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Papers by David Norris

Journal of Investigative Dermatology, 2016

Journal of Investigative Dermatology Symposium Proceedings, 2001

Skin infections with Staphylococcus aureus are not only an important cause of morbidity and even ... more Skin infections with Staphylococcus aureus are not only an important cause of morbidity and even mortality, but are thought to serve as initiation and/or persistance factors for numerous in¯ammatory skin diseases, including psoriasis and atopic dermatitis. One mechanism by which S. aureus can modulate the immune system is through the production of proteins such as superantigenic toxins, Protein A, as well through the cytolytic a-toxin. This review serves to discuss the biology of these three types of proteins, with emphasis on their ability to stimulate the production of powerful pro-in¯ammatory lipidand protein-derived cytokines in keratinocytes. Characterization of interactions between these proteins and the keratinocyte can provide a better understanding of how bacterial infection modulates in¯ammatory skin diseases, as well as provide the basis for improved therapies involving antibacterial agents.

The journal of investigative dermatology. Symposium proceedings / the Society for Investigative Dermatology, Inc. [and] European Society for Dermatological Research, 2013

Pharmaceuticals

Although treatment options for melanoma patients have expanded in recent years with the approval ... more Although treatment options for melanoma patients have expanded in recent years with the approval of immunotherapy and targeted therapy, there is still an unmet need for new treatment options for patients that are ineligible for, or resistant to these therapies. BH3 mimetics, drugs that mimic the activity of pro-apoptotic BCL2 family proteins, have recently achieved remarkable success in the clinical setting. The combination of BH3 mimetic ABT-199 (venetoclax) plus azacitidine has shown substantial benefit in treating acute myelogenous leukemia. We evaluated the efficacy of various combinations of BH3 mimetic + azacitidine in fourteen human melanoma cell lines from cutaneous, mucosal, acral and uveal subtypes. Using a combination of cell viability assay, BCL2 family knockdown cell lines, live cell imaging, and sphere formation assay, we found that combining inhibition of MCL1, an anti-apoptotic BCL2 protein, with azacitidine had substantial pro-apoptotic effects in multiple melanoma ...

Pharmaceuticals, 2021

Pediatric Dermatology

Alopecia areata (AA) is characterized by the loss of hair, often in well‐demarcated areas. While ... more Alopecia areata (AA) is characterized by the loss of hair, often in well‐demarcated areas. While the pathogenesis of AA is not entirely understood, it is known that CD8 T cell‐mediated destruction of the hair follicle occurs. There are no curative therapies for AA, although several therapies have been utilized with variable results. Oral tofacitinib, a JAK inhibitor, has been demonstrated to be efficacious and well tolerated in the treatment of adult AA. However, few studies have examined the clinical efficacy and tolerability of oral tofacitinib in the treatment of pediatric AA.

Cancers

There is an urgent need to develop treatments for patients with melanoma who are refractory to or... more There is an urgent need to develop treatments for patients with melanoma who are refractory to or ineligible for immune checkpoint blockade, including patients who lack BRAF-V600E/K mutations. This is often the case in patients diagnosed with rare melanoma subtypes such as mucosal and acral melanoma. Here, we analyzed data from the cutaneous melanoma The Cancer Genome Atlas Network (TCGA) transcriptomic and proteomic databases for differential expression of apoptosis molecules between melanomas with or without BRAF hotspot mutations. Our data indicated higher B-cell CLL/lymphoma 2 (BCL2) expression in melanoma without BRAF hotspot mutations, suggesting that BH3 mimetics, such as ABT-199 (venetoclax, a small molecule against BCL2), may be a potential therapeutic option for these patients. We explored the efficacy of combining two BH3 mimetics, ABT-199 and a myeloid cell leukemia sequence 1 (MCL1) inhibitor (S63845 or S64315/MIK665) in cutaneous, mucosal and acral melanomas, in vitro ...

Journal of Investigative Dermatology

Psoriasis is a chronic immune-mediated disease characterized by excessive proliferation of epider... more Psoriasis is a chronic immune-mediated disease characterized by excessive proliferation of epidermal keratinocytes and increased immune cell infiltration to the skin. Although it is well known that psoriasis pathogenesis is driven by aberrant production of proinflammatory cytokines, the mechanisms underlying the imbalance between proinflammatory and anti-inflammatory cytokine expression are incompletely understood. Here we report that the transcriptional coregulators C-terminal-binding protein (CtBP) 1 and 2 can transactivate a common set of proinflammatory genes both in the skin of imiquimod-induced mouse psoriasis model and in human keratinocytes and macrophages stimulated by imiquimod. We find that mice overexpressing CtBP1 in epidermal keratinocytes display severe skin inflammation phenotypes with increased expression of Th1 and Th17 cytokines. We also find that the expression of CtBPs and CtBP target genes is elevated both in human psoriatic lesions and in the mouse imiquimod psoriasis model. Moreover, we were able to demonstrate that topical treatment with a peptidic inhibitor of CtBP effectively suppresses the CtBP-regulated proinflammatory gene expression and thus attenuates psoriatic inflammation in the imiquimod mouse model. Together, our findings suggest new strategies for therapeutic modulation of the immune response in inflammatory skin diseases.

