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Tyrosine 370 Phosphorylation Of Atm Positively Regulates Dna Damage Response, Hong-Jen Lee

Dissertations and Theses (Open Access)

Ataxia telangiectasia-mutated (ATM) mediates DNA damage response by controlling irradiation (IR)-induced foci formation, cell cycle checkpoint, and apoptosis. However, how upstream signaling regulates ATM is not completely understood. Here, we show that upon IR stimulation, ATM associates with and is phosphorylated by epidermal growth factor receptor (EGFR) at Y370 at the site of double-strand breaks. Depletion of endogenous EGFR impairs ATM-mediated foci formation, homologous recombination, and DNA repair. Moreover, ATM Y370F mutant or pretreatment with an EGFR kinase inhibitor gefitinib blocks EGFR and ATM association, hinders CHK2 activation and subsequent foci formation, and increases radio-sensitivity. Thus, we reveal a critical …

Targeting The Redox System To Overcome Mechanisms Of Drug Resistance In Chronic Lymphocytic Leukemia, Marcia A. Ogasawara

Dissertations and Theses (Open Access)

Chronic Lymphocytic Leukemia (CLL) is the most common form of leukemia diagnosed in Western countries and is characterized by clonal expansion of B cells. The clinical course of CLL is diverse and nearly 50% of patients present with chromosomal abnormalities. Deletion of the short arm on chromosome 17 (del17p) occurs in 5-7% of cases and presents with the shortest median survival time and often respond poorly to therapy. The tumor suppressor gene, TP53 is located on this region and it is well established that the p53 protein regulates multiple functions including: mitochondria biogenesis, response to DNA damage and redox balance. …

Development Of Chimeric Type Iv Secretion Systems For Transfer Of Heterologous Substrates Across The Gram-Negative Cell Envelope, Trista M. Berry

Dissertations and Theses (Open Access)

Many bacteria use Type IV Secretion Systems (T4SSs) to aid in pathogenesis by translocating virulence factors across the cell envelope and into eukaryotic cells. These systems are structurally and functionally diverse, but are often compared to the archetypal VirB/VirD4 T4SS of Agrobacterium tumefaciens. This system is composed of the VirD4 type IV coupling protein (T4CP) and 11 VirB subunits (VirB1-11) that assemble as the secretion channel and an extracellular pilus. The T4CP is an inner membrane ATPase that interacts with T4SS substrates and the secretion channel, and is thought to link substrates with the secretion channel and possibly energize …

The Role Of The C5a Receptor In Host Defense Against Listeria Monocytogenes, Daniel Calame

Dissertations and Theses (Open Access)

Listeria monocytogenes (Lm) is a major cause of mortality resulting from food poisoning in the United States. While the complement component C5 is known to be protective in listeriosis, it is unknown how its cleavage fragment C5a participates. Here we show in a model of systemic Lm infection that the C5a receptor is essential for host defense. C5aR-/- mice have reduced survival and increased bacterial burden in the liver and spleen in comparison to WT mice. Surprisingly, C5aR-/- mice also have a dramatic reduction in splenocyte numbers resulting from elevated cell death as indicated by TUNEL staining and caspase 3 …

The Oncogenic Map Kinase Signaling Pathway Modulates Mhc-I Surface Expression In Melanoma, Sherille Denae Bradley

Dissertations and Theses (Open Access)

The mitogen-activated protein kinase (MAPK) pathway is a cascade of serine-threonine kinases involved in cell growth, proliferation, and apoptosis; it is one of the most well-known pathways associated with melanoma progression. The MAPK pathway is constitutively activated in melanomas due to mutations in the signaling components, particularly the proto-oncogene BRAF ^V600E that accounts for (40-50%) of these cases. Metastatic melanoma is one of the deadliest and most aggressive forms of cancer, with a 3-year survival rate of less than 15%. Immunotherapies that utilize cytotoxic T lymphocytes (CTLs) have proven to be very effective at inducing regressions of large, bulky tumors, …

Roles For B-Raf Kinase In The Specific Regulation Of Α4Β1 Integrin In T Cells, Wells S. Brown

Dissertations and Theses (Open Access)

The regulation of integrin-mediated adhesion is of vital importance to adaptive and innate immunity. Integrins are versatile proteins and mediate T cell migration and trafficking by binding to ECM or other cells, as well as initiating intracellular signaling cascades promoting survival or activation. The mitogen activated-protein kinase (MAPK) pathway is known to be downstream from integrins and regulate survival, differentiation, and motility. However, secondary roles for canonical MAPK pathway members are being discovered. We show chemical inhibition of RAF by Sorafenib or shRNA-mediated knockdown of B-Raf reduces T cell resistance to shear stress to α4β1 integrin ligands vascular cell adhesion …

