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375 The chromatin architectural protein CTCF regulates expression of pro-inflammatory cytokines in the skin cells
Increased evidence suggests that alterations in chromatin structure result in aberrant pro-inflammatory cytokines expression that leads to prolonged inflammatory responses. CCCTC-binding factor (CTCF) is a transcriptional repressor that insulates the expression of neighbouring genes and is involved in chromatin interactions between distal and proximal gene regulatory elements. However, the role of CTCF in the control of pro-inflammatory cytokines expression in the skin cells remains unknown. Here, we show that CTCF is expressed in the nuclei of normal human epidermal keratinocytes (NHEK) and dermal fibroblasts (DF), while ...
Source: Journal of Investigative Dermatology - April 19, 2019 Category: Dermatology Authors: M. Boboljova, I. Asamaowei, V. Botchkarev, M. Fessing, A.N. Mardaryev Tags: Genetic Disease, Gene Regulation, and Gene Therapy Source Type: research

812 Type VII collagen and Nesprin 2, LINCing the basement membrane to altered cell cycle and increased DNA damage
Epidermolysis Bullosa is a severe blistering disease caused by mutations in basement membrane genes and is characterised by severe blistering of the skin and increased predisposition to cancer. To investigate the role of the skin basement membrane, siRNA knockdown of type IV, VII and XVII collagens was performed in primary keratinocytes. Global transcriptomic analysis was carried out using RNA-Seq. Dysregulation of genes involved in DNA damage and cell cycle control was seen in cells with Col7 and Col17 knockdown.
Source: Journal of Investigative Dermatology - April 27, 2018 Category: Dermatology Authors: S. Marsh, M.P. Caley, V. Martins, M. Chen, J. McGrath, M. Barnes, E.A. O'Toole Tags: Genetic Disease, Gene Regulation, and Gene Therapy Source Type: research

761 Topically-delivered gene suppressing nanocontruct targets IL-17RA for psoriasis
Activated interleukin (IL)-23/Th17 signaling is critical for psoriasis pathogenesis, and systemic IL-17 inhibitors are highly effective therapy. However, most patients have mild to moderate disease and no targeted topical therapeutic option. We developed a topically-delivered gene regulating nanoconstruct, comprised of antisense DNA or siRNA in a dense spherical configuration. These spherical nucleic acids or SNAs penetrate the skin barrier to knock down cutaneous gene targets. We generated anti-human and anti-mouse liposomal DNA SNAs targeting the IL-17A receptor (ILRA) and tested their efficacy in reducing IL17RA and imp...
Source: Journal of Investigative Dermatology - April 27, 2018 Category: Dermatology Authors: H. Liu, R. Kang, K. Bagnowski, J. Yu, X. Cheng, S. Radecki, W. Daniel, D. Giljohann, A.S. Paller Tags: Genetic Disease, Gene Regulation, and Gene Therapy Source Type: research

812 Type VII collagen and Nesprin 2, LINCing the basement membrane to altered cell cycle and increased DNA damage
Epidermolysis Bullosa is a severe blistering disease caused by mutations in basement membrane genes and is characterised by severe blistering of the skin and increased predisposition to cancer. To investigate the role of the skin basement membrane, siRNA knockdown of type IV, VII and XVII collagens was performed in primary keratinocytes. Global transcriptomic analysis was carried out using RNA-Seq. Dysregulation of genes involved in DNA damage and cell cycle control was seen in cells with Col7 and Col17 knockdown.
Source: Journal of Investigative Dermatology - April 19, 2018 Category: Dermatology Authors: S. Marsh, M.P. Caley, V. Martins, M. Chen, J. McGrath, M. Barnes, E.A. O'Toole Tags: Genetic Disease, Gene Regulation, and Gene Therapy Source Type: research

761 Topically-delivered gene suppressing nanocontruct targets IL-17RA for psoriasis
Activated interleukin (IL)-23/Th17 signaling is critical for psoriasis pathogenesis, and systemic IL-17 inhibitors are highly effective therapy. However, most patients have mild to moderate disease and no targeted topical therapeutic option. We developed a topically-delivered gene regulating nanoconstruct, comprised of antisense DNA or siRNA in a dense spherical configuration. These spherical nucleic acids or SNAs penetrate the skin barrier to knock down cutaneous gene targets. We generated anti-human and anti-mouse liposomal DNA SNAs targeting the IL-17A receptor (ILRA) and tested their efficacy in reducing IL17RA and imp...
Source: Journal of Investigative Dermatology - April 19, 2018 Category: Dermatology Authors: H. Liu, R. Kang, K. Bagnowski, J. Yu, X. Cheng, S. Radecki, W. Daniel, D. Giljohann, A.S. Paller Tags: Genetic Disease, Gene Regulation, and Gene Therapy Source Type: research

