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Gene silencing approaches afford investigators the ability to gain important insight into the normal functional requirements of specific epidermal proteins and promise to yield a powerful therapeutic means to dampen the level of proteins that are mutated or frequently overexpressed in skin disease. The efficient and tractable delivery of siRNAs into epidermal keratinocytes is seminal to this process. Here, we describe techniques for transient and long-term silencing of a representative gene product, namely desmoglein 1, in primary human epidermal keratinocytes maintained as submerged cultures or three-dimensional organotypic raft cultures. As a complement to epidermal-specific gene targeting strategies in mice, these technical approaches permit relatively rapid loss-of-function studies purely in keratinocytes without some of the potential influences present in situ, such as an immune system or vasculature.
Methods Mol Biol 2010
PMID:RNA interference in keratinocytes and an organotypic model of human epidermis. 1990 1

The epidermis is a complex tissue composed principally of differentiated keratinocytes that form a keratinized stratified squamous epithelium. The gap junction proteins, connexins (Cx), are differentially expressed throughout the stratified layers of the epidermis and their exquisite regulation appears to govern the delicate balance between cell proliferation and differentiation in normal skin homeostasis and in wound healing. In the last 10 years, germ line mutations in the genes encoding five connexin family members have been linked to various types of skin diseases that appear to offset the balance between keratinocyte differentiation and proliferation. Consequently, in order to determine how these connexin gene mutations manifest as skin disease, disease-linked mutants must be expressed in 3D organotypic epidermis reference models that attempt to mimic the human condition. Given the complexity of organotypic epidermis, confocal optical and biochemical dissection of connexin or disease-linked connexin mutants within the regenerated epidermal layer is required. The procedures necessary to assess the architectural characteristics of genetically modified organotypic epidermis and its state of differentiation will be described in this chapter.
Methods Mol Biol 2010
PMID:Optical and biochemical dissection of connexin and disease-linked connexin mutants in 3D organotypic epidermis. 1990 13

Angiogenesis is a major factor in the development of benign, inflammatory, and malignant processes of the skin. Endothelial cells are the effector cells of angiogenesis, and understanding their response to growth factors and inhibitors is critical to understanding the pathogenesis and treatment of skin disease. Hemangiomas, benign tumors of endothelial cells, represent the most common tumor of childhood. In our previous studies, we have found that tumor vasculature in human solid tumors expresses similarities in signaling to that of hemangiomas, making the knowledge of signaling in hemangiomas widely applicable. These similarities include expression of reactive oxygen, NFkB and akt in tumor vasculature. Furthermore, we have studied malignant vascular tumors, including hemangioendothelioma and angiosarcoma and have shown distinct signaling abnormalities in these tumors. The incidence of these tumors is expected to rise due to environmental insults, such as radiation and lumpectomy for breast cancer, dietary and industrial carcinogens (hepatic angiosarcoma), and chronic ultraviolet exposure and potential Agent Orange exposure. I hypothesize that hemangiomas, angiosarcomas, and vascular malformations represent the extremes of signaling abnormalities seen in pathogenic angiogenesis.
Curr Mol Med 2009 Nov
PMID:Hemangiomas, angiosarcomas, and vascular malformations represent the signaling abnormalities of pathogenic angiogenesis. 1992 5

The rare skin disorder pachyonychia congenita (PC) is an autosomal dominant syndrome that includes a disabling plantar keratoderma for which no satisfactory treatment is currently available. We have completed a phase Ib clinical trial for treatment of PC utilizing the first short-interfering RNA (siRNA)-based therapeutic for skin. This siRNA, called TD101, specifically and potently targets the keratin 6a (K6a) N171K mutant mRNA without affecting wild-type K6a mRNA. The safety and efficacy of TD101 was tested in a single-patient 17-week, prospective, double-blind, split-body, vehicle-controlled, dose-escalation trial. Randomly assigned solutions of TD101 or vehicle control were injected in symmetric plantar calluses on opposite feet. No adverse events occurred during the trial or in the 3-month washout period. Subjective patient assessment and physician clinical efficacy measures revealed regression of callus on the siRNA-treated, but not on the vehicle-treated foot. This trial represents the first time that siRNA has been used in a clinical setting to target a mutant gene or a genetic disorder, and the first use of siRNA in human skin. The callus regression seen on the patient's siRNA-treated foot appears sufficiently promising to warrant additional studies of siRNA in this and other dominant-negative skin diseases.
Mol Ther 2010 Feb
PMID:First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder. 1993 78

