Allele-specific genome editing using the CRISPR/Cas9 system phenocopies alopecia areata symptomatic patched hair loss in mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE100630 | GEO | 2020/12/31
REPOSITORIES: GEO
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Project description:Alopecia areata is an autoimmune disorder characterized by transient, non-scarring hair loss and preservation of the hair follicle. Hair loss can take many forms ranging from loss in well-defined patches to diffuse or total hair loss, which can affect all hair-bearing sites. Patchy alopecia areata affecting the scalp is the most common type. Alopecia areata affects nearly 2% of the general population at some point during their lifetime. Skin biopsies of affected skin show a lymphocytic infiltrate in and around the bulb or the lower part of the hair follicle in the anagen (hair growth) phase. A breakdown of immune privilege of the hair follicle is thought to be an important driver of alopecia areata. Genetic studies in patients and mouse models have shown that alopecia areata is a complex, polygenic disease. Several genetic susceptibility loci were identified to be associated with signalling pathways that are important to hair follicle cycling and development. Alopecia areata is usually diagnosed based on clinical manifestations, but dermoscopy and histopathology can be helpful. Alopecia areata is difficult to manage medically, but recent advances in understanding the molecular mechanisms have revealed new treatments and the possibility of remission in the near future.
| S-EPMC5573125 | biostudies-other
Project description: Not available
| S-EPMC3230136 | biostudies-literature
Project description:Alopecia areata (AA) is a common disease characterized by nonscarring hair loss. There are no satisfactory therapies for extensive cases. Systemic immune suppressants are usually used despite their nonspecific actions and often associated side effects. Apremilast is an oral, small-molecule, inhibitor of phosphodiesterase 4 approved for the treatment of psoriasis and psoriatic arthritis. Its use in AA has shown variable results. Whereas a recent reduced clinical trial concluded a lack of efficacity, several case reports demonstrate a significant improvement. We report four cases of extensive AA successfully treated with apremilast.
| S-EPMC6830030 | biostudies-literature
Project description:We are examining the genes that control initiation and progression of murine medulloblastomas that result from loss of patched. Approximately 25% of human medulloblastomas have mutations in patched or in other elements of the sonic hedgehog pathway. However, the cells from which these tumors originate (neural progenitors or stem cells), the cells that are responsible for tumor propagation (cancer stem cells), and the genes that are required for tumor progression are poorly understood. To address these questions, we have developed conditional patched knockout mice in which the gene is deleted in neural stem cells or progenitors. In addition, we have isolated a population of tumor-propagating cells from these tumors. By studying these models we will gain insight into the mechanisms of tumorigenesis and identify new targets for therapy. To identify the molecular mechanisms that underlie tumor initiation and propagation, we will compare gene expression in tumors resulting from loss of patched in neural stem cells vs. progentors, and in cancer stem cells vs. non-cancer stem cells. We hypothesize that medulloblastomas initiated in neural stem cells (using GFAP-Cre) are more aggressive than those initiated in neural progenitors (using Math1-Cre), and will express more genes associated with self-renewal. In addition, we hypothesize that cancer stem cells (CD15+ cells) from a given tumor will express higher levels of self-renewal genes than non-stem cells (CD15- cells) from the same tumor. Cells from 5 GFAP-Cre tumors, 5 Math1-Cre tumors, and 5 conventional patched-knockout tumors will be isolated using enzymatic digestion and Percoll gradient centrifugation. These procedures have been found to result in 85-95% pure tumor cell populations. In addition, 5 tumors will be FACS-sorted to isolate CD15+ and CD15- populations. RNA will be prepared from each of these samples using an RNeasy kit from Qiagen. Samples of 2 micrograms will be resuspended in 10 microliters of RNase-free water, and sent to the Consortium for labeling, hybridization and analysis. Cells from the three types of tumors, and CD15+ and CD15- cells, will be compared to one another.
2009-02-09 | GSE12430 | GEO
Project description:Our goal was to develop a transcriptomic description of affected alopecic scalp skin from patients with alopecia areata. 5 biological replicates of skin samples from 5 separate AA patients compared with 5 similar scalp samples from healthy control patients
2014-08-17 | E-GEOD-45512 | biostudies-arrayexpress
Project description:IntroductionIndividuals with alopecia areata (AA) may experience significant impacts on their health-related quality of life. The novel Alopecia Areata Patient Priority Outcomes (AAPPO) questionnaire has been developed to assess hair loss signs, emotional symptoms, and activity limitations associated with AA. The objective of this study was to evaluate psychometric properties and establish scoring of the AAPPO in adults and adolescents with AA.MethodsScoring and measurement properties of the AAPPO were examined using baseline and 2-week follow-up data from a prospective, noninterventional, web-based study of 121 patients with AA (85 adults aged ≥ 18 years, 36 adolescents aged 12-17 years) with Severity of Alopecia Tool (SALT) ≥ 25% scalp hair loss.ResultsExploratory and confirmatory factor analysis supported four single Hair Loss (HL) items, an Emotional Symptoms domain (ES; 4 items), and an Activity Limitations domain (AL; 3 items). Among all patients, the multi-item ES and AL domains had strong internal consistency (α ≥ 0.87); all HL items and domain scores had strong test-retest reliability (weighted kappa or intraclass correlation coefficients ≥ 0.78). All HL item scores demonstrated strong construct validity (r ≥ 0.52) compared with the patient-reported Alopecia Areata Symptom and Impact Scale (AASIS) hair loss subscale score; ES and AL domain scores exhibited strong construct validity (r ≥ 0.66) compared with the SF-36 Mental Component Summary (MCS) score. Using SALT scores, HL mean item scores were better (lower) in the 25-49% SALT subgroup versus those with highest SALT scores (76-100%); however, ES mean domain scores were better in the SALT 76-100% subgroup in the same comparison (p < 0.0001). Using AASIS and MCS score-created subgroups, ES and AL mean domain scores demonstrated hypothesized differences across subgroups (all p values < 0.0001).ConclusionThe AAPPO questionnaire is a reliable, valid disease-specific measure of hair loss severity and impact in individuals with AA.
