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Strategies to Accomplish Targeted Gene Delivery Employing Tropism-Modified Adenoviral Vectors
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
Joanne T. Douglas, David T. Curiel
However, adenoviral vectors suffer from the disadvantage that the widespread distribution of the cellular receptor for serotypes 2 and 5 precludes the targeting of specific cell types. This feature would result in a decrease in the efficiency of transduction of lung cells by adenoviral vectors, as the number of virus particles available for delivery to the target cells would be decreased by sequestration by nontarget cells. Furthermore, this would allow ectopic expression of the delivered transgene, with possibly deleterious consequences. Therefore a means must be developed to redirect the tropism of the adenoviral vector specifically to lung cells. The ability to accomplish targeted gene delivery to specific cells of the pulmonary system would thus greatly enhance the various current gene therapy schemas for lung disorders.
Transgenic Mice with Cytokine Mutations Affecting the Skin
Published in John P. Sundberg, Handbook of Mouse Mutations with Skin and Hair Abnormalities, 2020
Manfred Blessing, Erby Wilkinson, Brigid L. M. Hogan
In conclusion, these results support the hypothesis that BMP-2 plays an active role in the changes that take place when cells leave the matrix. Ectopic expression shuts down proliferation as seen in the transgenic outer root sheath and matrix. However, the low percentage of follicles with trichocytic reactivity in transgenic outer root sheaths suggests that BMP-2/4 alone is not sufficient to trigger the complete set of changes, such as the onset of trichocytic markers.
The Regulatory Process and Gene Therapy 1
Published in Eric Wickstrom, Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors, 2020
In addition to toxicity, the goals of animal studies should be to study where the vector localizes, where it is expressed, and effects of overexpression or ectopic expression. Tumorigenicity may also be a concern in some cases. Possible adverse events might include effects of expression at higher than normal levels, or effects of expression in unintended cells or tissues. Such effects could include immune responses to a gene product in hosts not normally expressing it, or in hosts expressing a mutated form of that product. Such responses could result in autoimmunity or in alteration of the safety and/or efficacy of repeat treatment.
History of Drosophila neurogenetic research in South Korea
Published in Journal of Neurogenetics, 2023
Greg S. B. Suh, Kweon Yu, Young-Joon Kim, Yangkyun Oh, Joong-Jean Park
As the primary interest of the field transitioned from early embryogenesis to tissue and organ development and pattern formation, South Korea witnessed the emergence of highly talented scientists who made critical contributions to the field. For example, Jaeseob Kim discovered that vestigial gene is required for wing development and, intriguingly, is sufficient to induce the development of wing tissues in any organ, such as eyes or legs, when it is expressed ectopically in these organs (Kim et al., 1996). Such a breakthrough led to further development of the concept of a ‘master regulator’ for organ development. Just as wing development was found to be governed by vestigial gene, Walter Gehring’s laboratory discovered that the development of eye is governed by eyeless gene (Halder, Callaerts, & Gehring, 1995). Just a half decade earlier, investigators had observed a simpler master regulator that was able to induce the development of a specific cell type. Myogenesis, for instance, was found to be induced by the expression of a single gene MyoD (Tapscott et al., 1988). It was not yet conceivable, however, that an entire organ consisting of different cell types could be induced and reconstituted through the ectopic expression of a single gene. This novel concept of the master regulator has influenced enormously – in the fields of mammalian development, stem cell, and organ regeneration years to come.
Connection of ES Cell-derived Collecting Ducts and Ureter-like Structures to Host Kidneys in Culture
Published in Organogenesis, 2021
Developing kidneys are rich in signals, likely to be important in determining the differentiation of grafted eUBs.10 The metanephric mesenchyme expresses GDNF, which activates the expression of the receptor tyrosine kinase RET and the co-receptor GFRα1 on the UB tip cells to stimulate UB branching, while the UB produces Wnt9b which promotes nephron formation via mesenchymal to epithelial transition.13 The future ureter is surrounded by a Tbx18-expressing cell population, the peri-wolffian mesenchyme (PWM), and the UB and the PWM interact to form the urothelium and its contractile machinery.14 PWM cells express BMP4, which promotes differentiation of the nearby ureteric bud into urothelium, as well as their own differentiation into smooth muscle cells. The urothelium expresses SHH which binds PTCH1 receptor in the PWM cells to stimulate their proliferation. Both SHH and BMP4 are required for a successful differentiation of the smooth muscle cells.15 The possible roles of each of these molecules in specifying eUB differentiation could be tested by a combination of inhibition or ectopic expression/application.
Altered expression of the core circadian clock component PERIOD2 contributes to osteoarthritis-like changes in chondrocyte activity
Published in Chronobiology International, 2019
Jing Rong, Mark Zhu, Jacob Munro, Jillian Cornish, Geraldine M McCarthy, Nicola Dalbeth, Raewyn C Poulsen
The present study utilised genetic techniques such as knockdown and ectopic expression to manipulate PER2 expression in cells. To overexpress PER2 in our study, we used a plasmid in which expression of the mouse PER2 (mPer2) gene was driven by a constitutive promoter (CMV). This resulted in substantial upregulation of mPer2 levels and loss of any apparent circadian rhythm in mPer2 expression at the mRNA level. However, protein levels of mPER2 did vary over the course of a day in PER2-transfected cells. Similarly, Fujimoto et al. (2006) found that mPER2 protein continued to cycle in fibroblasts constitutively expressing mPer2, indicating that post-transcriptional regulatory mechanisms are involved in maintaining circadian oscillations in mPER2 protein (Fujimoto et al. 2006). Although PER2 is a core component of the circadian clock, it also has non-circadian effects (Albrecht U et al. 2007; McQueen et al. 2018). PER2 is involved in regulating the cell cycle, energy metabolism, immune function and tissue development (Albrecht et al. 2007; McQueen et al. 2018). Whether the timing of mPER2 expression is important for its effect on chondrocyte phenotype is unclear. Future studies examining the circadian versus non-circadian effects of PER2 will provide insight into the mechanisms of PER2 activity.