Gap junctions allow the exchange of ions and small molecules between adjacent cells through intercellular channels formed by connexin proteins, which can also form functional hemichannels in nonjunctional membranes. Mutations in connexin genes cause a variety of human diseases. For example, mutations in GJB2, the gene encoding connexin-26 (Cx26), are not only a major cause of nonsyndromic deafness, but also cause syndromic deafness associated with skin disorders such as palmoplantar keratoderma, keratitis-ichthyosis deafness syndrome, Vohwinkel syndrome, hystrix-ichthyosis deafness syndrome and Bart-Pumphrey syndrome. The most common mutation in the Cx26 gene linked to nonsyndromic deafness is 35DeltaG, a frameshift mutation leading to an early stop codon. The large number of deaf individuals homozygous for 35DeltaG do not develop skin disease. Similarly, there is abundant experimental evidence to suggest that other Cx26 loss-of-function mutations cause deafness, but not skin disease. By contrast, Cx26 mutations that cause both skin diseases and deafness are all single amino acid changes. Since nonsyndromic deafness is predominantly a loss-of-function disorder, it follows that the syndromic mutants must show an alteration, or gain, of function to cause skin disease. Here, we summarise the functional consequences and clinical phenotypes resulting from Cx26 mutations that cause deafness and skin disease.
Expert Rev Mol Med 2009 Nov 19
PMID:Connexin-26 mutations in deafness and skin disease. 1993

Psoriasis is a chronic inflammatory skin disease characterised by elevated red scaly plaques on specific body sites. Histologically, the plaques are defined by epidermal hyperplasia, epidermal and dermal infiltration by leukocytes, and changes in the dermal microvasculature. Differentiation and activation are disturbed in lesional psoriatic keratinocytes, and the pool of proliferating keratinocytes is increased, which is accompanied by enhanced production of proinflammatory cytokines, adhesion molecules and antimicrobial peptides. These changes in psoriatic keratinocytes are caused by altered expression of genes associated with epidermal differentiation, and by activation of signalling pathways involving signal transducer and activator of transcription 3 (STAT3), type I interferon (IFN) and mitogen-activated protein kinase (MAPK). The number of T cells, and myeloid and plasmacytoid dendritic cells (DCs) is markedly increased in psoriatic lesions. Myeloid DCs produce interleukin (IL)-23, tumour necrosis factor (TNF)-alpha and inducible nitric oxide synthase (iNOS), which are crucial cytokines in the pathogenesis of psoriasis. IL-23 stimulates the secretion of IL-22 by T helper 17 cells, and IL-22 induces epidermal hyperplasia. The crosstalk between keratinocytes and leukocytes via their proinflammatory cytokines creates the vicious circle of chronic skin inflammation seen in psoriasis. This suggests that optimal treatment of psoriasis needs to target pathogenic pathways in both leukocytes and keratinocytes.
Expert Rev Mol Med 2009 Dec 14
PMID:Molecular pathophysiology of psoriasis and molecular targets of antipsoriatic therapy. 2000 7

Human skin is a rich source of human antimicrobial peptides. Its cellular source is the keratinocyte, which terminally differentiates in the uppermost parts of the skin, eventually forming the stratum corneum, the horny layer. The easy availability of human stratum corneum makes it possible to identify and characterize human antimicrobial peptides with a biochemical approach. Moreover, the availability of lesional scales of patients with psoriasis, an inflammatory skin disease, allows the identification of human-inducible peptide antibiotics, which are absent in healthy skin. With this strategy, the beta-defensins hBD-2 and hBD-3, RNase-7 as well as psoriasin/S100A7 have been discovered as human antimicrobial peptides and proteins. A detailed description of the strategies and methods is presented, which allowed a successful identification and characterization of human antimicrobial peptides. We used various HPLC techniques, combined with antimicrobial testing as read-out system. In parallel, SDS-PAGE analyses as well as electrospray ionization mass spectrometry were used for further biochemical characterization as well as purity assessment.
Methods Mol Biol 2010
PMID:Purification of antimicrobial peptides from human skin. 2009 55

