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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.
11

Langevin, population density and moment-based modeling of local and global aspects of intercellular calcium signaling

Wang, Xiao 01 January 2015 (has links)
Markov chain models of the coupled gating of intracellular calcium (Ca 2+) channels are often used to study the stochastic dynamic of local Ca2+ release events and whole cell Ca2+ homeostasis. However, the runtime of the Markov chain description of Ca2+ channel gating is exponential in the number of Ca2+ channel states and may thus result in a combinatorial state space explosion when the number of channel states is large. This dissertation presents several novel stochastic modeling approaches that capture important aspects of Ca 2+ signaling while improving computational efficiency. This dissertation presents several novel stochastic modeling approaches that capture important aspects of calcium Ca2+ signaling. First, we present a Ca 2+ release site modeling approach based on a Langevin description of stochastic Ca2+ release. This Langevin model facilitates our investigation of correlations between successive puff/spark amplitudes, durations and inter-spark intervals, and how such puff/spark statistics depend on the number of channels per release site and the kinetics of Ca2+ -mediated inactivation of open channels. Second, we show that when the Ca2+ channel model is minimal, Langevin equations in a whole cell model involving a large number of release sites may be replaced by a single Fokker-Planck equation. This yields an extremely compact and efficient local/global whole cell model that reproduces and helps interpret recent experiments investigating Ca2+ homeostasis in permeabilized ventricular myocytes. Last but not least, we present a population density and moment-based approach to modeling L-type Ca2+ channels. Our approaches account for the effect of heterogeneity of local Ca2+ signals on whole cell Ca currents. Moreover, they facilitate the study of domain Ca-mediated inactivation of L-type Ca channels.
12

The Effects of Total Body Proton Irradiation on the Peripheral Plasma Corticosterone Concentration and the Ultrastructure of the Zona Fasciculata in Mus musculus

Young, Robert James 01 January 1972 (has links)
No description available.
13

Molecular basis of autism-like behavior in SAPAP3-deficient mice

Tesdahl, Natalya S. 01 May 2017 (has links)
Autism Spectrum Disorders (ASDs) are a diverse group of diseases that share the common features of deficits in social communication and rigid, repetitive behavior patterns. Most genetic alterations related to ASD can be broadly split into two categories – those pertaining to mTOR/PI3K signaling, and those pertaining to synaptic connections and structure. While a number of synaptic scaffolding proteins have been linked to ASD via human genetic studies and mouse models, SAP90/PSD95 associated protein 3 (SAPAP3) has not. Loss of SAPAP3 in mice, however, results in compulsive grooming behavior, which parallels one of the core features of ASD. On a molecular level, loss of SAPAP3 results in increased signaling via the group I metabotropic glutamate receptor mGluR5. As mGluR5 is known to regulate protein transcription and translation, we conducted a proteomic comparison of sapap3-/- mice relative to sapap3+/+ mice. We identified a number of differentially regulated proteins, the majority of which were upregulated in sapap3-/- mice. Of those, we chose to further investigate collapsin response mediator protein 2 (CRMP2), due to its role in regulating dendritic branching and neurogenesis. We found abnormalities in both dendritic branching and postnatal neurogenesis in sapap3-/- mice, changes which may contribute to some of their behavioral phenotypes. We also found that ultrasonic vocalization, a form of communication for mice, is altered in neonatal sapap3-/- mice. Taken together, these findings provide new direction that could lead to future therapeutics for patients with ASD, as well as an early read-out of the effectiveness of any potential treatment.
14

