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Pathogenesis Of Human Papillomaviruses And Novel Therapeutic Approaches
Program Director: Elliot J. Androphy, MD
Research focuses on the study of human papillomaviruses (HPV), a family of viruses that causes genital warts, cervical and other lower genital tract cancers, and a subset of head and neck cancers. The research is designed to understand viral gene expression and replication, induction of oncogenic transformation by viral gene products, and to develop novel strategies for medical treatment of these infections.
Atopic DermatitisProgram Director: Matthew J Turner, MD, PhD
This laboratory studies mechanisms of skin inflammation in atopic dermatitis and other dermatologic diseases. The objective of this work is to identify novel biomarkers and therapeutic targets that can be translated into improved diagnostic tools and treatments for patients with atopic dermatitis and other inflammatory diseases.
Atopic dermatitis (AD) is one of the most common inflammatory diseases known to man, with up to 20 percent of children and millions of adults being affected. This disease manifests as an intensely itchy skin rash that can sometimes be so severe that it covers the entire body surface. Itching in patients with AD commonly interferes with sleep and impairs quality of life. Patients commonly have concurrent asthma and other allergic diseases and frequently develop secondary bacterial and viral skin infections, further complicating care.
The Turner laboratory uses T cell dependent and T cell independent mouse models of the disease as well as patient samples to understand the pathogenic mechanisms of AD. Current projects in the lab include: 1) Investigating the functional effects of the cytokine interleukin 33 (IL-33) on T cells and keratinocytes to help understand if and how IL-33 contributes to AD pathogenesis; 2) Defining the requirement for basophils in AD lesion formation and persistence in a T cell dependent (i.e. Stat6VT) mouse model of AD; 3) Identifying novel biomarkers of AD using laser capture microdissection and RNA sequencing to analyze healthy and diseased skin from patients.
Influence Of The Insulin-like Growth Factor-1 Receptor (IGF-1R) On UVB-Induced CarcinogenesisProgram Director: Dan Spandau, PhD
The primary environmental factor that influences the development of skin cancer is exposure to the spectrum of ultraviolet wavelengths (particularly UVB) found in sunlight. In vitro evidence and epidemiological data from The Spandau Lab have indicated that one mechanism responsible for UVB-induced skin cancer involves the suppression of the IGF-1R signaling network in epidermal keratinocytes. Furthermore, there is a strong correlation between developing skin cancer and increasing age, as 80 percent of all non-melanoma skin cancers (NMSCs) are found in people over the age of 60. Dr. Spandau’s lab has identified that aging-associated squamous cell carcinoma is due in part to the accumulation of aging, senescent fibroblasts in the skin of geriatric patients. These senescent fibroblasts silence the expression of IGF-1 in the skin which in turn leads to a deficient activation of the IGF-1R on keratinocytes, increasing their sensitivity to photocarcinogenesis.
Fortunately, this newly identified mechanism has also generated potential new therapies to aid individuals that are highly susceptible to skin cancer by targeting senescent dermal fibroblasts. Treatment modalities which remove senescent fibroblasts and recruit new fibroblasts thereby normalizing the secretion of IGF-1 could potentially prevent the initiation of UVB-induced carcinogenesis caused by ongoing sun exposure. Taking advantage of routinely used cosmetic therapies, the research demonstrated that these wounding therapies could increase IGF-1 expression and restore the appropriate UVB response in geriatric individuals. This team of investigators is currently actively exploring the mechanism for IGF-1 silencing in geriatric fibroblasts and refining the wounding therapies so that they can be widely used as treatment to prevent squamous cell carcinoma in geriatric individuals.
Spinal Muscular Atrophy Pathogenesis Of A Motor Neuron Disease And TreatmentProgram Director: Elliot J. Androphy, MD
The Androphy Lab characterized the mechanism of alternative splicing of the SMN2 gene, which leads to skipping of exon 7 and failure to protect from motor neuron loss found in spinal muscular atrophy (SMA). Presently the lab team is investigating the functions of the survival motor neuron (SMN) protein in regard to axonal transport and neuronal development. They have performed large high throughput screens for compounds that increase levels of the SMN protein that is deficient in SMA, with the goal to increase the potency and optimize pharmacology of pre-clinical leads and initiate testing in murine models of SMA. This research is funded by a series of NIH grants, including a Dermatology Training grant (T32).
