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...
Barbed end regulation is critical to the formation of the actin-based protrusive structures, lamellipodia and filopodia. In this body of work we have chosen to focus on two main activities, filament termination by the heterodimeric Capping protein (CP) and continued filament elongation by the Ena/VASP family of proteins. We demonstrate...
The ubiquitin-proteasome system degrades regulatory proteins and thereby controls a broad range of cellular processes such as the cell cycle, DNA-repair, gene transcription and signal transduction. The proteasome typically degrades its substrates completely into small peptides. However, biological exceptions do occur. For example, the activity of a handful of transcriptional...
Epstein-Barr virus (EBV) is a human gamma-herpesvirus that primarily infects B cells and epithelial cells. While the glycoproteins required for entry into these two cell types differ, the gH/gL glycoprotein complex is essential for entry into both epithelial and B cells. Analysis of gH protein sequences from three gamma-herpesviruses: EBV,...
The T-box transcription factor, Tbx5, is involved in heart development and congenital disease. For example mutations in human TBX5 lead to Holt-Oram syndrome, a disease characterized by a range of heart and arm malformations. Tbx5 gene activity has been perturbed in several animal models including the chicken, mouse, and zebrafish....
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...
Herpes simplex virus (HSV) infection of host cells requires virus attachment to the cell surface and subsequent membrane fusion between the virus envelope and host cell membrane to deliver the nucleocapsid containing the viral genome into the host cell. A proposed mechanism for HSV glycoprotein-induced membrane fusion is gD binding...
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...
Desmosomes are adhesive complexes found at sites of intercellular contact that are essential for mediating cell-cell adhesion. These junctions undergo regulated assembly and reorganization during processes such as embryogenesis and wound healing. Plakophilins (PKPs) are armadillo family members related to the classic cadherin-associated protein p120ctn. PKPs localize to the cytoplasmic...
Latent membrane protein 2A (LMP2A) and LMP2B are viral proteins expressed during Epstein-Barr virus (EBV) latency in EBV-infected B cells both in cell culture and in vivo. Although Lyn has been shown to be important in mediating LMP2A signaling, it is still unclear if Lyn is used preferentially or if...
The orderly process of hematopoietic differentiation is governed in large part by the coordinated transcription of specific genes. Deregulation of normal differentiation processes can lead to disease states including immunodeficiency, autoimmune disease, and leukemia. This research focuses on the family of transcription factors known as the early growth response (Egr)...
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...
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...
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...
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...
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...
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...
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...
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...
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...