Search results

Title: TARGETING CELLULAR SIGNALING PATHWAYS IN ESTROGEN RECEPTOR POSITIVE BREAST CANCER
Creator: Gentile, Sonia Kumar
Date: 2018
Collection: Electronic Theses & Dissertations
Description: Estrogen receptor positive (ER+) breast cancer is the most common type of breast cancer diagnosed in women. While usually initially responsive to combinations of chemotherapy with hormonal therapies, resistance to current clinically used treatments is becoming more and more frequent. It is vital to continue to study the mechanisms of resistance to endocrine therapies and discover methods for combating this drug resistance to improve patient survival. The mixed lineage kinase (MLK) inhibitor,...
Show moreEstrogen receptor positive (ER+) breast cancer is the most common type of breast cancer diagnosed in women. While usually initially responsive to combinations of chemotherapy with hormonal therapies, resistance to current clinically used treatments is becoming more and more frequent. It is vital to continue to study the mechanisms of resistance to endocrine therapies and discover methods for combating this drug resistance to improve patient survival. The mixed lineage kinase (MLK) inhibitor, CEP-1347, was studied in culture and in pre-clinical models to evaluate its efficacy, alone and in combination with the clinically available selective estrogen receptor downregulator ICI 182,780, in treating endocrine sensitive and resistant ER+ breast cancers. Using cell lines models, its effects on cell viability, cell death, and cell cycle progression were analyzed, and nuclear and cellular morphology throughout mitosis were examined. Studies were expanded to animals to determine the efficacy of CEP-1347 against tumor growth in a pre-clinical setting. Tumor cell growth and death were studied, as well as the potential for tumor regrowth after the cessation of treatment. Investigation into drug efficacy were expanded into patient derived xenograft (PDX) lines and effects on cell cycle progression were analyzed.The data demonstrate that CEP-1347, especially in combination with ICI 182,780 has the potential to treat endocrine resistant disease through causing a cell cycle arrest which leads to a combination of decreasing proliferation and inducing apoptosis of tumor cells. Furthermore, inhibition of regrowth after cessation of treatment in endocrine sensitive cells suggests that perhaps if used as an earlier line therapy, CEP-1347 in combination with ICI 182,780 may slow or prevent the development of resistance.
Show less

Title: THE NUCLEO-CYTOPLASMIC FUNCTION OF ACTIN AND ACTIN DEPOLYMERIZATION FACTORS IN PLANT IMMUNITY
Creator: Li, Pai
Date: 2022
Collection: Electronic Theses & Dissertations
Description: The plant immune system is a multi-phase complex network that involves the collaboration of multiple subcellular structures. In the past two decades, the core signaling pathways of the immune process, including pattern-triggered immunity (PTI), effector-triggered immunity (ETI), and systemic acquired resistance (SAR), as well as the behavior of organelles, have been revealed to a level of clarity that is able to describe a general and well-covered process of the immune response. However,...
Show moreThe plant immune system is a multi-phase complex network that involves the collaboration of multiple subcellular structures. In the past two decades, the core signaling pathways of the immune process, including pattern-triggered immunity (PTI), effector-triggered immunity (ETI), and systemic acquired resistance (SAR), as well as the behavior of organelles, have been revealed to a level of clarity that is able to describe a general and well-covered process of the immune response. However, there are still many events during the immune response that remain mysterious. For instance, while higher plants live a sessile lifestyle, there are countless intracellular motions mediated by the cytoskeleton (including its associated proteins) in response to the external triggers, such as the invasion of pathogens. As our knowledge of plant immunity accumulates, the deficiency in knowledge on how immune signaling regulates the behavior of the cytoskeleton as a critical aspect of defense response, howbeit, becomes more evident. Therefore, this is a field of research that calls for powerful toolboxes to facilitate the analysis of the cytoskeleton in the context of immunity, as well as instructive biological model(s) that guide the direction of the multifarious studies. In this dissertation, I focus on the summary and prospective discussion on the immune function of the actin cytoskeleton and, more importantly, describe my original studies on two major aspects of this topic. First, a prerequisite to functional study of the actin cytoskeleton in the cytoplasm is the ability to accurately describe the status of the cytoskeleton. To achieve this goal, I developed an algorithm, namely implicit Laplacian of enhanced edge (ILEE), to accurately identify and analyze the biological status of the cytoskeleton from confocal image samples. This method significantly improves the accuracy, stability, and robustness of cytoskeleton segmentation, solves other technical hindrances, and enables abundant information to be extracted from images for biological interpretation (see Chapter 2). The ILEE algorithm will further help me to explore the phenotypes of actin architecture in response to immune signaling, which was not previously available due to the lack of the toolbox. Also, the ILEE has been packaged as a library released publicly to benefit the community with a powerful cytoskeleton analysis platform.For the second project of my total research, I focused on the immune function of the actin cytoskeleton in the nucleus. Previously, some Arabidopsis actin depolymerization factors were reported to genetically contribute to plant immunity by unknown mechanism(s), and my story began with a novel activity identified among Arabidopsis actin depolymerization factors – to interact with WRKYs, the stress-responsive transcription factors. During my research, I proved that certain ADFs can form a complex with WRKYs that binds to targeted promoters, hence regulating the activity of WRKYs and playing a positive role in the immune response. The knowledge obtained through this study, in combination with previous research (Lu et al., 2020; Porter et al., 2012a) of my lab, can be summarized into a biological model, in which ADF mediates a nuclear-cytoplasmic immune regulation that systemically facilitates both cytoskeleton dynamics and pro-immune transcriptome reprogramming. In general, this study reveals a novel yet general pattern of cytoskeleton mediated transcriptional regulation, as ADF and perhaps other components of the actin cytoskeleton can shuttle between the cytoplasm and nucleus to form a network with a higher level of complexity. As a potential broader impact, the application range of this model includes but is not necessarily limited to plant immunity.
Show less

