Medicine and Health Sciences Commons^™

The Role Of Mcl-1 In The Heart: Gateway From Life To Death, Xi Wang

Theses and Dissertations (ETD)

MCL-1 is an essential BCL-2 family member that promotes the survival of multiple cellular lineages, but its role in cardiac muscle has remained unclear. Here, we have demonstrated that cardiac-specific ablation of Mcl-1 results in a rapidly fatal, dilated cardiomyopathy preceded by loss of myofibrils and cardiac contractility, abnormal mitochondria ultrastructure, defective mitochondrial respiration, and impaired autophagy. Genetic ablation of both pro-apoptotic effectors (Bax and Bak) could largely rescue the lethality and impaired cardiac function induced by Mcl-1 deletion. However, Mcl-1-, Bax-, and Bak-deficient hearts still revealed mitochondrial ultrastructural abnormalities and displayed deficient mitochondrial respiration, and are hypersensitive to chronic …

Attenuation Of Parenteral Nutritionassociated Liver Disease By Omega-3 Long-Chain Polyunsaturated Fatty Acids, Emma Monique Tillman

Theses and Dissertations (ETD)

No abstract provided.

Functional Study Of Hemogen Knockout Mouse Model, Peng Gao

Theses and Dissertations (ETD)

Mouse Hemogen (Hemgn) is regarded as a homologue of human Erythroid Differentiation Associated Gene (EDAG). EDAG overexpression has been postulated for association with some leukemia cases. Meanwhile, Hemgn has been found to contribute to Hoxb4 mediated hematopoietic stem cell expansion. Based on these postulations and evidences, a Hemgn knockout mouse model has been generated to study its function in normal and stress hematopoiesis. I confirmed the Hemgn expression in hematopoietic organs including bone marrow and spleen, as well as round spematids in testis. Hemgn is expressed in mouse hematopoietic stem cells and erythroid progenitor cells. Moreover, Hemgn was also found …

Anti-Apoptotic Mcl-1 Localizes To The Mitochondrial Matrix And Couples Mitochondrial Fusion To Respiration, Rhonda Perciavalle

Theses and Dissertations (ETD)

MCL-1, an anti-apoptotic BCL-2 family member that is essential for the survival of multiple cell lineages, is also among the most highly amplified genes in cancer. Although MCL-1 is known to oppose cell death, precisely how it functions to promote survival of normal and malignant cells is poorly understood. Here, I report that different forms of MCL-1 reside in distinct mitochondrial locations and exhibit separable functions. On the outer mitochondrial membrane, a MCL-1 isoform acts like other anti-apoptotic BCL-2 molecules to antagonize apoptosis, whereas an amino-terminally truncated isoform of MCL-1 that is imported into the mitochondrial matrix is necessary to …

Preclinical Study Of Potential Antiglioma Novel Tetrahydroisoquinoline Analogs: Pharmacokinetics And Mechanism Of Action, Fei Ma

Theses and Dissertations (ETD)

Gliomas, the tumors of glial cells, account for 80% of primary malignant brain tumors. In 2011, there were about 18,300 new cases of maligant gliomas in the United States alone. Patients with glioblastoma multiforme or anaplastic astrocytoma, the two major types of malignant gliomas, have a median survival of 14 months or 2 to 3 years, respectively. Therefore novel treatments for malignant glioma are urgently needed.