The Role Of Traf6 Phosphorylation In Src/Traf6-Mediated Ikk, Jnk, Akt Activation And Tumorigenesis, Yun Seong Jeong

Dissertations and Theses (Open Access)

TRAF6 E3 ligase regulates numerous essential biological processes such as innate immune response, cell survival and osteoclast differentiation. Upon activation, it mediates activation of IKK/NF-κB and JNK signaling in response to engagement of toll-like receptor 4 (TLR4), interleukin-1 receptor (IL-1R), and receptor activator of NF-κB (RANK) to their cognate ligands, including lipopolysaccharide (LPS), IL-1, and RANK ligand (RANKL). Recently, TRAF6 has also been shown to be involved in Akt signaling activation upon activation of insulin-like growth factor-1 receptor (IGF-1R), in turn orchestrating cell survival and tumorigenesis. Therefore, TRAF6 is a key player for the activation of IKK, JNK and Akt …

Pancreatic Ribonuclease Functions As An Epidermal Growth Factor Receptor Ligand Independently Of Its Enzyme Activity And Contributes To Cetuximab Resistance, Heng-Huan Lee

Dissertations and Theses (Open Access)

Ribonuclease (RNase) with its catalytic enzyme activity to degrade RNAs has been shown as a diagnostic serum marker for pancreatic cancer and has also been suspected to have an unidentified cell surface receptor. Epidermal growth factor receptor (EGFR), a well-characterized receptor tyrosine kinase is an effective therapeutic target in multiple cancer types. However, clinical trials targeting EGFR have not demonstrated improved therapeutic efficacy in pancreatic cancer. Here, we show that both bovine pancreatic RNase A (bRNaseA) and human RNase 5 (hRNase5) act as EGFR ligands and directly activate EGFR to promote epithelial-mesenchymal transition. This ligand-like activity is independent of RNases’ …

Egfr Modulates Microrna Maturation In Response To Hypoxia Through Phosphorylation Of Argonaute2, Jia Shen

Dissertations and Theses (Open Access)

MicroRNAs (miRNAs) are generated by two-step processing to yield small RNAs that negatively regulate target gene expression at posttranscriptional level. Deregulation of miRNAs has been linked to diverse pathological processes, including cancer. Recent studies have also implicated miRNAs in regulatory roles to cope with a spectrum of stresses, such as hypoxia, which is frequently encountered in the poorly angiogenic core of a solid tumor. However, the upstream regulators of miRNA biogenesis machineries remain obscure, raising the question of how tumor cells efficiently coordinate and impose specificity on miRNA expression and function in response to stresses. Here, we show that EGFR, …

Targeting The Mdm2-P53 Axis For The Treatment Of Dedifferentiated Liposarcoma, Katelynn Bill

Dissertations and Theses (Open Access)

Dedifferentiated liposarcoma (DDLPS) is an aggressive malignancy characterized by a high rate of recurrence and dismal patient outcome. Minimal improvement in patient survival has been made in the last several decades, highlighting the crucial need for improved therapeutic strategies. A better understanding of the molecular deregulations underlying DDLPS would facilitate the discovery of improved therapeutic approaches. MDM2 is a well characterized oncoprotein and the most known negative regulator of p53. MDM2 amplification is considered the “hallmark” of DDLPS. Additionally, these tumors are known to harbor wild-type p53. We sought to take advantage of this knowledge and evaluate the role of …

Utilizing Haplotypes For Sensitive Snp Array-Based Discovery Of Somatic Chromosomal Mutations, Selina M. Vattathil

Dissertations and Theses (Open Access)

Somatic copy-number (CN) gains and losses and copy-neutral loss of heterozygosity (CNLOH) frequently occur in tumors and play a major role in the progression of disease by altering gene dosage and unmasking deleterious recessive variants. Characterizing these mutations in an individual tumor sample is therefore critical for research on the relationship of specific mutations to disease outcome and for clinical decision-making based on mutations with known impact. A pervasive hindrance to sensitive detection of these mutations is genetic heterogeneity and high levels of contaminating normal cells in tumor samples, which limit the fraction of cells carrying informative mutations. The method …

Brit1/Mcph1 Mediates The Dna Damage Response By Inducing P53 Stability And Promoting Atr Signaling, Edward Wang

Dissertations and Theses (Open Access)