Title: THE ROLE OF ARID1A IN ENDOMETRIOSIS-RELATED INFERTILITY
Creator: Marquardt, Ryan Michael
Date: 2022
Collection: Electronic Theses & Dissertations
Description: The inner lining of the uterus, the endometrium, is composed of a luminal epithelial cell layer supported by an underlying stroma which contains epithelial gland structures. These distinct cell types coordinate with complex and dynamic molecular crosstalk tightly controlled by ovarian steroid hormones to regulate a healthy menstrual cycle and support the initiation and maintenance of a healthy pregnancy. Endometriosis occurs when endometrium-like tissue forms lesions outside the uterine...
Show moreThe inner lining of the uterus, the endometrium, is composed of a luminal epithelial cell layer supported by an underlying stroma which contains epithelial gland structures. These distinct cell types coordinate with complex and dynamic molecular crosstalk tightly controlled by ovarian steroid hormones to regulate a healthy menstrual cycle and support the initiation and maintenance of a healthy pregnancy. Endometriosis occurs when endometrium-like tissue forms lesions outside the uterine cavity, and this painful disease afflicts about 10% of reproductive-age women, an estimated 176 million worldwide. Up to 50% of these individuals also experience infertility, and many cases cannot be explained by morphological or ovarian defects, which implicates a uterine environment that is non-receptive to embryo implantation. The molecular basis for the correlation between endometriotic lesion presence and a non-receptive endometrium is unclear, but available evidence suggests that dysregulation of epigenetic regulators may play a role. Expression of AT-rich interaction domain 1A (ARID1A), a chromatin remodeling factor, is lost in some endometriotic lesions and markedly reduced in endometrial biopsies from infertile women with endometriosis, but it is essential in the uterus for fertility. This dissertation evaluates the overarching hypothesis that ARID1A loss connects endometriosis and infertility by causing increased lesion development and a non-receptive endometrium. Chapter 1 provides a review of the current literature on the topics of normal ovarian steroid hormone regulation of endometrial function, the dysregulation that occurs in endometriosis with its clinical implications and therapeutic options, and the specific involvement of ARID1A in endometrial pathophysiology. Chapter 2 delineates a critical role for endometrial epithelial ARID1A in uterine gland function for fertility. Chapter 3 reports the need for endometrial epithelial ARID1A to maintain uterine immune homeostasis during early pregnancy. Chapter 4 explores the involvement of endometrial ARID1A loss in a mouse model of endometriosis-related infertility. Chapter 5 describes a method for in vivo photoacoustic imaging of this endometriosis mouse model through the application of nanoparticle labeling. Finally, Chapter 6 summarizes the findings, discusses conclusions from the synthesized data in the context of the current literature, and provides ideas for future studies of related topics. Together, the studies herein make the case that endometrial ARID1A loss contributes to endometriosis-related infertility by exacerbating endometriotic lesion formation and compromising the ability of the endometrium to maintain the gland function and immune homeostasis necessary for the establishment and maintenance of pregnancy. Continued investigation through studies like these is key to understanding endometrial pathophysiology at the molecular level in order to enable development of targeted treatment options for women suffering the devastating effects of endometriosis and related infertility.
Show less

