Medicine and Health Sciences Commons^™

Heteromerization Of G Protein-Coupled Receptors In Human Vascular Smooth Muscle Cells: Identification Of Hetero-Oligomeric Receptor Complexes Between Α1-Adrenergic Receptors, Arginine Vasopressin Recptor 1a, Chemokine (C-X-C Motif) Receptor Type 4, And Atypical Chemokine Receptor 3., Lauren J. Albee

Dissertations

G protein-coupled receptor (GPCR) heteromerization is rapidly evolving field. Traditionally, GPCRs were thought to behave has independent entities or protomers. However, that line of reasoning has since been brought into question. Currently, it appears that many, if not all, GPCRs signal and function as heteromeric receptor complexes. The roles of GPCR heteromerization are vast and can include: maturation and trafficking; dynamic regulation; allostery and cooperativity; signal transduction; and receptor internalization.

The majority of studies identifying and characterizing GPCR heteromers were performed using recombinant receptors. Only four receptor pairs have been identified and validated in native tissues. The overall objective of …

The Molecular Pathophysiology Of Sepsis-Associated Disseminated Intravascular Coagulation And Its Pharmacologic Modulation, Amanda Temple Walborn

Dissertations

Sepsis is a life-threatening syndrome characterized by a dysregulated host response to infection. Sepsis patients are at risk of disseminated intravascular coagulation (DIC), a severe blood coagulation disorder. In DIC, inappropriate coagulation leads to the deposition of fibrin in the microvasculature and subsequent organ failure. This consumes platelets and coagulation factors, leaving patients at risk of severe or fatal bleeding. No treatments are approved for DIC in the United States.

In order to test the hypothesis that DIC would be best described by a combination of biomarkers representative of multiple physiological processes, an array of biomarkers, representative of hemostasis, inflammation, …

Role Of Jagged1 In The Enrichment Of Cancer Stem Cells In Her2+ Breast Cancer, Deep Shah

Dissertations

Purpose: Breast cancer is the second leading cause of cancer-related deaths among women worldwide. Human Epidermal Growth Factor Receptor 2 (HER2) positive subtype of breast cancer is driven by a subpopulation of cells possessing stem cell properties of self-renewal and differentiation, known as Cancer Stem Cells (CSCs). CSCs are implicated in tumor growth as well as radiotherapy and chemotherapy associated resistance. Notch receptors promote breast CSCs survival and self-renewal, and overexpression of Notch ligand Jagged1 predicts poor prognosis. We showed previously that Notch could be an important target in trastuzumab/lapatinib resistant HER2+ breast cancer.

Experimental Design: Here, we sought to …

Creating A Bret Assay To Monitor The Interaction Between Β-Arrestin-1 And Stam-1, James Buhrmaster

Master's Theses

CXCR4 is a chemokine receptor that is overexpressed in multiple disease states, including cancer. Understanding the mechanisms by which cells regulate CXCR4 expression is of high importance, as they can reveal downstream effectors that can potentially be targeted pharmacologically to more effectively treat diseases with fewer side effects.

CXCR4 is internalized in response to stimulation by its ligand CXCL12, and localizes to early endosomes as part of a homologous desensitization mechanism. From the endosome, CXCR4 can enter one of two pathways whereby it is either recycled back to the plasma membrane, where it can undergo another signaling event, or it …

Comparative Studies On Biochemical And Pharmacological Profiles Of Bovine, Ovine And Porcine Heparins, Ahmed Kouta

Master's Theses

Heparin, a highly sulfated glycosaminoglycan (GAG), is used extensively as an anticoagulant. It consists of repeating disaccharide units, containing iduronic acid (or glucuronic acid) and glucosamine, exhibiting variable degrees of sulfation. Heparin, and its analogues, are used during surgery and dialysis, and are often used to coat indwelling catheters and other devices where the vascular system is exposed. Administered parenterally, often continuously due to its short half-life, over 0.5 billion doses are required per year. Heparin is currently obtained from mucosal tissue of meat animals, mainly porcine intestine, and to a lesser extent bovine and ovine sources. The early stages …