Bioluminescent mouse models of prostate cancer progression and therapy

Svensson, Robert Ulf 01 May 2010 (has links)
Prostate cancer is the most common visceral neoplasm and second leading cause of cancer death in US men. It is a complex heterogeneous and multi-factorial disease whose mechanistic basis is poorly understood. Furthermore, treatment options for advanced metastatic prostate cancer are limited and do not impart significant survival benefits, highlighting the need for novel and more effective therapeutic strategies. To this end we examined the use of RNAi therapy based on the systemic delivery of optimized small interfering RNAs (siRNAs) targeting the androgen receptor (AR). siRNA treatment induced massive cell death in vitro but was unable to induce tumor regression or improve survival in an animal model of advanced human prostate cancer due to inefficient cellular delivery and uptake of siRNAs at metastatic sites. To explore further, we developed a bioluminescent animal model that enables the high throughput screening of siRNA pharmacodynamic and biodistribution properties. Systemically delivered siRNAs, although potent, were only effective at inhibiting gene expression in the liver. Reliable and tractable animal models of prostate cancer are needed in order to help better understand the molecular mechanisms of disease progression. Here we describe an improvement on the previously characterized Pten mutant model of prostate cancer by incorporation of a luciferase reporter allele. Specifically, the cancer initiating event is coupled to activation of firefly luciferase from the endogenous ROSA26 promoter in the same prostate epithelial cells. Additionally, we have extensively backcrossed our model onto the albino C57BL6TYRC2J and BALB/c backgrounds which enhances bioluminescence imaging (BLI) sensitivity. Consistent with previous studies, we show that progression of prostate cancer from 3-12 weeks is rapid and correlates with an increase in bioluminescence. However, longitudinal BLI from 12-40 weeks reveals a plateau in bioluminescence signal that is correlated with a halt in cellular proliferation as evidenced by Ki67 staining at necropsy. In contrast to other studies, prostate cancer never progressed beyond a high grade prostatic intraepithelial neoplasm (HGPIN). Furthermore, we demonstrate for the first time that cancer progression is accompanied by increased inflammation, characterized by enhanced recruitment of myeloid derived suppressor cells (MDSCs). We further demonstrate the utility of B6-Luc mice in monitoring response to prostate cancer therapy. Relatively few established risk factors for prostate cancer have been identified. Obesity has been linked to increased mortality rates in prostate cancer patients. Using B6-Luc mice we demonstrate that obesity induced a prostatic inflammatory response characterized by increased expression of IL-6 and IL-1β. However, the effects of obesity on prostate cancer progression were inconclusive due to the small number of animals enrolled in the study. Taken together, we have developed novel model systems that will enable the mechanistic basis of prostate cancer progression and response to therapy to be evaluated in the appropriate experimental context.
15

Influence of matrix and fluid microenvironments on cancer cell migration, survival, and metastasis

Barnes, James Matthew 01 May 2011 (has links)
Metastasis is the most common cause of lethality in patients with solid tumors. This complex cascade of events begins with invasion of local tissue by cancer cells of the primary tumor and eventually leads to dissemination of cancer cells through the bloodstream. In order to colonize a distant tissue, circulating cancer cells must first survive the physical stresses within the vasculature, and then traverse the endothelium, by a process called extravasation. After extravasation, colonized cancer cells face several additional challenges including proliferation in a nutrient-deprived microenvironment. Epithelial-mesenchymal transition (EMT) is a process by which cells lose their epithelial characteristics and gain a mesenchymal, often migratory phenotype. There is much evidence that EMT augments cancer cell invasion, however little is known about how EMT-like cells interact with their microenvironment during metastasis. We investigated the migratory behavior of EMT-like cancer cells on different basement membrane constituents as well as in the presence of other cell types. We showed that ZEB1, a driver of EMT, regulates pro-migratory genes, resulting in cells which must co-opt with their matrix and cellular surroundings to elicit invasive migration. Additionally, we show that RNAi-mediated knockdown of ZEB1 results in significantly reduced anchorage-independent growth as well as metastatic colonization in mice. Thus, ZEB1 and EMT-states may facilitate both extravasation and survival of cancer cells in vivo. In experimental and clinical settings, metastasis is viewed as an inefficient process; of the many cancer cells which enter the bloodstream, very few go on to form secondary tumors. The events which contribute to this inefficiency are debated. A popular theory is that most cancer cells die in circulation, under hemodynamic shear forces. There is evidence, however, which challenges this paradigm. Direct analyses of the response of cancer cells to shear forces are lacking. Therefore, we designed an in vitro model of fluid shear stress, which allows high throughput analysis of various cell types. In a broad panel of cancer cell lines, derived from various tissues, we found a remarkably conserved inducible shear stress resistance response. This response was absent in normal epithelial cells or non-transformed cell lines. Mechanistically, this response requires extracellular calcium and actin polymerization. These studies revealed a novel mechanism which may be necessary for progressive metastasis, and has practical implications in the study of circulating tumor cells. To gain insight into the metastatic phenotype, we analyzed of a panel of cancer cell lines derived from metastatic passage in mice. We noticed that derivative cells were physically smaller than their respective parental cell lines. Reduced cell size was correlated with attenuated activation of the mTOR pathway, and an increase in autophagic flux. Autophagy allows cells to digest their own proteins and organelles, and thus benefits cells residing in a nutrient-depleted environment. Our data suggest that autophagic cells are selected for in the metastatic microenvironment Future directions aim to determine the role of autophagy in metastasis. Finally, we show that an aggressive subpopulation of prostate cancer cells exhibit stem cell-like features, which may be regulated by ZEB1. In sum, these studies provide mechanistic details underlying the interactions of cancer cells with matrix and fluid microenvironments, which in turn affect migration, survival, and metabolism during metastasis.
16

