The hairless mouse in skin research

Benavides, Fernando; Oberyszyn, Tatiana M.; VanBuskirk, Anne M.; Reeve, Vivienne E.; Kusewitt, Donna F.

doi:10.1016/j.jdermsci.2008.08.012

Cited by 230 publications

(250 citation statements)

References 84 publications

Supporting

Mentioning

242

Contrasting

Unclassified

Order By: Relevance

“…All data are expressed as mean AE SD. lation), immunocompetency, and increased normal epidermal thickness (to better simulate human skin) in comparison with most mouse strains (28). Studies were also conducted in hairbearing C57BL/6J mice (shaved 24 h before application to minimize epidermal barrier disruption).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation

Zheng

Giljohann

Chen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

368

288

View full text Add to dashboard Cite

Topical application of nucleic acids offers many potential therapeutic advantages for suppressing genes in the skin, and potentially for systemic gene delivery. However, the epidermal barrier typically precludes entry of gene-suppressing therapy unless the barrier is disrupted. We now show that spherical nucleic acid nanoparticle conjugates (SNA-NCs), gold cores surrounded by a dense shell of highly oriented, covalently immobilized siRNA, freely penetrate almost 100% of keratinocytes in vitro, mouse skin, and human epidermis within hours after application. Significantly, these structures can be delivered in a commercial moisturizer or phosphate-buffered saline, and do not require barrier disruption or transfection agents, such as liposomes, peptides, or viruses. SNANCs targeting epidermal growth factor receptor (EGFR), an important gene for epidermal homeostasis, are >100-fold more potent and suppress longer than siRNA delivered with commercial lipid agents in cultured keratinocytes. Topical delivery of 1.5 uM EGFR siRNA (50 nM SNA-NCs) for 3 wk to hairless mouse skin almost completely abolishes EGFR expression, suppresses downstream ERK phosphorylation, and reduces epidermal thickness by almost 40%. Similarly, EGFR mRNA in human skin equivalents is reduced by 52% after 60 h of treatment with 25 nM EGFR SNA-NCs. Treated skin shows no clinical or histological evidence of toxicity. No cytokine activation in mouse blood or tissue samples is observed, and after 3 wk of topical skin treatment, the SNA structures are virtually undetectable in internal organs. SNA conjugates may be promising agents for personalized, topically delivered gene therapy of cutaneous tumors, skin inflammation, and dominant negative genetic skin disorders.T he recent development of small molecule inhibitors and antibodies that target components of signaling pathways has revolutionized the treatment of cancers, inflammatory diseases, and genetic disorders, including those that largely manifest in skin (1-3). These protein-based therapeutics, however, are costly, have limited targeting ability, and, when delivered through traditional intravenous or gastrointestinal routes, can lead to systemic toxicity (4, 5). Topical delivery is particularly attractive for the therapy of skin disorders. However, proteins larger than a few hundred daltons cannot easily enter the skin, and high concentrations of proteins must be applied for a cutaneous effect (6). An alternative to protein-based pathway inhibition involves the blocking and/or degradation of precursor mRNA before translation into protein. Gene silencing leads to down-regulation of protein expression and functions with greater specificity than inhibitors of protein function (7). In fact, targeted gene suppression by antisense DNA and siRNA has shown promising preclinical results, and/or is currently in clinical trials for a variety of diseases, including many forms of cancer (e.g., melanoma, neuroblastoma, and pancreatic adenocarcinoma), genetic disorders, and macular degeneration (8). For gene su...

show abstract

Section: Resultsmentioning

confidence: 99%

“…We then evaluated SNA-NC penetration through human skin using Franz cell chambers (28). Flux of nonsense SNA-NCs through human skin in Franz cell chambers was maximal between 8 and 24 h after topical application of nonsense SNA-NCs, regardless of solvent (SNA-NCs in PBS, glycerol, or Aquaphor) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation

Zheng

Giljohann

Chen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

368

288

View full text Add to dashboard Cite

show abstract

“…The C57BL/6 mouse strain is commonly used in circadian research but the majority of UV carcinogenesis studies have been carried out with the SKH-1 hairless mouse strain for practical reasons and because these mice develop squamous cell carcinomas (SCCs) similar to humans (17,18). Hence, we decided to do our UV carcinogenesis study with this strain and first we examined the levels of XPA in epidermal keratinocytes, which are the target cells for UVB-induced DNA damage and precursor cells of SCCs.…”