The Integrated Stress Response (ISR) In The SkinProgram Director: Dan Spandau, PhD
Eukaryotic cells have evolved a myriad of mechanisms to protect themselves from environmental stressors such as UVB light. One such mechanism is the translational control of proteins, which allows stressed cells to conserve resources and rapidly reconfigure gene expression to enhance cell repair. A central mechanism directing translational control involves phosphorylation of the subunit of eukaryotic initiation factor 2 (eIF2~P). eIF2~P represses general translation initiation through a reduced ability of eIF2 to combine with GTP and transport the initiator Met-tRNAiMet to ribosomes for the initiation mRNA translation. Mammalian eIF2 can be phosphorylated by one of four eIF2 kinases, each of which is activated by distinct stress conditions, including UVB irradiation. The convergence of diverse stressors onto this one phosphorylation event has led to this stress response pathway being referred to as the Integrated Stress Response (ISR). This lab team has demonstrated one of these kinases, GCN2, is critically important for keratinocytes to survive exposures to UVB. Interestingly, GCN2 is also essential for normal differentiation of the epidermis. Investigators here hypothesize that abrogation of GCN2 signaling in the skin contributes to the development of a wide range of skin diseases and could provide an intervention point for future therapies.
The ISR is a mechanism by which cells response to a variety of stressors via the conservation of enAn emerging area of interest in my laboratory is how the regulation of protein translation affects the manner in which human keratinocytes respond to UVB irradiation. Thus far, this lab has demonstrated that UVB causes a global inhibition of protein synthesis and a corresponding increase in the translation of proteins necessary to manage the cellular consequences of UVB-induced damage.
Research in the laboratory centers on defining how keratinocytes in the epidermis respond to environmental stress, primarily the ultraviolet components of sunlight. The consequences of the failure to appropriately react to these stresses often lead to skin disease and neoplasia. Studies from this team have focused on two specific response pathways: the insulin-like growth factor signaling pathway and the integrated stress response.
Active Clinical Research
Dermatology Clinical Research Recruitment Database
Principal Investigator: Elizabeth A. Bryant, MD
The "Dermatology Clinical Research Recruitment Database" study is enrolling potential participants who would like to be contacted about Dermatology research studies. Qualified study participants are healthy individuals and individuals with any skin disease (any age).
Cutaneous T-Cell Lymphoma And Atypical T-Cell Lymphoid Skin Disease Database (CTCL Registry)Principal Investigator: Lawrence A. Mark, MD, PhD
The Indiana University Cutaneous T-Cell Lymphoma and Atypical T-Cell Lymphoid Skin Disease Database (CTCL Registry) is designed to populate a Melanoma Database. The initiative is enrolling children and adults (any age).
Immunomodulatory Effects Of IL-33 In Atopic Dermatitis (Eczema)Principal Investigator: Matthew J. Turner, MD, PhD
The “Immunomodulatory effects of IL-33 in atopic dermatitis (Eczema)” study is investigating the role of keratinocyte-derived cytokines in epidermal injury and atopic dermatitis (IL-33:VA). Tissue Bank for survey of Inflammatory and neoplastic skin disorders. Atopic Eczema in Proton Pump Inhibitor Responsive and Nonresponsive Esophageal Eosinophilia in Children (PPIREE Study). The study is enrolling potential participants who are ages 1 to <18 years old and also enrolling potential participants who are 18 years or older.
Impact On Satisfaction Of Resident Physician Involvement In Patient CarePrincipal Investigator: Nidhi Avashia-Khemka, MD
The “Resident Physician involvement in patient care as a determinant of patient satisfaction” study is enrolling patients who are 18 years old or older, and able to complete an online survey published in English.
Multicenter Phenotype-Genptype Analysis Of Vascular Overgrowth SyndromesPrincipal Investigator: Anita N. Haggstrom, MD
The “Multicenter Phenotype-Genptype Analysis of Vascular Overgrowth Syndromes” study focuses on the efficacy, safety and pharmacokinetics of topical Timolol in infants with infantile hemangioma (IH) (TIM01), covering the spectrum of hemangioma precursors in PHACE Syndrome. The study is enrolling children and adults (any age).
Registry Of HUMIRA (Adalimumab) In Adult Patients With Chronic Plaque Psoriasis (ESPRIT)Principal Investigator: Stephen E. Wolverton, MD
This 10-year, post-marketing, observational registry of HUMIRA (Adalimumab) in adult patients with chronic plaque psoriasis (ESPRIT) is a multicenter, open-registry of patients who are candidates for systemic therapy including biologics (PSOLAR). The study is closed to enrollment but currently follows enrolled participants.
Role Of Chronic Immunosuppression In UVB Irradiation EffectsPrincipal Investigators: Dan F. Spandau, PhD; Christiane Machado, MD; Ally-Khan Somani, MD, PhD
This pilot study of the role of chronic immunosuppression in UVB irradiation effects (immunosuppression/ transplant) is enrolling potential solid organ (e.g., kidney, lung, heart, liver) transplant participants age 25-60 years old
Utility Of Mesoscopic Imaging For Tumor And Tumor Margin Detection (TRASK)Principal Investigator: Ally-Khan Somani, MD, PhD
This pilot study to determine the utility of mesoscopic (i.e. between microscopic and macroscopic) imaging system for assisting tumor and tumor margin detection (TRASK) is assessing the functionality of patients when determining the appropriate treatment for non-melanoma skin cancers. Enrolling potential participants who are 18 years old or older.