Investigations in pigmentary dispersion and glaucoma using new mouse models and quantitative tools

Hedberg-Buenz, Adam 01 May 2015 (has links)
Pigment dispersion syndrome (PDS) and its potential sequela, pigmentary glaucoma (PG) are ocular diseases characterized by disruption of the iris with subsequent dispersion of pigment throughout the anterior chamber. In some cases, PDS can be accompanied by intraocular pressure (IOP) elevation and initiate conversion to PG. PG results in vision loss by the death of retinal ganglion cells (RGC). However, the pathophysiologic mechanisms that contribute to IOP elevation and conversion to PG are not known. Mice represent a powerful resource for studies of human eye disease. The DBA/2J (D2) mouse model of PG exhibit iris phenotypes that resemble PDS in humans, including pigment dispersion from the iris pigmented epithelium and a characteristic pattern of iris transillumination defects (iris-TID). Mutations in Lyst and Dct each elicit mild iris phenotypes of PDS in C57BL/6J mice (B6) and were hypothesized to exacerbate the PDS in D2. Using a genetic-background driven approach, the Lyst and Dct mutations were transferred onto the glaucoma-susceptible D2 strain (D2.Lyst and D2.Dct). Characterization of both strains show that the iris phenotypes of PDS were rapidly intensified, resulting in the development of two new mouse models with accelerated forms of PDS. A novel technique for grading severity of iris-TID revealed that a mutation in Tyrp1 modified the Lyst-mediated iris-TID in D2.Lyst. Using a physiologic approach to identify factors contributing to IOP elevation, PDS was experimentally induced in mice by intraocular infusion of homogenized irides from mouse donors. Induction led to characteristic features of PDS including pigment deposition along the cornea, lens, and trabecular meshwork. Induction also resulted in IOP elevation. This novel model provides a unique experimental platform for manipulating disease parameters of PDS, since the amount of pigment, frequency of infusions, and genotypes of the recipient and donor mouse strains may be modified. Studies of PDS and conversion to PG require high-throughput methods for detecting glaucomatous death of RGCs. To complement our studies, we developed a software tool that performs automated counting (RetFM-J) and classification (RetFM-J) of cells in the inner retina of flat-mounted retinas. In testing performance, output count data from these tools was determined to be consistent with previously published results for several well-characterized mouse models of eye disease and their controls, including: D2 (glaucoma), Jun-sufficient and Jun-deficient mice receiving controlled optic nerve crush (induced retinal damage), and B6 (normal). We show that these tools are feasible and can be utilized to study RGC death in a high-throughput manner. In conclusion, novel mouse models with severe forms of naturally occurring and experimentally-induced PDS were developed and characterized. An objective technique for measuring severity of iris-TID was developed. Automated software tools for quantitative analyses and random forest classification techniques of cellularity in the inner retina provide a new approach for measuring glaucomatous damage.
17

