November 24, 2008

Stephen I. Katz, M.D., Ph.D., NIAMS
Carl C. Baker, M.D., Ph.D., NIAMS
David A. Norris, M.D., University of Colorado Health Sciences Center


The Skin Biology and Diseases programs at the NIAMS cover basic, translational, and clinical research in skin, including work on the developmental and molecular biology of skin, the study of skin as an immune organ, and autoimmune, inflammatory, and genetic diseases of skin.


Stem Cell and Hair Follicle Biology, and Regenerative Medicine

Advances in the formation of new hair follicles (neogenesis) have revealed that adult skin has more regenerative capacity than recognized previously. Lineage tracing of hair follicle bulge epithelial stem cells has allowed researchers to follow the fate of their progeny. Studies have also shown that hair follicle stem cells contribute to wound healing.

There is a need for understanding developmental processes and adult stem cells, for applications to regenerative medicine. Approaches will include epigenetics and the role of microRNAs, which will require sophisticated technologies, data management, and coordination of shared resources. Skin stem cells can be studied to understand their role in skin cancers and the role of microRNAs in development, differentiation, regeneration, and wound healing.

Chronic wounds, including diabetic and pressure ulcers, are enormous public health problems. Wound healing research would benefit from further understanding of skin stem cell biology.

There have been continued improvements in producing induced pluripotent stem (iPS) cells from easily accessible skin cells (dermal fibroblasts, cells from plucked hair follicles, keratinocytes). These cells may create opportunities for gene correction in diseases with single gene defects, and improved artificial skin for grafting. They are also seen as alternative pluripotent stem cells to embryonic stem (ES) cells, for developmental biology research and regenerative medicine.

Many researchers believe there is a continued need for ES cell research, because iPS cells may not be suitable substitutes for ES cells. Other stem cell populations (melanocytic, adipose, SKPs-dermis-derived progenitors) also need to be defined. Skin stem cells may enlighten understanding of signals and interactions between the different components of the dermis and epidermis, to generate hair follicles, sweat glands, and sebaceous glands. The dermis-derived SKP progenitor cells may be useful in therapeutic tissue repair (including neurons).

Epidermal and Developmental Biology

The recent identification of molecular defects that underlie the pathogenesis of atopic dermatitis and related disorders has provided better understanding of the role of epithelial barrier function defects in immunological diseases. Future work will include investigation of links with the development of asthma. Recent advances include insights into the role of signaling pathways (e.g., Wnt, sonic hedgehog homolog, Notch, and bone morphogenic proteins) and individual genes in skin and hair follicle development, homeostasis, and disease. These discoveries identify potential therapeutic targets for diseases such as skin cancers, which can be pursued further by investigators supported by the National Cancer Institute. In addition, recent information about the influence of ultraviolet light on pigment cell biology may contribute to better understanding of the mechanisms of damage to skin from ultraviolet light.

There is a call to continue investigation of fundamental structures and processes, to obtain a complete understanding of these pathways and their interactions, because of a rush to therapeutic development after initial identification of potentially pathogenic molecules. Improvements or redirection of these efforts have followed persistent basic research. Full understanding of these biological systems is key to "smart" therapeutic development.

The emergence of epigenetics research approaches will enable investigations in the effects of nutrition, environmental factors, and aging on skin. Research in non-melanoma skin cancer and other cancers will contribute to the understanding of stromal-epithelial interactions.

Immunobiology and Immune Diseases of the Skin

Several immune mechanisms of autoimmune skin diseases have been uncovered, including the role of helper T 17 (Th17) cells and the interleukin (IL)-6/IL-17/IL-23/IL-22 pathways in psoriasis. Recent clinical trials targeting these pathways with biologics have yielded long-lasting relief of symptoms. The success of a psoriasis clinical trial for targeting the p40 subunit shared between IL-12 and IL-23 (which was originally designed to block IL-12 activity, but was more effective in blocking IL-23 activity) demonstrates the utility of pursuing pathways rather than just target genes. Immune modulators and biological treatments are expected to receive continued attention in therapeutic development for skin diseases.

Findings on the role of anti-microbial peptides (AMPs) in skin homeostasis and disease have opened new roads to understanding psoriasis and atopic dermatitis, which are accompanied by increases and decreases, respectively, in AMPs. In that vein, there is new knowledge of the innate immune system's involvement in skin inflammatory diseases, particularly the inflammasome—a complex of proteins, intrinsic to the innate immune system's function, that drives a cascade of inflammatory cytokine activation. The role of the inflammasome and interaction of the innate and adaptive immune systems in skin diseases, such as psoriasis and psoriatic arthritis, are promising avenues for future research.

Genetics Research

Single gene defects have been identified for some skin diseases, and have generated targets for therapeutic development. These findings have also been instrumental in understanding developmental processes in skin.

Linkage association and genome-wide association studies (GWAS) have yielded important results for complex skin disorders, such as psoriasis and vitiligo, and have revealed genetic associations with other autoimmune diseases and comorbidities. They have uncovered single nucleotide polymorphisms (SNPs) that are shared between psoriasis and Crohn's disease, and demonstrated an increased risk for rheumatic diseases among family members of vitiligo patients.

The odds ratios for individual SNPs from GWAS are frequently quite small, and the collection of several gene variants appear to contribute to pathogenesis. Hence, researchers stress the need to catalogue as many human genetic defects as possible, to understand complex diseases. In addition, very large cohorts are needed for GWAS in order to see the subtle genetic differences across patients' entire genomes, relative to control populations without the disease. Assembling these sizeable study populations requires multi-institutional and, frequently, international collaborations.

