NEBRASKA MELANOMA CENTER ®: Midwestern Values Nebraska Focused

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NEBRASKA MELANOMA CENTER ® intends to be in the forefront in transferring new information regarding the evaluation and treatment of skin diseases for Nebraskans. There are many ongoing national research opportunities and efforts to understand fundamental skin biology as well as the pathogenesis of skin disorders and diseases. The following subjects are being actively pursued in the USA. As applied technologies, preventive and interventional therapeutics become available to patients in Nebraska, NEBRASKA MELANOMA CENTER ® will update this website.

Molecular Genetics of Rare and Common Skin Diseases

Within this area, the research has been very successful in identifying the genes responsible for single gene based skin diseases such as the epidermolysis bullosa group of diseases as well as some of the ichthyoses. Some broad areas of recommended research directions include:Continuing the cataloguing of specific gene defects and determining exactly how these defects are translated into the clinical appearance of the various diseases. This genotype-phenotype correlation is important not only in understanding and predicting the severity of disease, but also in opening possible new avenues to amelioration of the effects of the disease;

Continuing the development of skin gene therapy using in vivo and ex vivo approaches; and Uncovering the genetic basis of diseases such as vitiligo, psoriasis, alopecia areata, and other diseases, through population or family based molecular genetic studies.

Molecular Biology of Skin and its Appendages

Within this area are the basic studies of the molecules that make up the skin and its cells, how they are assembled into the structures that we see under the light and electron microscope, how skin cells interact with one another via cell to cell signaling and attachment, how the skin protects itself from the external environment and how that protection can be breached in a controlled manner to apply drugs to treat skin and systemic diseases.

Some broad areas of recommended research directions include: Conducting stem cell research in skin as a precursor to gene therapy approaches; Conducting studies of skin blood vessel cells and angiogenesis;

Conducting basic studies of skin appendages, including the hair follicle, which is of interest both for itself and as a model system for cycling cells and structures and for developmental and cell signaling pathways; and

Fostering basic wound healing research, including research into the control of cell maturation and differentiation, which includes changes that underlie disruption of this normal process and result in malignancy.

Inflammatory and Immune Skin Diseases and the Skin as an Immune Organ

Many skin diseases have an autoimmune basis, some of them specific to the skin as the primary or exclusive end organ being attacked. Many other skin diseases are inflammatory without being autoimmune.

Some broad areas of recommended research directions include: Conducting research to understand the process of autoimmunity in general and the end organ specific autoimmune diseases of skin in particular, including pemphigus, pemphigoid, psoriasis, lupus erythematosus, alopecia areata, vitiligo, and others;

Performing research into the mechanisms of inflammation and how to control it, since this is a key to treating these diseases; Exploring how to better treat skin infections since the response to infection is basically via the inflammatory mechanisms, and also because some infections may trigger autoimmune responses or dysregulated inflammatory responses (psoriasis may be initiated by these mechanisms);

Studying the skin as an active immune organ, with a focus on immunocompetent cells that are both resident within skin and trafficking through skin. This is important in the study of many diseases, the most frequent being irritant and allergic contact dermatitis (poison ivy and others, often occupationally related) and HIV; Developing new drugs and devices to treat inflammatory and immunological as well as other skin diseases; and Investigating the role of the immune system in the initiation, development, and treatment of skin cancer.

Outcomes Research and Clinical Trials

Outcomes research has been hampered by the relative lack of agreed upon measures of disease severity for most skin diseases, and the lack of agreement among researchers even in those few diseases where specific severity measures exist. There is also a relative paucity of fully trained clinical researchers in the field. Thus, the needs are many, and need to be addressed at several levels. Some broad areas of recommended research directions include: Expanding the base of well trained and supported clinical researchers and clinical trials experts in medicine via an increased emphasis on epidemiology and clinical trial design in residency as well as research training programs; Nurturing new researchers to work in this area as well as supporting the few role models/mentors in the field and using related expertise in schools of public health and elsewhere to supplement those in medicine; and Developing new instruments to provide uniformity to the description of disease severity, both disease specific and globally for the impact of skin disease on the individual.