Dystrophic epidermolysis bullosa is a heritable skin disorder with dominant and recessive genetic patterns. Numerous studies underline that both forms are caused by mutations of the COL7A1 gene, which encodes collagen type VII. It has been reported that most mutations detected in the recessive disease form are nonsense mutations or small insertions or deletions leading to frameshift and premature translational termination, which tend to produce severe phenotypes. In contrast, missense mutations causing amino acid substitutions, which result in variable phenotypes, predominate in the dominant form of dystrophic epidermolysis bullosa. Genomic DNA from the patient and parents was subjected to PCR amplification of the coding region of the COL7A1 gene. Direct sequencing of the PCR products revealed a homozygous single-base deletion in the patient (c.6269-6270delC). The parents were heterozygous for the same mutation. This deletion is a novel mutation in the human COL7A1 gene based on comparisons with the Human Genome Mutation Database. To our knowledge, this is the first report of dystrophic epidermolysis bullosa in an Iranian patient confirmed by molecular diagnosis.
J Mol Diagn 2010 May
PMID:A novel COL7A1 gene mutation in an Iranian individual suffering dystrophic epidermolysis bullosa. 2019 17

Expression of serotonin 2A receptor (5-HTR2A) is known to increase in psoriasis, a chronic inflammatory skin disease. We investigated a possible association between the -1438A/G single nucleotide polymorphism (rs6311) in the promoter region of 5-HTR2A gene and psoriasis in a Thai population. One hundred and twelve psoriatic patients and 151 unrelated healthy controls were included in our study. Genotyping was performed using the polymerase chain reaction and restriction fragment length polymorphism techniques. We found no overall differences in genotype distributions and allele frequencies when comparing between the two groups. When we analyzed a subset of psoriatic patients classified by onset and severity, only the -1438A allele was significantly increased in patients with late-onset psoriasis when compared with the healthy control group (chi(2) = 4.77, d.f. = 1, P = 0.029, odds ratio = 2.298 [95% confidence interval = 1.126-4.691]). This single nucleotide polymorphism may be involved in late-onset psoriasis in this Thai population.
Genet Mol Res 2010 Feb 02
PMID:Association between the -1438A/G polymorphism of the serotonin 2A receptor gene and late-onset psoriasis in a Thai population. 2019 76

Mannose-binding lectin (MBL) and the Mannose-binding lectin-associated serine proteases (MASPs) are an essential aspect of innate immune responses that probably play an important but understudied role in cutaneous function. The MBL-MASP pathway appears to exert its primary role by assisting in the clearance of apoptotic skin cells (thus preventing accumulation and a subsequent autoimmune response) and promoting opsonophagocytosis of invading pathogens, limiting their dissemination. Deficiencies of the pathway have been described and are associated with infectious, autoimmune and vascular complications. However, the role of this pathway in dermatological disease is essentially unexplored. We describe 6 patients presenting with recurrent inflammatory and/or infectious skin conditions who also demonstrated severely low MBL levels. One patient also had a defect in the MASP2 gene. Genotype analysis revealed specific point mutations in the MBL2 promoter in all 6 patients and a variant MASP-2 gene in one patient. Five patients presented recurrent pustular skin infections (cellulitis, folliculitis and cutaneous abscess). A case of Grover's disease and one forme fruste of Behcet's syndrome (orogenital ulcers) were also observed. The patients responded to antimicrobial therapy, although in some, recurrence of infection was the rule. It appears that MBL deficiency may contribute to recurrent skin infections and to certain forms of inflammatory skin disease. The mechanisms may relate to the role of this pathway in innate immunity, removal of apoptotic cells and in immune complexes. Further study of MBL pathway defects in dermatological disease is required.
Clin Mol Allergy 2010 Mar 25
PMID:Molecular defects in the mannose binding lectin pathway in dermatological disease: Case report and literature review. 2033 57


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