Identifying Oncogenic Drivers In Nsclc Cells Harboring Egfr Kinase Domain Mutation With Resistance To Egfr Tki And Mesenchymal Phenotype, Yandi Gao

Master's Theses

EGFR kinase domain mutant NSCLC cells are exquisitely dependent on mutant EGFR for cell survival and proliferation. Patients with mutant EGFR respond well to the EGFR inhibitors. However, acquired drug resistance greatly limits the efficacy of the treatment. About 15% of the resistant tumors present an evidence of epithelial to mesenchymal transition (EMT). We hypothesize that the induction of mesenchymal promotes aberrant upregulation of other oncogenic drivers to replace the oncogenic mutant EGFR.

We observed overexpression of CXCR7 in NSCLC models of acquired resistance to EGFR TKI with mesenchymal phenotype. Additionally, our studies demonstrate that ectopically overexpressing CXCR7 in EGFR …

Investigation Of Pharmaceutical Mass Transfer Phenomena Using Molecular Dynamics Simulations, Yi Gao

Dissertations

Molecular dynamics (MD) simulation has been widely used in understanding the physical basis of the structure and function of biological macromolecules. However, its application in pharmaceutical research is still at an early stage. This dissertation attempts to establish the use of MD simulation in studying several important pharmaceutical mass transfer processes. The three-series study included (1) the understanding of drug crystal dissolution at molecular level, (2) the elucidation of an unique mechanism for facile polymorphic transformation of crystalline drugs in solutions, and (3) the determination of drug-polymer interactions at water-crystal interface and the implications to crystallization inhibition.

A drug crystal …

Development Of Cell Based Reporter Assay To Measure Pkc-Delta Promoter Activity, Kushal Prajapati

Master's Theses

Protein kinase C- δ (PKC-δ) acts as a tumor suppressor in skin cancer and is lost in 30% of human Squamous Cell Carcinoma (SCC). This loss is at the transcriptional level and involves the pathway leading to PKC-δ promoter repression after activation of Ras,PI3K,Fyn, and NF-κB. We proposed development of a high throughput, cell-based luciferase reporter assay on Ras transformed keratinocyte cell line, HaCaT-Ras to screen compounds having potential to inhibit this pathway and re-induce PKC-δ expression. First we developed a stable, PKC-δ promoter-reporter transfected HaCaT-Ras cell line. Next, we tested 13 compounds for their abilities to induce PKC-δ …

Snail Induces Mesenchymal Transition And Promotes Egfr Tki Resistance In Nsclc Cells Harboring Efgr Kinase Domain Mutations, Rutu Gandhi

Master's Theses

Lung cancer is the leading cause of cancer related death, accounting for one third of all deaths from cancer worldwide. About 85-90% of lung cancers are non-small cell lung cancers (NSCLCs). Molecular targeted therapies such as epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) provide an effective treatment option for oncogene addicted NSCLC. However, the development of resistance to EGFR TKIs continues to be the major limitation in the treatment of NSCLC. Resistance to EGFR TKIs has been associated with the loss of canonical epithelial protein E-cadherin, suggesting involvement of epithelial to mesenchymal transition (EMT) in conferring EGFR TKI …

Effects Of Dopamine And Dopaminergic Agents On Neuronal Activity Of The Ventral Pallidum/Substantia Innominata, Renata J. Maslowski-Cobuzzi

Dissertations

No abstract provided.

A Comparative Study Of The Effect Of Temperature On Testicular Protein Labeling In Common Laboratory Animals, Richard Buyer

Master's Theses

No abstract provided.

Studies Pertaining To The Anatomy, Histology And Nervous Organization And Transmission In The Tunicate Ciona Intestinalis, Charles L. Scudder

Dissertations

No abstract provided.