Translational Research

There have been numerous advances in our basic understanding of the normal structure and function of skin and the abnormalities that result in disease. Often, these approaches are technology driven and efforts in this area need to be fostered. Some broad areas of recommended research directions include:

Placing greater emphasis on technology-driven research, as it has the potential to directly affect the health and welfare of the population. The application of gene chip and microarray development and application to skin disease is but the newest of these technologies; Determining the gene or genes underlying a disease as the first step in understanding and treating it; and Studying gene translation and expression, as well as pathophysiologic studies of how the abnormal gene product results in the disease state.

Percutaneous Penetration and Absorption

A major function of the skin is to prevent water loss from the inside and penetration of chemicals from the outside. It is not completely clear, however, how this function is accomplished. Some broad areas of recommended research directions include: Research into increasing the understanding of how the skin acts as a barrier; and

Developing skin disease treatments, as well as topical or skin-based treatments of systemic disease. In the past, this has simply been the use of patches to deliver the few pharmaceuticals that structurally could easily penetrate the skin (for example, scopalamine for motion sickness and nicotine patches). However, we are now on the verge of developing techniques that allow charged molecules (which the skin resists more strongly) to bypass the barrier. This opens a much larger realm of potential pharmaceuticals that could be active via this route.

Aging Skin

The population in the United States is aging. The consequences of aging on skin occurs as a result of not only chronologic effects but probably more from accumulated environmental damage, much of it from ultraviolet radiation (UV) radiation from the sun (and artificial sources for those who frequent tanning salons). These effects are both in the: (1) epidermis, which discolors, dries out (thus changing its resistance to chemical penetration), and develops skin cancers, precancers, and benign tumors; and (2) dermis which loses adnexal structures (hair, sebaceous and sweat glands), thins, and becomes fragile.

Some broad areas of recommended research directions include: Developing interventions that reverse, not just delay, the adverse changes that occur in aging skin; and Increasing research into prevention. Since most of the adverse effects due to aging are from UV, behavioral modification research will be necessary to maximize realistic UV avoidance and protective behaviors, particularly during the teenage years of life.

Developmental Biology of Skin

The study of embryologic events in the development of skin and its appendages has been greatly facilitated by the understanding of basic signaling molecules and events as the skin and its appendages develop. Naturally occurring and inbred animal models have been invaluable in this area and will continue to be studied. Transgenic technology has been applied to these studies. This allows the molecules of interest to be selectively deleted (knock out models) or over expressed either generally or in selected tissues (knock in models). The effects of these molecules on skin development can thereby be studied in more detail and more mechanistically. Some broad areas of recommended research directions include: Continuing research into the finding that some apparently critical molecules have no effect when deleted because of back up or alternative pathways, whereas other molecules are unexpectedly lethal when deleted;

Elucidating the finding that molecules thought to act in one organ system have completely unexpected effects when deleted or over expressed in the skin. One example is an internal cell signaling molecule that, when over expressed in skin, initiates hair development that would not otherwise take place in that skin. The hair is disorganized and tumors later develop, but these findings point the way to the potential of this methodology to bring an understanding of these pathways, and the use of these findings to effect clinically relevant outcomes when applied to adults as well as embryologically; and Taking an active role in both monitoring research using gene technology and developing safeguards for its ethical application.

Wound Healing

The inability of chronic wounds to heal is a major health problem in the United States, and will increase in magnitude as the population ages. Various aspects of this problem are within the mission of several NIH Institutes; thus, the NIAMS-led Skin Diseases Interagency Coordinating Committee (SDICC) has taken the lead in organizing research in this area. The SDICC has worked in cooperation with other Federal agencies, particularly the FDA, and with relevant outside organizations, most recently the Wound Healing Society and the Wound, Ostotomy and Continence Nurses Association. There have been a number of meetings on the topic, and several mechanisms used to stimulate research in the area. Most recently, a consensus development conference was held by the two private groups cited above to review the state of the science, based on evidence in the literature, on the standard approaches used in the treatment of the four most common prototypic chronic wounds: stasis ulcers, arterial ulcers, diabetic ulcers, and decubitus ulcers. Some broad areas of recommended research directions include: Coordinating future research by the SDICC and FDA focusing particularly on the clinical aspects of wound healing with the hope of facilitating drug and other intervention development by establishing acceptable control arms for studies of new agents; Studying growth factors in normal wound healing; Developing more effective wound coverings, including methods to keep the wound moist and the use of artificial bioengineered skin replacements; and Conducting research of the combined use of growth factors and bioengineered artificial skin with gene therapy approaches to develop wound coverings that are genetically manipulated to produce growth factors in a sequence more similar to that in the normal state.

