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A Noncanonical Function Of The Telomerase Rna Component In Human Embryonic Stem Cells, Kirsten Ann Brenner

Arts & Sciences Electronic Theses and Dissertations

Telomeres are stretches of TTAGGG nucleotide repeats located at the ends of linear chromosomes that shorten with progressive cell division and prevent genomic instability at the cost of limiting a cell’s capacity to proliferate. This limitation can be overcome by telomerase, a ribonucleoprotein complex that elongates telomeres via reverse-transcription of the template telomerase RNA component (TERC). Recent studies have reported potential functions of TERC outside of its role in telomere maintenance. These noncanonical functions of TERC are however poorly defined, and the molecular mechanisms and biological relevance behind such functions remain elusive. Here, we generated conditional TERC knock-out human embryonic …

Exploration Of Ataxia Telangiectasia And Rad3-Related’S (Atr’S) Role In Cell Death Regulation: Implications In Development, Cancer, And Stroke, Brian Cartwright

Electronic Theses and Dissertations

From gametogenesis until death an organism’s genome is under constant bombardment from endogenous and exogenous sources of DNA damage. To maintain genomic integrity amid this damage, cells have evolved responses which allow them to either preserve viability for recovery or initiate self-destructive pathways depending on the severity of DNA damage. One protein involved in initiating and carrying out these responses is the protein kinase ataxia telangiectasia and Rad3-related (ATR). ATR is known primarily for its regulatory role in initiating the checkpoint-signaling cascade following DNA damage and replicative stress. These signaling events lead to cell cycle arrest, DNA repair, or apoptosis …

Hei-Oc1 Cochlear Cells As An In Vitro Model To Study The Role Of Connexins In Ototoxicity And Hearing Loss, Rianne Beach

Electronic Thesis and Dissertation Repository

Connexin 26 (Cx26) and Cx30 mediate the intercellular exchange of metabolites and ions within the cochlea in a process known as gap junctional intercellular communication (GJIC). Cochlear cell death and subsequent hearing loss can arise after treatment with ototoxic therapeutics and Cx26 mutant expression. We investigated the role of connexins and GJIC in the development of ototoxicity in HEI-OC1 cochlear-derived cells. The susceptibility of HEI-OC1 cells to aminoglycoside antibiotics and cisplatin-induced cell death was not influenced by the ablation of connexins and GJIC. However, the expression of mitochondrial apoptosis or ER stress markers was altered by the degree of GJIC. …

Epigenetic Reprogramming, Apoptosis, And Developmental Competence In Cloned Embryos, Laura A. Moley

All Graduate Theses and Dissertations, Spring 1920 to Summer 2023

Cloning through somatic cell nuclear transfer (SCNT) remains highly inefficient twenty years after the first demonstration of the technology with the birth of Dolly. By increasing efficiency by selecting the embryos early in development that are most likely to succeed following transfer into a surrogate mother, the technology could be more routinely utilized to enhance animal agriculture production. SCNT is believed to be highly inefficient as a result of incorrect DNA methylation and gene expression that are accumulated because of the SCNT technique. We proposed the use of a non-toxic, non-invasive detector of cell death, to quantitatively assess embryo competency …

Analyzing The Effect Of Apoptotic Mutations On The State Of The Nascent-Polypeptide Associated Complex In Caenorhabditis Elegans, Monica Gerber

Senior Honors Projects, 2010-2019

Cells experiencing misfolded protein stress can become debilitated and die, contributing to the onset of disease. The nascent polypeptide-associated complex (NAC) is a heterodimeric translational chaperone that protects against misfolded protein stress by mediating proper protein folding and localization during translation. Depletion of this complex results in misfolded protein accumulation in the endoplasmic reticulum (ER). To determine the importance of the NAC to proteostasis, we have previously depleted the complex in C.elegans via RNA interference and observed numerous dose-dependent effects, including apoptosis of neuronal cells and changes in gene expression of hypodermal cells. While we have observed these cell-specific responses …

Effects Of Global Warming On Gonadal Functions, Cellular Apoptosis, And Oxidative Stress In The American Oyster, Sarah B. Nash

Theses and Dissertations

Global warming due to climate change is predicted to intensify the heat stress in marine and coastal organisms, affecting their development, growth and reproductive functions. In this study. I analyzed gonadal development, heat shock protein 70 (HSP70), nitrotyrosine protein (NTP), dinitrophenyl (DNP) expressions, cellular apoptosis, and coelomic fluid (CF) conditions in American oyster. Oysters were placed in six aquariums and exposed to control (24°C), medium (28°C), and high (32°C) temperatures for one week. Higher temperature significantly decreased the number of eggs and sperm. CF protein concentrations also declined compared to control. In contrast, CF pH and HSP70 expression in gonad …

Telomeric Dna Damage And Repair Machineries In Hiv Infection, Lam Nguyen

Electronic Theses and Dissertations

In this thesis, we investigated T cell homeostasis and DNA damage repair machineries in HIV infection. We found that the frequencies of CD4T cells were low, which is associated with cell apoptosis in HIV patients compared to healthy subjects. Importantly, these events were closely correlated to the increase in T cell exhaustion, senescence, DNA damage, and telomere attrition. Mechanistically, while the DNA damage sensors Mer11, Rad50, and NBS1 (MRN) complexes remained intact, the ataxia-telangiectasia mutated (ATM) kinase and its downstream checkpoint kinase 2 (CHK2) were significantly inhibited during HIV infection. Additionally, telomeric repeat-binding factor 2 (TRF2) that functions to protect …