Chonnam Medical Journal

Psoriasis is a chronic, recurrent, heterogeneous, cutaneous inflammatory skin disease for which t... more Psoriasis is a chronic, recurrent, heterogeneous, cutaneous inflammatory skin disease for which there is no cure. It affects approximately 7.5 million people in the United States. Currently, several biologic agents that target different molecules implicated in the pathogenic processes of psoriasis are being assessed in diverse clinical studies. However, relapse usually occurs within weeks or months, meaning there is currently no cure for psoriasis. Therefore, recent studies have discovered diverse new potential treatments for psoriasis: inhibitors of bacteria such as Staphylococcus aureus, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and neuropilin 1 (NRP1). A promising approach that has recently been described involves modifying antimicrobial peptides to develop new cutaneous anti-bacterial agents that target inflammatory skin disease induced by Staphylococcus. Increased expression of TRAIL and its death receptors DR4 and DR5 has been implicated in the pathogenesis of plaque psoriasis. In addition, TRAIL has the ability to inhibit angiogenesis by inducing endothelial cell death and by negative regulation of VEGF-induced angiogenesis via caspase-8-mediated enzymatic and non-enzymatic functions. Since NRP1 regulates angiogenesis induced by multiple signals, including VEGF, ECM and semaphorins, and also initiates proliferation of keratinocytes through NF-B signaling pathway in involved psoriatic skin, targeting NRP1 pathways may offer numerous windows for intervention in psoriasis. In this review, we will focus on the current knowledge about the emerging role of synthetic antimicrobial peptides, TRAIL and NRP1 blocking peptides in the pathogenesis and treatment of psoriasis.

Journal of Investigative Dermatology Symposium Proceedings

In this perspective, we identify emerging frontiers in clinical and basic research of melanocyte ... more In this perspective, we identify emerging frontiers in clinical and basic research of melanocyte biology and its associated biomedical disciplines. We describe challenges and opportunities in clinical and basic research of normal and diseased melanocytes that impact current approaches to research in melanoma and the dermatological sciences. We focus on four themes: (1) clinical melanoma research, (2) basic melanoma research, (3) clinical dermatology, and (4) basic pigment cell research, with the goal of outlining current highlights, challenges, and frontiers associated with pigmentation and melanocyte biology.

Cell death & disease, Jan 5, 2018

Despite the recent advancement in treating melanoma, options are still limited for patients witho... more Despite the recent advancement in treating melanoma, options are still limited for patients without BRAF mutations or in relapse from current treatments. BH3 mimetics against members of the BCL-2 family have gained excitement with the recent success in hematological malignancies. However, single drug BH3 mimetic therapy in melanoma has limited effectiveness due to escape by the anti-apoptotic protein MCL-1 and/or survival of melanoma-initiating cells (MICs). We tested the efficacy of the BH3 mimetic combination of A-1210477 (an MCL-1 inhibitor) and ABT-263 (a BCL-2/BCL-XL/BCL-W inhibitor) in killing melanoma, especially MICs. We also sought to better define Dynamin-Related Protein 1 (DRP-1)'s role in melanoma; DRP-1 is known to interact with members of the BCL-2 family and is a possible therapeutic target for melanoma treatment. We used multiple assays (cell viability, apoptosis, bright field, immunoblot, and sphere formation), as well as the CRISPR/Cas9 genome-editing technique...

Journal of the American Academy of Dermatology, Apr 1, 2018

International Journal of Biological Sciences

Carboxyl-terminal binding protein 1 (CtBP1) is a transcriptional co-repressor that represses expr... more Carboxyl-terminal binding protein 1 (CtBP1) is a transcriptional co-repressor that represses expression of various tumor suppressor genes. In the present study, we identified miR-137 as a potential regulator of CtBP1 expression in melanoma cells. Expression of miR-137 in melanoma cell lines was found to inversely correlate with CtBP1 levels. Target Scan predicted a putative site for miR-137 within the CtBP1 3′ untranslated region (3′UTR) at nt 710-716, which is highly conserved across species. To explore the mechanism of miR-137 targeting CtBP1, we performed an Argonaute 2 (Ago2)-pull down assay, and miR-137 was identified in complex with CtBP1 mRNA. miR-137 suppressed CtBP1 3' UTR luciferase-reporter activity, and this effect was lost with deletion of the putative 3' UTR target-site. Consistent with the results of the reporter assay, ectopic expression of miR-137 reduced expression levels of CtBP1. Furthermore, expression of miR-137 increased the immediate downstream effectors of CtBP1, such as E-cadherin and Bax. The human miR-137 gene is located at chromosome 1p22, which has previously been determined to be a susceptive region for melanoma. This study suggests miR-137 may act as a tumor suppressor by directly targeting CtBP1 to inhibit epithelial-mesenchymal transition (EMT) and inducing apoptosis of melanoma cells, thus illustrating a functional link between miR-137 and CtBP1 in melanoma development.