The BRCT-repeat inhibitor of hTERT (BRIT1)/MCPH1 protein promotes the process of homologous recombination (HR) to repair DNA double strand breaks (DSBs). In response to DSBs, BRIT1 foci form at damaged sites, and recruits downstream repair proteins including 53BP1, MDC1, NBS1, and the SWI/SNF complex to the DSB region to promote DNA repair. BRIT1 copy number deficiency correlates with increased genomic instability in ovarian cancer specimens and breast cancer cell lines. Here, we propose that additional functions of BRIT1 include a direct interaction with the p53 tumor suppressor protein to promote p53 stability, and binding and recruitment of TopBP1 to sites …

Nuclear Translocation Of Met Via Internet Mechanism, Mei-Kuang Chen

Dissertations and Theses (Open Access)

MET is one of the receptor tyrosine kinases (RTKs) that are overexpressed in malignant cancer types, including breast cancer. While RTKs are traditionally known for their roles in signaling transduction from the cell surface, recent studies have provided evidence demonstrating that most of RTKs can translocate into nucleus to regulate cellular processes in response to both ligand and stress stimulation. Oxidative stress is a common stress in cancer cells due to alteration of metabolism, and constitutive oxidative stress related to reactive oxygen species (ROS) has been observed in breast cancer cells. Here, we show that hepatocyte growth factor (HGF) as …

Dissecting The Roles Of Trim24 In Regulation Of Hepatic Lipid Metabolism And Inflammation, Lindsey C. Minter

Dissertations and Theses (Open Access)

DISSECTING THE ROLES OF TRIM24 IN REGULATION OF HEPATIC LIPID

METABOLISM AND INFLAMMATION

Lindsey Cauthen Minter, B.S., B.A.

Advisory Professor: Michelle C. Barton, Ph.D.

In this dissertation, I report the characterization of a new mouse model that recapitulates development of hepatocellular carcinoma (HCC) following spontaneous hepatic lipid accumulation, inflammation, and damage of liver tissue, due to complete loss of Trim24 expression. In human HCC and other cancers, TRIM24 expression is aberrantly high, while deletion of TRIM24 in the mouse has been shown to act as a liver specific tumor suppressor. The hypothesis tested here was that TRIM24, the E3 ubiquitin …

Development And Implementation Of An Anthropomorphic Pediatric Spine Phantom For The Assessment Of Craniospinal Irradiation Procedures In Proton Therapy, Dana Lewis

Dissertations and Theses (Open Access)

Proton therapy is gaining acceptance as a cancer treatment modality, as it allows for dose deposition to the target volume while sparing the surrounding healthy tissue. This technique is advantageous for craniospinal pediatric patients, as it reduces the radiation side effects that can occur. The purpose of this study is to design an anthropomorphic pediatric spine phantom for use in the evaluation of proton therapy facilities for clinical trial participation by the Imaging and Radiation Oncology Core (IROC) Houston QA Center. It was hypothesized that the designed phantom would evaluate patient simulation, treatment planning and delivery, assuring agreement between the …

Angiomotin Is A Novel Cadherin-11 Interacting Protein That Mediates Migration In Prostate Cancer Cells, Angelica Ortiz

Dissertations and Theses (Open Access)

Prostate cancer (PCa), the second leading cause of cancer-related deaths among men in the United States, has the proclivity to metastasize to bone resulting in sclerotic lesions. These cancer induced bone growths cause bone pain and fractures. Therefore, understanding the molecular mechanisms contributing to PCa bone metastasis is required in order to find better prognostic tools and suitable targets for metastasis treatment and/ or prevention. Previous work in our laboratory showed increased expression of cadherin-11 (Cad11), a mesenchymal cadherin, during PCa progression. Furthermore, Cad11 expression endows PCa cells with increased migratory potential and metastasis to bone. Deletion of the Cad11 …

Genomic Characterization Of Polyps In Familial Adenomatous Polyposis Patients And Identification Of Candidate Chemopreventive Drugs, Francis A. San Lucas

Dissertations and Theses (Open Access)

Familial adenomatous polyposis (FAP) is an autosomal dominant disease characterized by APC germline mutations and the development of hundreds to thousands of premalignant adenomas in the gastrointestinal tract at a young age. If left untreated, these patients inevitably develop colon cancer (CRC) and small bowel tumors. We performed exome sequencing of samples from 12 FAP patients to characterize adenomas and to identify candidate genes of adenoma development that may serve as potential targets for chemoprevention drug development. From each patient, a blood and at least one polyp were sequenced with a total of 25 polyps analyzed. In some cases, normal …

Targeting Sequence And Function-Dependence Of Subcellular Localization Of Transient Receptor Potential Mucolipin Channels And Characterization Of Engineered Molecule Probes For Detecting Lysosomal Calcium Release, Jian Xiong