532 siRNA based non-viral gene therapy for the treatment of epidermolysis bullosa simplex(EBS)
EBS is an inherited, skin fragility disorder predominantly caused by dominant-negative mutations in genes encoding for the cytoskeletal proteins, Keratin5 and Keratin14 within the basal cell layer. To date, EBS is incurable with only symptomatic therapies currently available. The downregulation of these mutant genes would provide an excellent curative therapy for treating EBS. siRNA therapeutics have been identified as an attractive therapy option for EBS given the highly accessible nature of skin tissue.
Source: Journal of Investigative Dermatology - April 12, 2017 Category: Dermatology Authors: J. O'Keeffe Ahern, D. Zhou, L. Cutlar, I. Lara-S áez, W. Wang Tags: Genetic Disease, Gene Regulation and Gene Therapy Source Type: research

482 Inhibition of cyclooxygenase-2 and prostaglandin E-PGE receptor 4 pathway restores ultraviolet B-induced ATP2A2/SERCA2 downregulation in keratinocytes
Background: ATP2A2 encoding the sarcoplasmic/endoplasmic reticulum Ca2+ -ATPase2 (SERCA2) is a responsible gene for Darier disease (DD). Ultraviolet (UV) B irradiation downregulates ATP2A2/SERCA2 expression in keratinocytes, whereas cyclooxygenase-2 (COX-2) expression is dramatically upregulated by UVB. Objectives: To analyze the involvement of COX-2 and subsequent Prostaglandin E (PGE) -PGE receptor signaling in ATP2A2/SERCA2 expression. Methods: Normal human keratinocytes (NHKs) were transfected with COX-2 siRNA, PGE receptor (EP1-4) siRNA and treated with COX-2 inhibitor, celecoxib, to evaluate the effect of COX-2 and P...
Source: Journal of Investigative Dermatology - April 12, 2017 Category: Dermatology Authors: M. Kaga-Kamijo, A. Wada, R. Mineki, T. Sakanishi, C. Nishiyama, S. Ikeda Tags: Genetic Disease, Gene Regulation and Gene Therapy Source Type: research

478 Mutation-specific siRNA Knockdown of GJB2 − Potential gene therapy for Keratitis-ichthyosis-deafness Syndrome
Mutations in the GJB2 gene, which encodes connexin 26 (Cx26), cause keratitis-ichthyosis-deafness (KID) syndrome. 87% of patients carry a dominant mutation D50N, which is thought to cause a dominant negative effect on the normal allele product. Current treatment is limited to symptomatic care. We hypothesised that a mutation-specific siRNA to selectively suppress the D50N mutant allele may potentially reverse the disease phenotype. We first tested whether suppression of a single Cx26 allele can lead to haplo-insufficiency in human keratinocytes (KCs).
Source: Journal of Investigative Dermatology - April 12, 2017 Category: Dermatology Authors: M. Lee, V.A. Kinsler, S.L. Hart, W. Di Tags: Genetic Disease, Gene Regulation and Gene Therapy Source Type: research

375 Modelling and understanding pathomechanisms of X-linked recessive ichthyosis in vitro
X-Linked Recessive Ichthyosis (XLRI) results from a deficiency of steroid sulfatase (STS) and is characterized by an accumulation of cholesterol sulfate in the upper layers of the epidermis, resulting in a scaling phenotype and barrier dysfunction. We have generated an RNA-Seq data set of the transcriptome of keratinocytes with siRNA-induced loss of the enzyme steroid sulfatase (STS) to further understand the pathomechanisms of XLRI. To validate these data, we generated a 3D XLRI model using 2 telomerase-immortalized keratinocyte cell lines with stable knockdown of STS using different lentiviral shRNA clones.
Source: Journal of Investigative Dermatology - April 20, 2016 Category: Dermatology Authors: F.T. McGeoghan, E. O’Toole, M. Caley, M. Menon, P. Dewan, M. Donaldson Tags: Genetic Disease, Gene Regulation & Gene Therapy Source Type: research

405 Hydrophobically modified siRNAs (hsiRNAs) provide a platform to silence gene expression in inflammatory skin diseases
RNA interference (RNAi) is a highly conserved biological process in which small RNA molecules inhibit gene expression. It has great potential to treat different human diseases, including inflammatory skin disorders. Despite promising results in vitro, therapeutic application of RNAi has been limited mainly due to difficulties in efficient delivery of the therapeutic oligonucleotides to target cells. Here we describe that direct conjugation of fully stabilized siRNA (hsiRNAs) to cholesterol (Chol) or biologically occurring lipids results in widespread distribution in the skin following local administration.
Source: Journal of Investigative Dermatology - April 20, 2016 Category: Dermatology Authors: M. Rashighi, M. Nikan, A.H. Coles, A. Khvorova, J.E. Harris Tags: Genetic Disease, Gene Regulation & Gene Therapy Source Type: research