Title: The cyanelle and the cyanelle genome of Cyanophora paradoxa
Creator: Wasmann, Catherine Clair
Date: 1985
Collection: Electronic Theses & Dissertations

Title: The cytologic responses of normal beagle dogs utilizing the skin window technic
Creator: Drees, David T.
Date: 1966
Collection: Electronic Theses & Dissertations

Title: The roles of C/EBPbeta and c-Jun in transcription of the gene encoding the murine progesterone receptor
Creator: Do, Han Ngoc
Date: 2014
Collection: Electronic Theses & Dissertations
Description: Progesterone (P) and its receptor, the progesterone receptor (PR), are important for mammary gland development. Moreover, P/PR signaling also contributes to mammary tumorigenesis. Thus, studying the mechanism of PR expression is important in breast cancer research. C/EBPB-deficient mice and mice blocked for AP-1 activity show similar defects in mammary gland development as do PRB-deficient mice, especially during pregnancy, suggesting that these transcription factors might act in the same...
Show moreProgesterone (P) and its receptor, the progesterone receptor (PR), are important for mammary gland development. Moreover, P/PR signaling also contributes to mammary tumorigenesis. Thus, studying the mechanism of PR expression is important in breast cancer research. C/EBPB-deficient mice and mice blocked for AP-1 activity show similar defects in mammary gland development as do PRB-deficient mice, especially during pregnancy, suggesting that these transcription factors might act in the same pathway or may regulate overlapping sets of downstream target genes. An overall decrease in PR observed in sexually mature wild type mice fails to occur in C/EBPB-deficient mice, while no alterations in C/EBPB expression are observed in PR-deficient mice. Moreover, AP-1 has been found to regulate PR expression. These observations suggest that C/EBPB and AP-1 act upstream of PR. This leads us to study the possibility that C/EBPB and AP-1 are required for PR expression.We examined whether C/EBPB participated in the transcriptional regulation of PR expression in the mammary gland. Transient co-transfection of a PR promoter-reporter construct with expression vectors that individually express C/EBPB isoforms (LAP1, LAP2, or LIP) into a mouse mammary carcinoma cell line revealed that all C/EBPB isoforms, surprisingly including LIP (the shortest isoform lacking transactivation domains), can transactivate the PR promoter. Importantly, we found that LIP, in particular, robustly synergizes with an AP-1 member, c-Jun, to drive PR transcription. Consistent with significant roles for C/EBPB and c-Jun in PR expression, knockdown experiments showed that endogenous levels of C/EBPB and c-Jun expression were sufficient to drive the PR promoter-reporter. Additionally, overexpression of LIP elevated PR protein expression from the intact endogenous gene encoding PR. Furthermore, in vivo immunofluorescence studies showed that C/EBPB and PRA expression are mutually exclusive in the mammary epithelium, while PRB is only expressed in cells that express C/EBPB. This suggests an important role for C/EBPB in PRB expression during pregnancy. Then, we studied the mechanism by which LIP and c-Jun synergistically activate the PR promoter. We demonstrated in the reporter assay that the integrity of C/EBP- and AP-1-binding sites was required for the respective C/EBPB; and c-Jun activities on the PR promoter. Moreover, we showed in ChIP assay that efficient promoter occupancy of both LIP and c-Jun and their synergistic transactivation of the PR promoter required at least one C/EBP- and one AP-1-binding site. In addition, as indicating in the sequential ChIP assay, C/EBPB and c-Jun simultaneously occupied PR promoter. This leads us to propose a model where the synergy of C/EBPB and c-Jun in transactivation of the PR promoter is dependent on the two factors mutually stabilizing their recruitment to the PR promoter. Collectively, our data suggest a critical role for C/EBPB, particularly LIP, in PRB expression.
Show less