The Journal of investigative dermatology, Jan 17, 2017

Vitiligo repigmentation is a complex process in which the melanocyte-depleted interfollicular epi... more Vitiligo repigmentation is a complex process in which the melanocyte-depleted interfollicular epidermis (IE) is repopulated by melanocyte precursors from hair follicle (HF) bulge that proliferate, migrate, and differentiate into mature melanocytes on their way to the epidermis. The strongest stimulus for vitiligo repigmentation is narrow band UVB (NBUVB), but how the HF melanocyte precursors are activated by UV light has not been extensively studied. To better understand this process, we developed an application that combined laser capture microdissection and subsequent whole transcriptome RNA sequencing of HF bulge melanocyte precursors, and compared their gene signature to that of regenerated mature epidermal melanocytes from the NBUVB-treated vitiligo skin. Using this strategy, we found upregulation of Tenascin C (TNC), Gap junction beta-6 protein (GJB6) and Thrombospondin 1 (THBS1) in the HF bulge melanocytes and of Tyrosinase (TYR) in the epidermal melanocytes of the NBUVB-trea...

Dermatologic Clinics, 2017

Repigmentation in vitiligo is the process that replaces, in the epidermal basal layer of vitiligo... more Repigmentation in vitiligo is the process that replaces, in the epidermal basal layer of vitiligo skin, the mature melanocytes that have been killed by cytotoxic T cells specific for melanocyte antigens. It consists of mobilization of melanocyte precursors in the hair follicle bulge and infundibulum to proliferate, migrate, and differentiate into mature melanocytes, moving from the hair follicle bulge to the interfollicular epidermis. The most common clinical presentation of repigmentation in vitiligo is the perifollicular pattern. The most potent stimulus for repigmentation is the UV light.

Experimental dermatology, Oct 19, 2016

In order to characterize the gene expression profile of regenerated melanocytes in the narrow ban... more In order to characterize the gene expression profile of regenerated melanocytes in the narrow band UVB (NBUVB)-treated vitiligo epidermis and their precursors in the hair follicle, we present here a strategy of RNA isolation from in situ melanocytes using human frozen skin. We developed a rapid immunostaining protocol using the NKI-beteb antibody which labels differentiated and precursor melanocytes, followed by fluorescent laser capture microdissection. This technique enabled the direct isolation, from melanocyte and adjacent keratinocyte populations, of satisfactory quality RNA that was successfully amplified and analyzed by qRT-PCR. The melanocyte-specific gene transcripts TYR, DCT, TYRP1, and PMEL were significantly upregulated in our NBUVB-treated melanocyte samples as compared with the keratinocyte samples, while keratinocyte-specific genes (KRT5 and KRT14) were expressed significantly higher in the keratinocyte samples as compared with the melanocyte samples. Furthermore, in ...

EBioMedicine, 2016

Alopecia areata (AA) is an autoimmune disease typified by nonscarring hair loss with a variable c... more Alopecia areata (AA) is an autoimmune disease typified by nonscarring hair loss with a variable clinical course. In this study, we conducted whole genome gene expression analysis of 96 human scalp skin biopsy specimens from AA or normal control subjects. Based on gene expression profiling, samples formed distinct clusters based on the presence or absence of disease as well as disease phenotype (patchy disease compared with alopecia totalis or universalis). Differential gene expression analysis allowed us to robustly demonstrate graded immune activity in samples of increasing phenotypic severity and generate a quantitative gene expression scoring system that classified samples based on interferon and cytotoxic T lymphocyte immune signatures critical for disease pathogenesis.

The journal of investigative dermatology. Symposium proceedings / the Society for Investigative Dermatology, Inc. [and] European Society for Dermatological Research, 2015

Alopecia areata is a common autoimmune skin disease resulting in the loss of hair on the scalp an... more Alopecia areata is a common autoimmune skin disease resulting in the loss of hair on the scalp and elsewhere on the body that affects over 146 million people worldwide at some point in their lives. Founded in 1981, the National Alopecia Areata Foundation (NAAF) is a nonprofit organization that supports research to find a cure or acceptable treatment for alopecia areata, supports those with the disease, and educates the public about alopecia areata. NAAF conducts research summits every 2 years that are central to achieving the goals of a major strategic initiative, the Alopecia Areata Treatment Development Program, which are: to accelerate progress toward a safe, effective, affordable treatment or a cure for alopecia areata. These summits have played a key role in transforming the understanding of alopecia areata from largely inflammatory and dermatological perspectives to a focus on the genetic and immunological factors that are now recognized as driving and active determinants of t...