Dissertations and Theses (Open Access)

Both TRPML1 and TRPML3 are members of the mucolipin subfamily of Transient Receptor Potential (TRP) channels. They have been implicated in endolysosomal functions such as divalent cation release, luminal pH regulation, autophagy and vesicle trafficking. Interestingly, whereas TRPML1 is almost extensively localized in lysosomes, TRPML3 is typically found in both lysosomes and the plasma membrane (PM). It has been shown that TRPML3 localization depends on TRPML1, but the mechanism remains unknown. Recently, a number of TRPML1 mutants have been reported to be either retained in the endoplasmic reticulum (ER) or preferentially targeted to the PM. Coexpressing these mutants with either …

Discovery And Elucidation Of The Fgfr3-Tacc3 Recurrent Fusion In Glioblastoma, Brittany C. Parker Kerrigan

Dissertations and Theses (Open Access)

Fusion genes occur due to chromosomal instability where two previously separate genes rearrange and fuse together, forming a hybrid gene. The first fusions were reported in leukemias; however, with the advent of more powerful sequencing technologies, fusions have recently been reported in several solid tumors. Using next-generation deep sequencing approaches, we discovered a fusion gene connecting the fibroblast growth factor receptor 3 (FGFR3) gene to the transforming coiled-coil containing protein 3 (TACC3) gene in glioblastoma multiforme. The fusion occurred in 8.3% of patient samples, but not in low grade or normal samples. FGFR3-TACC3 produced an in-frame …

The Role Of Glutamine And Mevalonate Pathway In Affecting The Stemness And Viability Of Glioblastoma Stem Cells, Naima Hammoudi

Dissertations and Theses (Open Access)

Glioblastoma (GBM) remains the deadliest form of brain tumors. The poor prognosis of glioblastoma patients is associated with a high rate of relapse after therapy. It has been suggested that the presence of cancer stem cells, which are relatively resistant to radiation and chemotherapy, may play a significant role in the recurrence of brain tumor. Understanding the biological property of glioblastoma stem cells is important to develop effective therapeutic strategies for glioblastoma. In vitro, glioblastoma stem cells cultured in serum-free medium form self-renewing neurospheres, express the neural stem marker CD133, and are highly tumorigenic. On the other hand, in the …

Stochastic Data Assimilation Approaches For Magnetic Resonance Temperature Imaging, Joshua P. Yung

Dissertations and Theses (Open Access)

During magnetic resonance (MR)-guided thermal therapies, proton resonance frequency shift (PRFS) based MR temperature imaging can quantitatively monitor tissue temperature changes. It is widely known that the PRFS technique is easily perturbed by tissue motion, tissue susceptibility changes, magnetic field drift, and modality–dependent applicator induced artifacts. Due to recent advances in computational algorithms and hardware, much more powerful statistical analysis methods are becoming realizable in the real-time processing environment. To this end, my dissertation research focused on the development, validation, and implementation of stochastic data-driven processing techniques to increase the robustness of MR temperature monitoring during thermal therapies. MR temperature …

Energy Stress Causes Chaperones To Assemble Into Cytoplasmic Complexes, Kimberly J. Cope

Dissertations and Theses (Open Access)

The majority of proteins require molecular chaperones to assist their folding into tertiary and quaternary structures. Certain stresses can compromise the weak hydrophobic forces responsible for these structures and lead to protein unfolding, misfolding, and aggregation. Aggregates of proteins are hallmarks of devastating diseases such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. Fortunately, bacteria, plants, and fungi have a potent disaggregase, named Hsp104 in Saccharomyces cerevisiae. Recently, heat-induced aggregates, termed Q-bodies, were found to contain three molecular chaperones: Hsp70, Hsp104, and Hsp42. Their coalescence from small puncta into larger inclusions required Hsp104. During glucose deprivation, a stress that isn’t known to …

Integrating Domain Knowledge To Improve Signal Detection From Electronic Health Records For Pharmacovigilance, Ning Shang

Dissertations and Theses (Open Access)

The intent of this dissertation is to make a contribution to the field of pharmacovigilance. Pharmacovigilance, also known as post-marketing drug surveillance, is the process of continued monitoring for adverse drug reactions (ADRs) after drugs are released into the market. An ADR is a harmful or unpleasant reaction related to the use of a medical product. ADRs were reported to be between the fourth and sixth leading cause of death in the United States in 1994, accounting for 3-7% of medical hospital admissions. On account of the practice of pharmacovigilance, Vioxx (Rofecoxib) and Avandia (Rosiglitazone) are examples of high profile …