Model Systems

In order to have value in biomedical research and therapeutic development, information from in vitro and genomic research must be evaluated in the complex context of living organisms. Animal models may be the most desirable in vivo experimental system, but finding suitable models for skin research has been challenging. Attempts to duplicate human wound healing in mice have been controversial; healing by contraction plays a role in mice, but not in humans. The transplantation of human skin to a mouse, or reconstituting the human immune system in a mouse, has not been very useful in studying psoriasis, but these approaches may be successful in investigating other diseases.

Complex diseases are unlikely to be recapitulated with transgenic animal models. Some polygenic diseases have emerged spontaneously in mice (e.g., alopecia areata and type 1 diabetes), and can be maintained in mouse colonies. Mouse models have also been useful in studying cutaneous carcinogenesis.

There are many opportunities to exploit systems biology. However, these approaches rely on raw data from multiple sources. To support the development of rigorous model systems, consensus on standards for collecting and reporting results from gene expression studies will be critical.

Multi-disciplinary Teams

Fruitful collaborations between skin researchers and engineers have capitalized on technology breakthroughs in areas such as imaging, to study skin structure, interactions of immune cells, and nanotechnology, which has driven biosensor development for field detection of environmental contaminants on skin. Conferences that bring together researchers from different fields have been instrumental in developing multidisciplinary collaborations, and will be needed for future research advances.

New disciplines, such as epigenetics research, will also require cross-cutting, cooperative research efforts, with a particular emphasis on managing large amounts of complex data. More bioinformatics experts, as well as broader education in biostatistics across basic, translational, and clinical research teams, will be critical as these fields move forward.

With recent successes in skin genetics and immunology, there are new opportunities in clinical and outcomes research, to pursue linkage studies in gene-environment interactions, as well as mechanistic studies that leverage investments in existing cohort studies. Many of these approaches will depend on access to patient data, well-defined phenotypes, and phenotype-linked samples that are gathered in registries and biorepositories from multiple sites. These team efforts will require biostatistical and study design support, and will provide essential clinician training in important aspects of complex trial management.

Preliminary studies have suggested that cardiovascular disease may be a comorbidity of psoriasis and rheumatoid arthritis. As mentioned earlier, genetic studies have found associations between inflammatory skin diseases and other autoimmune diseases. Further study will rely on combined efforts in immunology and epidemiology.

Models for Healthcare and Health Disparities Research

Skin diseases, which frequently create enormous quality-of-life issues, are not always seen as important research targets, relative to illnesses with greater morbidity, such as cancer and cardiovascular disease. However, the impact on patients' lives is significant, and some skin diseases are accompanied by systemic effects and comorbidities.

Health services are affected by access to care. Those seeking cosmetic dermatology services, which garner higher revenue for practitioners, are often given priority over patients seeking treatment for skin diseases or skin cancer screening. In addition, inadequate reimbursement creates barriers to clinical attention to some health problems (e.g., decubitus ulcers).

Rapid translation of research findings to the clinic is unique to skin research, because topical therapies can be tested with greater safety and control than systemic treatments. Similar advantages are seen in trials of skin grafting, in comparison with transplantation of other organs.

Applications of Skin Research to Broader Health Problems

A variety of skin cells have been highly accessible sources for recent advances in iPS cell research and development, and cultured skin substitutes are very instrumental for in vitro toxicology research.

Treatments for hyperpigmentation (melasma) and vitiligo have provided important information for the evaluation of preneoplastic lesions, and understanding the biological effects of ultraviolet radiation in basal and squamous cell carcinomas.

Because complex injuries, such as limb regeneration and trauma from military combat, all involve skin, important collaborations can be formed between skin investigators and the musculoskeletal and trauma research communities.

Non-NIH Participants

Associate Professor, Departments of Medicine and Biological Chemistry
School of Medicine
University of California, Irvine

BOYCE, Steven, Ph.D.
Professor, Department of Surgery
University of Cincinnati

CHREN, Mary-Margaret, M.D.
Professor in Residence, Department of Dermatology
University of California, San Francisco

Associate Professor, Departments of Molecular Dermatology, and Genetics and Development
Columbia University

COULOMBE, Pierre, Ph.D.
Professor, Biological Chemistry and Dermatology
The Johns Hopkins University School of Medicine

FALANGA, Vincent, M.D.
Professor, Departments of Dermatology and Biochemistry
Boston University School of Medicine
Chairman, Department of Dermatology and Skin Surgery
Roger Williams Medical Center

FISHER, David E., M.D., Ph.D.
Chief, Department of Dermatology
Director, Melanoma Program in Medical Oncology
Massachusetts General Hospital
Professor, Pediatric Hematology and Oncology
Harvard Medical School

Patient Advocate
San Rafael, California

MILLAR, Sarah, Ph.D.
Associate Professor, Departments of Dermatology and Cell and Developmental Biology
University of Pennsylvania School of Medicine

MODLIN, Robert, M.D.
Chief, Division of Dermatology
Professor, Department of Medicine
David Geffen School of Medicine
University of California, Los Angeles

NORRIS, David, M.D. (Co-Chair)
Chair, Department of Dermatology
University of Colorado Health Sciences Center

James H. Sterner Professor of Dermatology
Chair, Department of Dermatology
University of Rochester

POLSKY, David, M.D., Ph.D.
Assistant Professor, Departments of Dermatology and Pathology
Director, Pigmented Lesion Section
Langone Medical Center
New York University

SUNDBERG, John, D.V.M., Ph.D.
Professor, Experimental Dermatology and General Mouse Pathology
The Jackson Laboratory

YANCEY, Kim., M.D.
Professor, Department of Dermatology
University of Texas Southwestern Medical Center

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