Gene Therapy Using Skin

Gene therapy is an area of great promise. The skin is unique in its accessibility for gene therapy approaches, both for skin diseases and for the use of the skin as a factory for the production of molecules in the treatment of systemic diseases including, but not limited to, hormones such as insulin and human growth hormone. Among the advantages of skin is the ability to remove the genetically altered skin by simple excision if problems develop.Some broad areas of recommended research directions include: Development of gene therapy based interventions. While several avenues of approach are in the last stages of testing prior to human testing, problems remain before this can be a widely used approach; and Increase the level of interest in the field of gene therapy using skin.

Bioengineering of Skin

The development of artificial skin, originally from simple keratinocyte sheets, but more recently in the form of a multicomponent material including an artificial dermis, is a rapidly advancing applied field with application to numerous areas of research, including treatment of burn wounds, chronic wounds, and as the basis for gene therapy interventions. Much of this is applied research and may be supported by the pharmaceutical and biotechnology industries, but much of it is at or near the cutting edge of basic research, not only in genetic manipulations of the skin, but also in the development of artificial matrices to support the cellular components. Some broad areas of recommended research directions include: Encouraging bioengineering approaches to the study and treatment of skin diseases;

Developing hybrid models to study diseases in which no good model systems exist. This is not meant to refer to genetically altered mouse models (discussed elsewhere as it represents a major area of new work expected in the future), but to bioengineered artificial constructs in which diseased human skin is transplanted to an animal host modified to accept the foreign tissue. In a number of skin diseases in which no other good model exists, most notably psoriasis, this opens a new avenue for pursuing hypothesis-driven research on the disease. It also provides a means for studying potential interventions in treatment or gene therapy based modifications of the disease; and Conducting research using normal appearing skin from genetically susceptible people in order to study trigger factors for disease expression or the mechanisms involved in disease development, progression, and involution.

Stem Cells of Skin and Skin Appendages

Skin stem cells include those necessary for the continued repopulation of the skin itself as well as those related to skin appendages, hair, nails, and eccrine and apocrine glands. Some broad areas of recommended research directions include: Facilitating research into stem cell biology since it is relevant to gene therapy (sustained gene therapy requires the targeting of stem cells), hair biology research (hair cycling studies and study of many hair diseases requires the identification of hair stem cells), and other genetic skin diseases; and Conducting research into additional ways that stem cells can be identified and cultured. Stem Cells and Melanoma

NEBRASKA MELANOMA CENTER ® is a public-private effort in healthcare services related to educating Nebraskans about proper skin care as well as the prevention, diagnosis and treatment of skin conditions, especially benign skin growths and skin cancers.

NEBRASKA MELANOMA CENTER ® has a growing network of talented licensed healthcare professionals who deliver coordinated, high quality, cost effective skin cancer diagnosis and treatment across the State of Nebraska as well as healthy skin and skin cancer prevention programs. These professionals include primary healthcare providers, dermatopathologists, pathologists, surgeons, medical oncologists, and radiation therapists.

If you undergo a skin biopsy, the skin specimen may be sent to NEBRASKA MELANOMA CENTER ® and its affiliate, Pathology Services, P.C. for processing, evaluation, diagnosis, and inclusion in its database. Having your skin biopsy specimen(s) sent to Pathology Services, PC. is not required to avail yourself of the resources of NEBRASKA MELANOMA CENTER ®. If your healthcare provider sends your skin biopsy specimen elsewhere, NEBRASKA MELANOMA CENTER ® would appreciate a copy of your pathology report to include its diagnosis in its Nebraska cancer registry.

Nebraskans may contact Healthy Nebraska, Inc. to request additional information about skin care and skin diseases as well as obtain an appointment for skin cancer screening by licensed healthcare professionals in our NEBRASKA MELANOMA CENTER ® network in Nebraska.

For more information, contact

NEBRASKA MELANOMA CENTER ®: Midwestern Values Nebraska Focused

NEBRASKA MELANOMA CENTER ® is a service mark of Pathology Services, P.C.

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611 West Francis Street
North Platte, Nebraska 69101

Byron L. Barksdale, M.D.
Phone: 308-532-4700

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