Pattern Of Mutation Rates In The Germline Of Drosophila Melanogaster Males From A Large-Scale Mutation Screening Experiment, Jian-Jun Gao, Xue-Rong Pan, Jing Hu, Li Ma, Jian-Min Wu, Ye-Lin Shao, Shi-Meng Ai, Shu-Qun Liu, Sara A Barton, Ronny C Woodruff, Ya-Ping Zhang, Yun-Xin Fu

Faculty, Staff and Student Publications

The sperm or eggs of sexual organisms go through a series of cell divisions from the fertilized egg; mutations can occur at each division. Mutations in the lineage of cells leading to the sperm or eggs are of particular importance because many such mutations may be shared by somatic tissues and also may be inherited, thus having a lasting consequence. For decades, little has been known about the pattern of the mutation rates along the germline development. Recently it was shown from a small portion of data that resulted from a large-scale mutation screening experiment that the rates of recessive …

Who Participates In An Internet-Based Research Program For Mothers Of Infants? A Secondary Prevention Research Study Among Low-Income Families, Edward G. Feil, Kathleen Baggett, Betsy Davis, Craig Leve, Susan H. Landry, Lisa B. Sheeber

Journal of Applied Research on Children: Informing Policy for Children at Risk

Objective: The objective of this study was to evaluate the participation rates and factors associated with nonparticipation among mothers living in low-income households who were invited to join a parent-education and -support research program delivered via the Internet with professional support.

Methods: Four hundred and seventy-seven mothers of infants were contacted via a variety of recruitment methods, including presentations at clinics/classes, direct mailings, print advertisement, and Internet posts. Research staff attempted to contact these mothers by phone, to assess their eligibility, and interest in participation. For those who were eligible but declined participation, we assessed reasons for declining and collected …

Reintegration Work: Parental Support In Foster Care, Whitney Davidson

Journal of Applied Research on Children: Informing Policy for Children at Risk

The world of child welfare is a challenging one. In order to ensure long-term stability, a worker must be committed, caring, and flexible. It is important to look at each case individually, to remember that they are not just cases but children and families who have been separated. Workers must ensure they are providing all available resources to facilitate successful reintegration, but that they are also teaching independence and lifelong skills. Children and families need ways to cope with their past and present trauma along with methods to healthily deal with future traumas. The ultimate goal is to send a …

Is It Time To Do More Homework On The Impact Of Childhood Obesity On Academic Achievement?, Shreela V. Sharma

Journal of Applied Research on Children: Informing Policy for Children at Risk

Purpose: To provide commentary on the research article “Impact of Pediatric Obesity on Grades in Elementary School,” by Craig A. Johnston, Jennette P. Moreno, Sandra A. Stansberry, and Deborah Woehler .

Findings: In this cross-sectional study the authors examine the association between weight status and math, science and reading grades among 798 2^nd grade children in Texas. The authors show that academic performance, specifically math grades are lower in obese students compared to normal weight students. Finally, the authors propose several physiological and psychological mechanisms including the potential for teacher bias and lower expectations from children who are obese. …

The Path To Effective Child Maltreatment Prevention Strategies, Philip V. Scribano

Journal of Applied Research on Children: Informing Policy for Children at Risk

The burden of child maltreatment in the U.S. remains a substantial problem with life-course implications, yet systematic efforts to prevent its occurrence and the associated impairments have been limited. The review of universal and targeted child maltreatment prevention interventions to address child physical abuse by Nelson and Caplan provide a thoughtful critique of the child maltreatment prevention efforts and a recognition of the importance of developing a public health framework to address this problem. An overriding prevention strategy should be derived from a systems level approach, which embraces the socio-ecological, and public health frameworks (with integration of policy and practice). …

Contact In Foster Care: Bridge Or Collision Between Two Worlds?, João M. S. Carvalho, Paulo Delgado

Journal of Applied Research on Children: Informing Policy for Children at Risk

This study aims not only to analyze the contact in foster care in Portugal compared to results collected from other studies but also to define the implications of its practice so as to propose improvements to the child protection system. It involves 289 foster children from the District of Porto whose results were obtained from official records. Subsequently, this study discusses the insights and practical consequences, the importance of maintaining up-to-date information on the changes of the biological family, the need to improve specific skills in social workers, and how to overlook the negative results of visits regarding the advantages …

Family Well-Being: A Complex Challenge Worth Pursuing, Susan H. Landry

Journal of Applied Research on Children: Informing Policy for Children at Risk

Issue Editor, Susan Landry's point of view and summary of the articles in Family Well-Being and Social Environments.