High Molecular-Weight Hyaluronan Prevents Basal Cell Carcinoma Via Promoting Apoptosis In Cancer-Initiating Adult Stem Cells, Violet Liu

Electronic Thesis and Dissertation Repository

Basal cell carcinoma (BCC), a keratinocyte cancer, is the most common human neoplasm worldwide. Although rarely metastatic, BCC is associated with high morbidity rates with globally rising incidence rates. Accompanying the increase in newly diagnosed cases, the societal cost for BCC treatment in Canada is also expected to inflate, exceeding over $900 million/year by 2031. Chronic UVB exposure has been identified as the primary carcinogen that causes activating mutations in the hedgehog signaling pathway. However, there are no effective preventative methods against BCC, since meta-analyses report sunscreen application does not reduce BCC in compliant patients. The native high molecular-weight hyaluronan …

Mechanisms Of Oriented Cell Division And Their Roles In Tissue Development, Evan Blake Dewey

Biology ETDs

Properly executed cell division is crucial to development, maintenance, and longevity of multicellular organisms. Defects in both symmetric and asymmetric divisions can lead to improper developmental patterning, as well as genomic instability, disruption of tissue homeostasis, and cancer. Our research focuses on how regulators orchestrate proper cell divisions. Mushroom Body Defect (Mud) is one such regulator, and here we describe how Mud is regulated via the Hippo signaling pathway kinase Warts (Wts), showing Wts phosphorylates Mud to enhance interaction with the polarity protein Partner of Inscuteable, promoting spindle orientation activity. We next focus on another regulator, Shortstop (Shot), describing a …

Deciphering The Molecular Mechanism Through Which Rhus Coriaria Exerts Its Anti-Cancer Activity, Khawlah Najib Saeed Athamneh

Dissertations

Cancer remains a major health problem around the globe. Among various types of treatments, plants have been shown to have great capacity in cancer treatment, one of which is Rhus coriaria. Commonly known as sumac, Rhus coriaria is a culinary herb that is known to possess different therapeutic values including anti-oxidant and anti-microbial activities.

In this Ph.D. project, we tested the effect of Rhus coriaria extract (RCE) on the migration, invasion, and metastasis of MDA-MB-231 human breast cancer cells. We showed that non-cytotoxic concentrations of RCE inhibited migration and invasion, blocked adhesion to fibronectin, and downregulated MMP-9. Additionally, we found …

Evaluating The Therapeutic Potential Of Crocin Against Diethylnitrosamine Induced Experimental Hepatocellular Carcinoma In Rats, Basma Ali Mustafa Awad

Theses

Hepatocellular carcinoma (HCC) is the fifth most common type of cancer and the third cause of cancer-related death worldwide. Liver cancer is the result of repeated injuries to the liver triggered by different causes. Currently, sorafenib is the only drug U.S. Food and Drug Administration approved targeted therapy. Sorafenib, an oral multikinase inhibitor, which inhibits the proliferation of tumor cells and blocks angiogenesis. Sorafenib has been shown to treat early and mild HCC lesions and it helped increase the survival rates at one year, but for only 44% of patients. Chemotherapies are an important line of defense when it comes …

Probing Apoptotic Caspase Allostery And Exosite Interactions For Alternative Regulation, Derek J. Macpherson

Doctoral Dissertations

Programmed cell death, or apoptosis is a critical homeostatic pathway that monitors the balance of cell life and death. Apoptosis is regulated by a class of enzymes known as the cysteine aspartic proteases, or the caspases. The 12 human caspases that play important roles in the progression and regulation of apoptosis and inflammation. Caspases are tightly regulated by numerous factors including enzymatic activation, post-translational modifications, metal ligand binding, and protein modulation. Aberrant caspase activation and regulation has been implicated in the progression of numerous diseases such as proliferative diseases and neurodegeneration. The deeply entwined nature of caspases and apoptosis makes …

An In Vitro And In Vivo Evaluation Of The Anticancer Potential Of Resveratrol And Pterostilbene Against Hpv-E6 Positive Cancers, Kaushiki Chatterjee

Dissertations, Theses, and Capstone Projects

Cervical cancer remains as one of the most prevalent cancers effecting women globally. Lack of awareness and affordable prophylactic and therapeutic options in developing countries drive the need for alternative low-cost approaches. Dietary polyphenols have gained increased attention as possible anti-cancer agents. Our study aims to investigate whether two natural structural analogs, resveratrol and pterostilbene, exhibit anti-HPV (Human papillomavirus) activity in cervical cancer. To determine the efficacy of these polyphenols, extensive in vitro and in vivo analyses were carried out. For the in vitro studies we utilized human HeLa cells (HPV18 positive) and murine TC1 cells (HPV 16 oncogene positive). …

The Role Of The Cell-Surface Protease Tmprss13 In Colorectal Cancer, Fausto Alexander Varela

Wayne State University Dissertations

Colorectal cancer (CRC) is one of the most common and deadly cancers in both men and women in the United States. Extracellular proteolysis is often dysregulated in cancer including (CRC), resulting in degradation of extracellular matrix, as well as cleavage, processing, or shedding of cell adhesion molecules, growth factors, and cytokines. Several members of the type II transmembrane serine protease (TTSP) family have been shown to play critical roles in cancer progression; however, many family members have not yet been characterized in malignancy. We identified TMPRSS13 transcript to be upregulated in CRC compared to normal colon. This increase was confirmed …