescent conditions, basal levels of Nrf2 are relatively low due to tight regulation by Keap1, a substrate adaptor protein for a Cullin 3 (Cul3)-E3 ubiquitin ligase complex that facilitates the ubiquitination and degradation of Nrf2. It is thought that when cells are exposed to oxidative stress, naturally-occurring compounds, or synthetic chemicals, cysteine residues in Keap1, particularly cysteine 151 (C151), are modified causing a conformational change that compromises the ability of the Keap1-Cul3-E3 ubiquitin ligase complex to properly ubiquitinate Nrf2. It is then stabilized and allowed to translocate into the nucleus to transcriptionally activate downstream genes. Interestingly, recent emerging data has revealed the "dark side" of Nrf2. Epigentic alterations and somatic mutations in either Nrf2 or Keap1 disrupting the Nrf2-Keap1 axis and causing constitutive activation of Nrf2 have been found in many human cancer cell lines and tumors. Thus, Nrf2 provides mutated cells a protective advantage against cytotoxic chemotherapeutics, allowing for further cell survival and growth. It is well known that arsenic is a human carcinogen and can activate the Nrf2 pathway through a Keap1-C151 independent mechanism. It has also been shown that arsenic can activate autophagy, a bulk-lysosomal degradation pathway. In this dissertation, we establish the cross-talk between the Nrf2-Keap1 pathway and autophagy by elucidating a novel non-canonical mechanism of Nrf2 activation. We found that deregulation of autophagy causes accumulation of p62, a substrate adaptor protein, which sequesters Keap1 into autophagosomes and activates the Nrf2 pathway. Moreover, we also demonstrate how arsenic blocks autophagic flux and prolongs Nrf2 activation through this novel mechanism. Additionally, activation of the Nrf2 pathway has been shown to confer protection against arsenic-induced toxicity and carcinogenicity. We demonstrate that co-treatment with sulforaphane alleviates arsenic-mediated autophagy. These studies suggest that the Keap1-C151 dependent mechanism triggers the chemopreventive role of Nrf2 while activation through p62 elicits the dark side. Therefore, the use of Keap1-C151-dependent compounds to counteract environmental insults continuous to be a promising strategy for cancer prevention.

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