Title: Therapeutically targeting autophagy in non-small cell lung cancer
Creator: Yco, Lisette Pangilinan
Date: 2019
Collection: Electronic Theses & Dissertations
Description: Autophagy is a conserved catabolic pathway which sequesters intracellular components in lysosomes to recycle macromolecules for cell maintenance. The role of autophagy in tumor cells is dynamic and depends on many factors including tumor types, tumor stages, and activity of several tumor suppressors and oncogenes. In this thesis, I wanted to improve our understanding of the unique relationship of autophagy with tumor suppressor p53 and oncogenic KRAS in cancer cells, particularly in NSCLC....
Show moreAutophagy is a conserved catabolic pathway which sequesters intracellular components in lysosomes to recycle macromolecules for cell maintenance. The role of autophagy in tumor cells is dynamic and depends on many factors including tumor types, tumor stages, and activity of several tumor suppressors and oncogenes. In this thesis, I wanted to improve our understanding of the unique relationship of autophagy with tumor suppressor p53 and oncogenic KRAS in cancer cells, particularly in NSCLC. First, I demonstrated that stabilized nuclear wild-type p53 through HDM2 inhibition with MK-8242 or nutlin-3a could induce autophagy in tumor cells through transactivation of several autophagy-related genes (DRAM, FOXO3A, SESN2, and MRCKα) and autophagy core genes (ATG4A and ULK1). In addition, I found that inhibiting of KRAS G12C signaling and suppressing mTORC1 activity by selective KRAS G12C inhibitor, ARS-853, could drive autophagy response in KRAS G12C NSCLC cell lines. Since autophagy could also promote survival under stress induced by several anticancer agents, I designed a combination study using newly reported selective ULK1 inhibitor, ULK-101, with ARS-853 in KRAS mutant NSCLC. Autophagy inhibition with ULK-101 dramatically enhanced the ability of selective KRAS G12C inhibitor to impair the viability of KRAS G12C NSCLC. Together, my study provided evidence that autophagy serves as a survival pathway in tumor cells and that future assessment of small molecule that target autophagy core proteins may be potential cancer therapeutic option in p53 wild-type and KRAS G12C NSCLC.
Show less

Title: ZIKA VIRUS-INDUCED PREGNANCY LOSS : LESSONS FROM THE MOUSE EMBRYO
Creator: Watts, Jennifer Leticia
Date: 2021
Collection: Electronic Theses & Dissertations
Description: Adults contracting Zika virus (ZIKV) exhibit mild cold-like symptoms, whereas newborn babiesexhibit fetal defects ranging from mild growth retardation to miscarriage. Aside from transmission via mosquito, ZIKV is also sexually transmitted, which introduces the possibility that ZIKV infection could occur shortly after conception. However, the mechanisms underlying ZIKV-induced birth defects in early development are not understood. I hypothesize that sexually transmitted ZIKA virus infects...
Show moreAdults contracting Zika virus (ZIKV) exhibit mild cold-like symptoms, whereas newborn babiesexhibit fetal defects ranging from mild growth retardation to miscarriage. Aside from transmission via mosquito, ZIKV is also sexually transmitted, which introduces the possibility that ZIKV infection could occur shortly after conception. However, the mechanisms underlying ZIKV-induced birth defects in early development are not understood. I hypothesize that sexually transmitted ZIKA virus infects embryos around the time of conception, leading to the most severe congenital defects. Consistent with this hypothesis, I have discovered that candidate proviral factors are present in mouse embryo-derived stem cell lines and preimplantation development. However, embryo-derived stem cell lines exhibited low viral infection and replication. Nevertheless, Puerto Rican (ZIKVPR) and the Ugandan (ZIKVUG) strains of ZIKV caused two-cell embryos to undergo developmental arrest. Moreover, infected blastocyst exhibited reduced SOX2 expression, an epiblast cell marker, CDX2 a trophectoderm cell marker, and SOX17, a primitive endoderm marker. Therefore, my results suggest that preimplantation ZIKV infection causes embryonic demise or embryonic cell fate defects depending on the time of infection. My studies are significant to human health because they will further our knowledge of viral infection in early pregnancy and the outcomes.
Show less

MSU Libraries

Digital Repository

Enabled Filters

Pages

Pages

MSU Libraries

Digital Repository

You are here

Search results

Pages

Pages