Browsing by Subject "Disease Progression"
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Item Decellularized Normal and Cancer Susceptible Mice Colons to Study the Contribution of the Extracellular Matrix to Cell Behavior and Colon Cancer Progression(2020-05-01T05:00:00.000Z) Alabi, Busola Ruth; Fiolka, Reto; Shay, Jerry W.; Conacci-Sorrell, Maralice; Eberhart, Robert; Welch, TreCurrent 3D culture models to study colorectal cancer lack architectural support and signaling proteins provided by the tissue extracellular matrix (ECM) which may influence cell behavior and cancer progression. Therefore, the ability to study cancer cells in the context of a matrix that is physiologically more relevant and to understand how the ECM affects cancer progression has been understudied. To address this, I developed an ex-vivo 3D system, provided by intact wild type (WT) and colon cancer susceptible decellularized mouse colons (DMC), to support the growth of human cancer cells. DMC are free of viable cells but still contain extracellular matrix proteins including subsets of collagens. Stiffness, an important mechanical property, is also maintained in DMCs. Importantly, I observed that the DMC is permissive for cell proliferation and differentiation of a human colon cancer cell line (HT-29). Notably, the ability of cells in the WT DMC to differentiate was also greater when compared to Matrigel TM, an extracellular matrix extract from a mouse tumor cell line. Additionally, I observed using invasion assays that DMC obtained from polyps from a colon cancer susceptible mouse model facilitated increased cell migration/invasion of colorectal cancer cells and immortalized non-tumor colonic epithelial cells compared to DMC from WT mice. Finally, using mass spectrometry, I identified extracellular matrix proteins that are more abundant in DMC from a colorectal cancer mouse model compared to age and sex-matched WT mice. I propose that these abundantly expressed proteins in the tumor microenvironment are potentially involved in colorectal cancer progression.Item Early Events Following Oral Transmission of Simian Immunodeficiency Virus: From Viral Entry to Host Immune Response(2005-08-11) Milush, Jeffrey Martin; Sodora, Donald L.Approximately 40 million people worldwide are infected with HIV, the causative agent of AIDS. The primary mode of HIV transmission (75% of all transmissions) between individuals occurs across mucosal tissues (vaginal, rectal, oral). The goal of this thesis was to assess the virologic and immunologic events following oral inoculation of macaques with Simian Immunodeficiency Virus (SIV) and correlate these findings with disease progression. To assess the virologic events involving viral entry and spread, macaques were orally inoculated with SIV and necropsied at early times post-infection (days 1 - 14). These studies were the first to identify the preferential entry sites for the virus as the oral and esophageal mucosa, as well as the tonsils. Furthermore, SIV rapidly disseminated to peripheral lymph nodes resulting in systemic infection by 2 to 4 days post-infection. The rapidity with which SIV spreads throughout the lymphatics indicates a major obstacle for a vaccine recall immune response to eliminate infected cells prior to dissemination. Analyses of immunologic events through the assessment of mucosal innate immune gene expression, as well as the initiation of the adaptive immune response, were undertaken in a second group of SIV orally inoculated macaques. Two hypotheses were proposed: 1) An innate mucosal immune response at the site of entry (oral mucosa) would result in the induction of a timely SIV-specific adaptive immune response; and 2) Maintaining a healthy mucosal barrier during chronic infection would prevent the onset of opportunistic infections. My data support hypothesis one, as during early times post-infection (2 - 21 days), gingival mucosal innate response gene expression correlated with the ability toinduce timely SIV antibodies and reduce plasma viral loads. In addition, my data assessing events during chronic infection (day 70) indicated an association between elevated expression of mucosal innate response genes, particularly chemokines, with an absence of opportunistic infections, thus supporting hypothesis two. From these studies assessing viral and immune correlates of SIV transmission, I conclude that vaccines capable of inducing high titer neutralizing antibodies at the mucosa, as well as increased mucosal innate immune responses, will be most efficacious in preventing mucosal HIV transmissions.Item Molecular Imaging in Noninvasive Assessment of Diabetes Progression(2013-07-16) Lo, Su-Tang; Lenkinski, Robert; Sun, Xiankai; Öz, Orhan K.; Lingvay, Ildiko; Ahn, Jung-MoMolecular imaging is a recently emerged multidisciplinary scientific field comprised of diverse technologies. The goal of this branch of science is to understand molecular mechanism of diseases and facilitate drug development, namely the interplay of non-invasive imaging techniques with molecular biology and medicine. The goal of this dissertation is to reflect the roles of molecular imaging in biomedical applications by longitudinal and non-invasive detection of the initiation and progression of diabetes. Diabetes is a chronic disease caused by a gradual loss of pancreatic β-cell mass (BCM). The current clinical diagnosis measures the parameters of the β-cell function (BCF) post the onset of the disease, which cannot accurately reflect the BCM loss during the initiation and progression of the disease. Therefore, a non-invasive imaging technique that enables the direct assessment of BCM change would be highly desirable. In this dissertation, Positron Emission Tomography (PET) imaging was conducted to non-invasively and longitudinally monitor the change of glucagon-like peptide 1 receptor (GLP-1R), a specific biomarker of pancreatic β-cell, during disease progression. Through a two-fold screening method, a modified bicyclic GLP-1 analog, which enhances biological stability while maintaining the receptor binding affinity, was selected. An imaging probe was therefore developed based on this selected stable GLP-1 analog for noninvasive imaging assessment of BCM. In vivo evaluation was carried out to determine the BCM targeting properties of the probe followed by ex vivo PET imaging and histology. Further, a reliable and reproducible multimodality imaging technique was developed by combining PET imaging with the GLP-1R targeted probe with anatomical imaging techniques including BaSO4-enhanced CT and MRI for quantitative analysis of BCM imaging in mouse models. To test the potential of the imaging technique for longitudinal monitoring of BCM change during the diabetes initiation and progression, a serial PET/CT imaging was performed in a streptozotocin (STZ)-induced diabetic mouse model. With the successful development of the BCM imaging probe, a valid imaging technique has been established for noninvasive assessment of the progression of diabetes, which may find applications in early diagnosis of diabetes and monitoring therapeutic interventions of the disease.Item [Southwestern News](2000-12-05) Shields, AmyItem [Southwestern News](2005-01-31) Satyanarayana, MeghaItem [UT Southwestern Medical Center News](2012-06-28) Bolles, DebbieItem [UT Southwestern Medical Center News](2009-12-10) McKenzie, AlineItem [UT Southwestern Medical Center News](2011-07-26) Russell, RobinItem [UT Southwestern Medical Center News](2010-07-22) Piloto, ConnieItem [UT Southwestern Medical Center News](2008-01-15) Stafford, Erin PratherItem [UT Southwestern Medical Center News](2007-01-29) Rian, RussellItem Why kidney disease always gets worse: what can we do about it?(2014-08-08) Lu, Christopher Y.