Although non-viral gene therapy has great potential for use in the lung, several problems including inefficient gene transfer and expression and the relative lack of cell-specific targeting have limited its applications. The two approaches that have been used to target genes to desired cell types are through specific ligand-receptor interactions...
HspB2 was discovered as a chaperone of muscular dystrophy protein kinase (DMPK) and originally named, DMPK binding protein (MKBP) and presently called HspB2. Functionally, MKBP binds to DMPK and stabilizes its kinase activity, thereby accelerating the progression of muscular dystrophy. Although other binding partners of HspB2 have been found, the...
Early-life seizures increase susceptibility to seizures in adulthood. However, mechanisms by which seizures in the developing brain lead to increased vulnerability to seizures and exacerbation of neurological injury in adulthood remain unknown. We test the hypothesis that upregulation of proinflammatory cytokine levels and chronic glial activation following early-life seizures result...
MHC class II-restricted T cell responses are a common driving force of autoimmune disease. Numerous therapeutic strategies target CD4+ T cells hoping to attenuate autoimmune responses and restore self-tolerance. We have previously reported that i.v. treatment with antigen-pulsed, ethylenecarbodiimide (ECDI)-fixed splenocytes (Ag-SP) is an efficient protocol to induce Ag-specific tolerance...
Cellular interactions are important for the development and maintenance of tissue structural integrity. In the developing neuroepithelium, the adherens junction proteins, N-cadherin and β-catenin, are highly enriched at the apical surface of the proliferative ventricular zone and have been suggested to have critical functions in ensuring the proper development of...
The perinucleolar compartment is a nuclear substructure that is associated with, but structurally distinct from the nucleolus. Previous studies have shown that the PNC preferentially forms in cancer cells and PNC prevalence (% of non-mitotic and non-apoptotic cells in a population with one or more PNC) is a prognostic in...
A primary limitation of non-viral gene therapy is the low level of expression achieved. One of the reasons that higher expression is not achieved is that there are many physical obstacles that prevent the DNA from reaching the nucleus to be expressed. A plasmid must cross the cell membrane, traverse...
Actin polymerization is responsible for the protrusion of filopodia and lamellipodia in immune, cancer, and other motile cells, as well as for propulsion of some intra cellular pathogens. Protrusion of a lamellipodium by the very filaments supporting the membrane load operates by the Brownian ratchet mechanism, with overall organization governed...
IL-6 is a pleiotropic cytokine involved in both immune and non-immune functions. In the immune system, IL-6 induces terminal differentiation of B cells into plasma cells, thereby promoting antibody production. IL-6 stimulates growth of T cells by enhancing the expression of the IL-2 receptor, and IL-6 also causes differentiation of...
Filopodia play a central role in proper cell navigation; they extend from the cell surface and scan the local environment to guide the cell to its proper destination. These dynamic events require precise mechanisms for the turnover of key molecules which determine the morphology of filopodia. As of yet, such...
The kinetoplastid protozoan <em>Trypanosoma brucei</em> is the causative agent of African trypanosomiasis, affecting humans, and Nagana disease, affecting cattle, prevalent in regions of sub-Saharan Africa. Our lab demonstrated that the flagellum of <em>T. brucei</em> is enriched in lipid rafts, membrane areas composed of sphingolipids, sterols, and proteins that serve as...
Tonia René Holverson The HPV genome contains a bipartite promoter system that regulates the expression of early and late gene transcripts. The early proteins include the replication proteins E1 and E2, the oncoproteins E6 and E7, and the late functioning proteins E4 and E5. The late proteins include the capsid...
Epstein Barr Virus (EBV) is associated with malignancies of lymphoid and epithelial origin. While the precise role of EBV in oncogenesis remains elusive, latent membrane protein 2A (LMP2A) is detected in all EBV-associated malignancies, implicating LMP2A in their pathogenesis. Interestingly, LMP2A is expressed in EBV-associated malignancies such as Burkitt's Lymphoma,...
The small heat shock protein αB-crystallin is expressed primarily in lens and muscle tissue, but it is also found in lung, kidney and many cancers. Regulators of αB-crystallin have been identified almost exclusively using mouse muscle and lens specific models. It has been well documented that αB-crystallin is expressed in...
Herpesviruses require axonal transport for the successful establishment of infection in peripheral ganglia (retrograde transport), and the subsequent spread to exposed body surfaces following reactivation from latency (anterograde transport). Viral progeny are assembled and spread to other tissues or hosts during egress. I focused on viral proteins which modulate directed...
Inactivation of tumor suppressors genes, which encode regulatory proteins critical for maintaining normal cellular function, is a common occurrence in cancer. Ikaros is a hematopoietic-specific zinc finger protein that functions as a differentiation regulator and has properties of a tumor suppressor. Ikaros functions to regulate gene expression as a component...
PilD is an enzyme that processes prepilins that are part of the type II protein secretion apparatus and the type IV piliation machinery. Using a <em>Legionella pneumophila pilDlacZ</em> fusion strain to measure transcription, we observed a 20% increase in beta-galactosidase levels at 30°C vs. 37°C. At 25°C and 17°C vs....
Embryonic stem cells have the potential to differentiate into ectodermal, mesodermal and endodermal derivatives. This property makes them a valuable source of tissue specific progenitor and differentiated cells that can be used for cell replacement therapy. The first goal of this thesis is to test if cardiogenesis from embryonic stem...
Plants, animals, and yeast have the capacity to produce and accumulate neutral lipids, sterol esters and triacylglycerol (TAG). However, their accumulation and the genes underlying their synthesis in intracellular microorganisms are poorly understood.
Plasmodium falciparum is a parasitic protozoan that causes the most virulent form of human malaria. During erythrocytic...
Senescence, permanent, irreversible replication arrest that occurs in all primary cells studied to date, is considered a cellular model of aging. Recently, senescence has gained attention as a potential tumor-suppressing mechanism. However, despite the obvious importance of senescence, its exact mechanisms remain unclear. One current hypothesis to explain senescence postulates...