A novel series of tetrahydroisoquinoline derivatives with antiglioma activity has been undergoing drug metabolism/pharmacokinetics (DMPK)-guided lead optimization. EDL-291 was result from structure modification of last generation compound EDL-155. Its preclinical pharmacokinetics were characterized in …

Compound 49b: A Novel Beta-Adrenergic Receptor Agonist In The Treatment Of Diabetic Retinopathy, Kimberly Williams-Guy

Theses and Dissertations (ETD)

Diabetic retinopathy is the leading cause of blindness in working Americans. While there are therapeutic regimens for the disease, more effective methods are needed. We have previously shown that a non-specific beta-adrenergic receptor agonist, isoproterenol, was effective in preventing functional and morphological changes associated with diabetic retinopathy in the rat. Isoproterenol also produced left ventricle remodeling suggesting it entered the systemic circulation. We therefore synthesized various novel beta-adrenergic receptor compounds and screened these compounds in vitro for their ability to reduce markers of inflammation and apoptosis. Of the various compounds tested, Compound 49b was able to reduce both inflammation and …

Insights Into P53-Dependent Apoptotic Signaling And Cell Fate Vis-A-Vis Functional Cooperation Among Bcl-Xl, Cytoplasmic P53, And Puma, John C. Fisher

Theses and Dissertations (ETD)

Following DNA damage, nuclear p53 induces the expression of PUMA (p53 upregulated modulator of apoptosis), a BH3‑only protein that binds and inhibits the anti‑apoptotic BCL‑2 repertoire, including BCL‑xL. Structural investigations of PUMA and the BCL‑xL×PUMA BH3 domain complex by X‑ray crystallography and nuclear magnetic resonance (NMR) spectroscopy reveal a novel, PUMA‑induced, domain‑swapped dimerization of BCL‑xL that requires a π‑stacking interaction between PUMA W71 and BCL‑xL H113. PUMA is an intrinsically disordered protein, but upon interaction with BCL‑xL, PUMA W71 and the PUMA BH3 domain residues fold into an alpha helix and subtly remodel BCL‑xL to trigger its dimerization. Wild type …

Chitosan/Ellagic Acid Composite Materials For Local Cancer Therapy, Sung Woo Kim

Theses and Dissertations (ETD)

Current advances in the drug delivery have improved the therapeutic efficacy of the drug and minimized risks of side effects associated with toxicity of the drug. Implantable polymeric delivery system has gained increasing attentions for controlled drug release and localized treatments. In comparison to conventional chemotherapy, polymeric delivery systems are implantable at a local targeted site and biodegradable after a sufficient therapeutic span. The objectives of this project were to fabricate and characterize an implantable polymeric vehicle for a local chemotherapy and investigate its biological properties against cancer cells including human WM115 melanoma, human U87 glioblastoma, and rat C6 glioma …

Role Of The Lpa2 Receptor In Protecting Against Apoptosis, Shuyu E

Theses and Dissertations (ETD)

Lysophosphatidic acid (LPA) is a naturally occurring lipid mediator. It exists abundantly in biological fluids such as serum, saliva, follicular fluid, seminal fluid and malignant effusions and induces a vast array of biological responses affecting cell growth, survival, differentiation, migration and morphology. We recently identified lysophosphatidic acid (LPA) as a potent antiapoptotic agent for the intestinal epithelium. Based on computational modeling octadecenyl thiophosphate (OTP) was synthesized: a novel rationally designed, metabolically stabilized LPA mimic. OTP was more efficacious than LPA in reducing g-irradiation-, camptothecin-, or TNF-a/cycloheximide-induced apoptosis and caspase 3, 8 and 9 activity in the IEC-6 cell line. The …

The N-Terminal Domain Of The Y-Box Binding Protein Yb-1 Plays A Major Role In Cell Proliferation And Apoptosis, Payal Khandelwal

Theses and Dissertations (ETD)

Y-box binding protein, YB-1, is a member of the cold shock domain superfamily of proteins. It is involved in a plethora of cellular functions, including cell proliferation. The molecular mechanisms governing the involvement of YB-1 in cell proliferation are still unclear. Earlier studies done in chicken pre-B lymphocyte DT-40 cells in our laboratory have shown that a targeted disruption in one allele of chicken YB-1

(Chk-Yb-1b) gene at its N-terminal domain resulted in multiple abnormalities in the heterozygous mutants, including slower growth rate, abnormal cell morphology, increased cell size, increased genomic DNA content and significant changes in levels of cell …