| S-EPMC8776917 | biostudies-literature
Project description:The role of microbial dysbiosis in scalp disease has been recently hypothesized. However, little information is available with regards to the association between microbial population on the scalp and hair diseases related to hair growth. Here we investigated bacterial communities in healthy and Alopecia areata (AA) subjects. The analysis of bacterial distribution at the genus level highlighted an increase of Propionibacterium in AA subjects alongside a general decrease of Staphylococcus. Analysis of log Relative abundance of main bacterial species inhabiting the scalp showed a significant increase of Propionibacterium acnes in AA subjects compared to control ones. AA scalp condition is also associated with a significant decrease of Staphylococcus epidermidis relative abundance. No significant changes were found for Staphylococcus aureus. Therefore, data from sequencing profiling of the bacterial population strongly support a different microbial composition of the different area surrounded hair follicle from the epidermis to hypodermis, highlighting differences between normal and AA affected the scalp. Our results highlight, for the first time, the presence of a microbial shift on the scalp of patients suffering from AA and gives the basis for a larger and more complete study of microbial population involvement in hair disorders.
| S-EPMC6459526 | biostudies-literature
Project description:Alopecia areata (AA) is an immune-mediated disease in which autoantigens play an important part in activating T-lymphocytes. Vitamin D has been associated with various autoimmune diseases, and Vitamin D receptors are strongly expressed in hair follicles and their expression in keratinocytes is necessary for the maintenance of the normal hair cycle.The aim of this study was to find the association between Vitamin D level and AA.This was a hospital-based cross-sectional study in which 50 patients with clinically and trichoscopically diagnosed AA cases, and 35 healthy age- and sex-matched controls were studied in summer months. Blood samples were taken from both cases as well as controls and samples were immediately processed by centrifugation (4000 rpm) at room temperature. Plasma 25-hydroxyvitamin D (25(OH)D) was analyzed by chemiluminescence method. A deficiency in Vitamin D was defined as serum 25(OH)D concentrations <30 ng/ml.The mean body mass index in cases was 20.96 ± 1.91, whereas in controls, it was 21.37 ± 1.70 (P = 0.31). The mean serum 25(OH)D levels of AA patients was 16.6 ± 5.9 ng/ml, whereas in control group, the mean level was 40.5 ± 5.7, the difference being statistically significant (P < 0.001). A significant negative correlation was found between severity of alopecia tool score and Vitamin D level (P < 0.001; r = -0.730) and also between the number of patches and Vitamin D level (P < 0.001, r = -0.670).In our study, we found that the levels of 25(OH)D were low in AA patients when compared to healthy controls. Furthermore, there was a significant negative correlation between the levels of serum Vitamin D and severity of AA. Thus, the study suggests the role of Vitamin D in pathogenesis of AA and hence a possible role of Vitamin D supplementation in treatment of same.Our study was limited by the lesser number of patients and lack of therapeutic trial of Vitamin D for these patients.
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Project description:The advancement of genetic and preclinical studies has uncovered the mechanisms involved in the pathogenesis of alopecia areata (AA). The development of targeted therapies using small molecules blocking specific pathways for the treatment of AA is underway. By repurposing Food and Drug Administration-approved small molecule JAK inhibitors as treatments for AA, it has been demonstrated that JAK inhibitors can effectively reverse hair loss in patients with moderate to severe AA. In this review, we summarize and discuss the current preclinical and clinical studies on JAK inhibitors, as well as the prospects of using JAK inhibitors for the treatment of AA.
| S-EPMC6475885 | biostudies-literature
Project description:Alopecia areata is an autoimmune hair loss disorder with an incompletely understood etiology. Although trace elements, serum metabolites, and inflammatory factors are implicated in the disease, the potential causal relationships between these factors and alopecia areata require further investigation. This study employed Mendelian randomization (MR), utilizing data from genome-wide association studies, to explore the causal relationships between 15 trace elements, 1400 serum metabolites, and 91 inflammatory factors and alopecia areata. The analysis was conducted using the inverse variance weighted (IVW) method complemented by various sensitivity analyses, including Cochran's Q test, MR-Egger regression intercept test, MR-PRESSO global test, and leave-one-out analysis, to assess the robustness of the results. MR analysis indicated a negative correlation between copper levels and the risk of developing alopecia areata (odds ratio = 0.86, 95% confidence interval: 0.75-0.99, p = 0.041). Additionally, causal relationships were identified between 15 serum metabolites and 6 inflammatory factors and the risk of alopecia areata (IVW, all p values < 0.05). This study provides genetic evidence of the relationships between trace elements, serum metabolites, and alopecia areata, underscoring the potential value of targeted therapeutic strategies and preventive measures. Future research should expand to diverse populations and further explore the specific roles of these biomarkers in the disease mechanism.
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