Section: Resultsmentioning

confidence: 99%

Control of skin cancer by the circadian rhythm

Gaddameedhi

Selby²,

Kaufmann

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

205

266

View full text Add to dashboard Cite

Skin cancer is the most common form of cancer in the United States. The main cause of this cancer is DNA damage induced by the UV component of sunlight. In humans and mice, UV damage is removed by the nucleotide excision repair system. Here, we report that a rate-limiting subunit of excision repair, the xeroderma pigmentosum group A (XPA) protein, and the excision repair rate exhibit daily rhythmicity in mouse skin, with a minimum in the morning and a maximum in the afternoon/evening. In parallel with the rhythmicity of repair rate, we find that mice exposed to UV radiation (UVR) at 4:00 AM display a decreased latency and about a fivefold increased multiplicity of skin cancer (invasive squamous cell carcinoma) than mice exposed to UVR at 4:00 PM. We conclude that time of day of exposure to UVR is a contributing factor to its carcinogenicity in mice, and possibly in humans.circadian clock | cryptochrome | sunbathing | tanning salons S kin cancer is the most common form of cancer in the United States. With over 1.3 million new cases each year, it constitutes nearly 40% of all diagnosed cancers (1). Moreover, because of changes in lifestyle and the environment, the incidence of skin cancer is steadily increasing (2). The main causative agent of skin cancer is the UV component of sunlight. UV radiation (UVR) produces two major lesions in DNA, the cyclobutane pyrimidine dimer (CPD) and the (6-4) photoproduct [(6-4) PP], both of which are mutagenic and carcinogenic in animal model systems and are thought to be the primary cause of skin cancer in humans (3-7).In mice and humans, nucleotide excision repair is the sole repair system for removing CPDs and (6-4) PPs from DNA. As a consequence, humans with hereditary mutations in excision repair genes suffer from xeroderma pigmentosum, a syndrome characterized by a nearly 5,000-fold increase in skin cancer in sunlight-exposed areas of the afflicted individuals (8). Excision repair involves photoproduct removal by dual incisions bracketing the lesion, removal of the damage in the form of a 24-to 32-nt-long oligomer, filling in the resulting single-stranded gap, and sealing by ligase (9). The dual incision is carried out by six excision repair factors: RPA, xeroderma pigmentosum group A (XPA), XPC, TFIIH, XPG, and XPF-ERCC1 (10). Recently, in a study that analyzed liver and brain tissues from mice, it was found that XPA, a critical protein involved in damage recognition and a rate-limiting factor in excision repair, is controlled by the core molecular circadian clock (11, 12). As a consequence, excision repair activity exhibited circadian rhythmicity in these organs, increasing during the day to reach a maximum at 4-6:00 PM and decreasing during the night to a minimum at 4-6:00 AM.Here we analyzed the expression pattern of XPA and excision repair activity in mouse skin. We found that protein and repair activity exhibit a circadian rhythm similar to that found in the liver and brain. To determine whether this rhythmicity affected UV-induced skin cancer development we exposed a...

show abstract

“…It is known that C57BL/6 (haired) is resistant, whereas FVB (haired) and SKH-1 (hairless) are sensitive mouse strains to cutaneous chemical injury. 15 In addition, we developed a mouse model Ptch1 þ/À /SKH-1, which is highly sensitive to cutaneous inflammation, particularly induced by UVB. 12 Therefore, we used these mouse strains to evaluate their relative sensitivity to arsenicals.…”

Section: Screening For Murine Model Of Arsenicals-induced Cutaneous Imentioning

confidence: 99%

Molecular Mechanism Underlying Pathogenesis of Lewisite-Induced Cutaneous Blistering and Inflammation

Srivastavá

Weng

et al. 2016

The American Journal of Pathology

View full text Add to dashboard Cite

Lewisite is a potent arsenic-based chemical warfare agent known to induce painful cutaneous inflammation and blistering. Only a few modestly effective antidotes have so far been described in the literature. However, the discovery of effective antidotes for lewisite was hampered by the paucity of the exact molecular mechanism underlying its cutaneous pathogenesis. We investigated the molecular mechanism underlying lewisite-induced cutaneous blistering and inflammation and describe its novel antidotes. On the basis of our initial screening, we used a highly sensitive murine model that recapitulates the known human pathogenesis of arsenicals-induced cutaneous inflammation and blistering. Topically administered lewisite induced potent acute inflammation and microvesication in the skin of Ptch1 þ/À /SKH-1 mice. Even at a very low dose, lewisite up-regulates unfolded protein response signaling, inflammatory response, and apoptosis. These cutaneous lesions were associated with production of reactive oxygen species and extensive apoptosis of the epidermal keratinocytes. We confirmed that activation of reactive oxygen speciesedependent unfolded protein response signaling is the underlying molecular mechanism of skin damage. Similar alterations were noticed in lewisitetreated cultured human skin keratinocytes. We discovered that chemical chaperone 4ephenyl butyric acid and antioxidant N-acetylcysteine, which significantly attenuate lewisite-mediated skin injury, can serve as potent antidotes. These data reveal a novel molecular mechanism underlying the cutaneous pathogenesis of lewisite-induced lesions. We also identified novel potential therapeutic targets for lewisite-mediated cutaneous injury.

show abstract

The hairless mouse in skin research

Cited by 230 publications

References 84 publications

Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation

Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation

Control of skin cancer by the circadian rhythm

Molecular Mechanism Underlying Pathogenesis of Lewisite-Induced Cutaneous Blistering and Inflammation

Contact Info

Product

Resources

About