Targeting DNA repeat sequences with Py-Im polyamides

Hairpin pyrrole-imdazole polyamides are cell-permeable, sequence-programmable oligomers that bind in the minor groove of DNA. This thesis describes studies of Py-Im polyamides targeted to biologically important DNA repeat sequences for the purpose of modulating disease states. Design of a hairpin polyamide that binds the CG dyad, a site of DNA methylation that can become dysregulated in cancer, is described. We report the synthesis of a DNA methylation antagonist, its sequence specificity and affinity informed by Bind-n-Seq and iteratively designed, which improves inhibitory activity in a cell-free assay by 1000-fold to low nanomolar IC50. Additionally, a hairpin polyamide targeted to the telomeric sequence is found to trigger a slow necrotic-type cell death with the release of inflammatory molecules in a model of B cell lymphoma. The effects of the polyamide are unique in this class of oligomers; its effects are characterized and a functional assay of phagocytosis by macrophages is described. Additionally, hairpin polyamides targeted to pathologically expanded CTG•CAG triplet repeat DNA sequences, the molecular cause of myotonic dystrophy type 1, are synthesized and assessed for toxicity. Lastly, ChIP-seq of Hypoxia-Inducible Factor is performed under hypoxia-induced conditions. The study results show that ChIP-seq can be employed to understand the genome-wide perturbation of Hypoxia-Inducible Factor occupancy by a Py-Im polyamide.

Generation of millimeter-wave in optical pulse carrier by using an apodized Moire fiber grating

A novel scheme is proposed to transform a Gaussian pulse to a millimeter-wave frequency modulation pulse by using an apodized Moire fiber Bragg grating in radio-over-fiber system. The relation between the input and output pulses is analyzed theoretically by Fourier transformation method and the requirements for the proposed fiber grating are presented. An apodized Moire fiber Bragg grating is designed and its characteristics are studied. It is shown that the proposed device is feasible, and the new scheme is believed to be an effective solution for the generation of millimeter-wave sub-carrier in future radio-over-fiber systems. (c) 2006 Elsevier B.V. All rights reserved.