Altered mTOR signaling in Huntington's Disease

Lee, John Hung 01 May 2015 (has links)
Huntington's Disease (HD) is caused by a polyglutamine tract expansion in huntingtin (HTT). Despite HTTs ubiquitous expression, there is selective vulnerability in a specific brain region known as the striatum, the cause of which is poorly understood. Here, we provide evidence that impaired striatal mTORC1 activity underlies varied metabolic and degenerative phenotypes in striatal tissues from HD mouse models and patients, and show that further mTORC1 impairment in mouse models, achieved through the knockdown of Rhes, a striatum-enriched mTORC1 activator, exacerbates disease phenotypes. In contrast, exogenous addition of Rhes or the constitutively active form of the mTORC1 regulator, Rheb, into HD mouse brain, alleviates mitochondrial dysfunction, aberrant cholesterol homeostasis, striatal atrophy, and elicits increased autophagy, and reverses impaired dopamine signaling. Furthermore, while HD has been considered primarily a neurological disease, organs with high metabolic demand, such as heart, are also severely affected. The mechanism by which mHTT disrupts cardiac function remains unknown. I provide evidence that mTORC1 is impaired in HD mouse model hearts, causing hyperactive FoxO1 signaling which may render HD hearts vulnerable to stress induced cardiomyopathy. In sum, my combined work indicates impaired mTORC1 signaling as a primary mechanism underlying the neurodegenerative and heart-related disease phenotypes in HD, and thus presents a rational therapeutic target.
18

The role of dystroglycan in the prostate epithelium and prostate cancer

Esser, Alison K. 01 December 2011 (has links)
Interactions between cells and the extracellular matrix are essential to the organization and maintenance of tissue architecture and function. ECM receptors serve as a link between the cell and the ECM. Through interactions with various matrix molecules and activation of intracellular signaling pathways, ECM receptors allow cells to sense and respond to their microenvironment. The matrix receptor dystroglycan (DG) has been shown to have roles in tissue morphogenesis, basement membrane formation as well as in the regulation of cell proliferation, differentiation and survival. DG is expressed in many tissues but has primarily been studied in muscle. The function of dystroglycan within the epithelium is currently unknown. To gain insight into the role of dystroglycan in the prostate epithelium, we generated individual prostate luminal cell (Probasin Cre) and basal cell (Keratin 5 Cre) specific DG knockout mice. DG was not required for maintenance of the basement membrane, polarity or cellular homeostasis in the prostate. Furthermore, gland morphology and ability to regenerate following androgen depletion were normal. These studies indicate DG may have more subtle roles within the epithelium. Disruption of cell/ECM interactions is a hallmark of cancer and contributes to cancer progression. DG expression is lost in many carcinomas including prostate yet the molecular mechanism behind loss of expression and the functional consequences remain unclear. To elucidate the molecular mechanism in prostate cancer, we examined DG expression in metastatic prostate cancer cell lines. alpha-DG was heterogeneously glycosylated across the cell line panel. Surprisingly, we show that LARGE2 is able to functionally glycosylate alpha-DG and loss of LARGE2 expression is a mechanism for DG hypoglycosylation in prostate cancer. Additionally, initial results suggest that oncogene expression modulate alpha-DG glycosylation status through regulation of LARGE2 expression. This work has shown a novel mechanism for alpha-DG hypoglycosylation in prostate cancer. In summary, these studies have contributed new information on the role of DG in the prostate epithelium. Furthermore, we have shown a novel mechanism for loss of alpha-DG glycosylation in prostate cancer and have provided initial data suggesting oncogene expression modulates alpha-DG glycosylation. These insights may lead to advances in the treatment of prostate cancer.
19

Computer Simulations of Protein Folding and Evolution

Xu, Jiabin 14 October 2013 (has links)
Computer simulations for investigating protein folding and evolution are presented. In chapter 1, an all-atom model with a knowledge-based potential is used to study the folding kinetics of Formin-Binding protein. We study the folding kinetics by performing Monte Carlo simulations. We examine the order of formation of two beta-hairpins, the folding mechanism of each individual beta-hairpin, and transition state ensemble (TSE) and compare our results with experimental data and previous computational studies. Further, a rigorous Pfold analysis is used to obtain representative samples of the TSEs showing good quantitative agreement between experimental and simulated phi values.
20

Mechanics and Dynamics of Biopolymer Networks

Morris, Eliza January 2014 (has links)
The three major mechanical components of cells are the biopolymers actin, microtubules, and intermediate filaments. Cellular processes are all highly reliant on the mechanics of the specific biopolymers and the networks they form, rendering necessary the study of both the kinetics and mechanics of the cytoskeletal components. Here, we study the in vitro mechanics of actin and composite actin/vimentin networks, and the effect of various actin-binding proteins on these networks. / Engineering and Applied Sciences

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