Pathology is the mother of medicine.
Our laboratory's primary interest is the identification and characterization of skin and adnexal diseases in laboratory mice as models for genetically based human skin diseases. However, since our group includes veterinarian and physician scientists, all with broad medical training, we are involved with identifying and defining mouse models for many different types of diseases including inflammatory bowel disease, autoimmune diseases, vascular and lymphatic abnormalities, and many other diseases affecting a variety of organ systems. Our horizons broadened even further when we became a critical part of the new Jackson Aging Center at The Jackson Laboratory.
Alopecia areata is a long-term major focus of our laboratory group. Alopecia areata and its more severe forms, alopecia totalis and universalis, are forms of a cell-mediated autoimmune skin disease that targets actively growing (anagen stage) hair follicles. Building on previous work done with Dr. Lloyd King (Vanderbilt U.) and several Jackson Laboratory Staff Scientists (Drs. Gregory Cox, Gary Churchill, and Renhua Li) in which we identified four quantitative trait loci (QTL) for our C3H/HeJ mouse model of alopecia areata, we used the haplotype in silico mapping approach, with the help of Benjamin King (The Jackson Laboratory), to identify a critical gene in the activation of CD8+ T cells, the primary effector cell. These findings are being confirmed in collaboration with immunologist Dr. Derry Roopenian (The Jackson Laboratory Professor).
With funding from the National Alopecia Areata Foundation (NAAF), we set up a preclinical screening system for novel drug efficacy trials at Jackson’s facility in Sacramento, Calif., initially working with Dr. Kara Koehler and then with Dr. Leon Hall. To support this drug screening system, as well as to investigate the fundamental mechanisms involved in onset and progression of alopecia areata, we performed large-scale longitudinal gene expression analysis of our skin graft-induced C3H/HeJ mouse model using the Ingenuity Network Analysis program to identify known drug targets. This is part of Dr. Jing Sun's (The Jackson Laboratory) Ph.D. thesis project. Our results clearly confirmed that drug targets change throughout the development and progression of alopecia areata, indicating that effective treatment requires that specific drugs be used alone or in combination at various stages of the disease.
These results help explain the frustration of patients with current treatment options. More importantly, we are identifying a variety of important molecular networks involved in the pathogenesis of alopecia areata. Our findings will help us create alopecia areata-specific molecular assays to provide physicians with more accurate diagnostic and prognostic tools. We are working closely with Dr. Derry Roopenian to develop and make these new tools available to the medical community.
Rosemarie Seymour, D.V.M., a veterinarian working on a Ph.D. through collaboration with the University of Maine in Orono, is studying the genetics and immunologic defects of the chronic proliferative dermatitis mutant mouse (cpdm). These mice develop severe alopecia and scaling due to large numbers of eosinophils in the dermis. Working with Dr. Harm HogenEsch (Purdue U.), we are investigating the cytokine and chemokine pathways in this disease. Previously we found that mutant mice fail to develop Peyer's patches in the intestine and that the secondary lymphoid tissues do not develop properly. Dr. Seymour's work focuses on the pathways involved in normal development of these structures and how this relates to the severe skin and overall systemic effects of this single-gene defect. Dr. Seymour recently identified the mutated gene in the cpdm mouse, and we are currently creating floxed alleles as well as yellow fluorescent protein-expressing transgenic mice to define the biological function of this novel gene in several organs. Drs. Gregory Cox and Leonard Shultz (The Jackson Laboratory) are active partners in this project.
We are also investigating the relatively common forms of hair loss and skin ulcers that arise spontaneously in C57BL/6 (B6) substrains of mice. This disease process is commonly referred to as B6 alopecia, chronic ulcerative dermatitis, or B6 dermatitis, and the severe form results from a primary hair follicle dystrophy. Working with Drs. Helen Everts, David Ong, and Lloyd E. King (all of Vanderbilt U.), we are focusing on abnormal vitamin A metabolism as an underlying mechanism in this disease. Comparative work with Drs. King and Leonard Sperling (Uniformed Services U.) indicates that this may be a new and much-needed preclinical model for a form of human cicatrical alopecia.
Dr. Alexander Awgulewitsch (Medical U. South Carolina), an expert in homeobox gene regulation of hair follicle function, approached us to help his group characterize mutant mice with hair medulla defects resulting from overexpression or lack of expression of Hoxc13. Among the genes Hoxc13 interacts with is Foxq1, the gene mutated in satin mice, which also have a hair medulla abnormality. Dr. Baojin Wu, a visiting investigator here for a year from the Medical School of Yangzhou U., Yangzhou Jiangsu, China, recently identified the mutation in a new allelic mutation of satin (MRL/LpJ-Foxq1sa-J). He also recently identified the mutated gene responsible for the spontaneous mutation called hair interior defect (hid), which also has a hair medulla defect. All AKR/J mice are homozygous for this autosomal recessive mutation. Hid is located in an interval with no known genes involved in hair follicle development. We have narrowed our list of candidate genes and these are currently being sequenced. These results are part of a larger project with Dr. Awgulewitsch and his graduate students, Christopher Potter and Nathan Pruett (Medical U. South Carolina), to use hair medulla formation as a paradigm for analyzing gene networks involved in hair follicle differentiation. We have an expanding group of novel and historical mutant strains and stocks with hair medulla defects that involve many different autosomal recessive mutations. These unique tools are critical to define the gene networks involved in normal and abnormal skin and hair biology.
Working with Drs. Derry Roopenian and Jason Bubier (The Jackson Laboratory) we discovered a new spontaneous mutant mouse that results in blistering of the skin, particularly around the ears. It was initially named sore ears for this reason. Abnormalities in the basement membrane indicate that this is a form of junctional epidermolysis bullosa. We are doing comparative studies with Drs. Joe-David Fine and Lloyd E. King, Jr. (Vanderbilt U.). We recently identified the mutated gene and are using the model to identify modifier genes that affect quality and length of life.
Our laboratory provides the pathology infrastructure for the Jackson Aging Center. All mice utilized in this project are brought to us for detailed physiologic and pathologic phenotyping, which includes designing and coordinating numerous ancillary studies with scientists in-house and around the world. We coordinate our work with Drs. David Harrison and Beverly Paigen (The Jackson Laboratory). Histopathology results and disease frequency are posted on the Mouse Phenome Database and Mouse Tumor Biology Database (with Drs. Janan Eppig and Dale Begley, The Jackson Laboratory). These data are also included in Pathbase (with Dr. Paul Schofield, Cambridge U., Cambridge, UK), a mouse pathology database that integrates the expertise of many mouse pathologists to make public annotated images of all diseases in laboratory mice. These data will be part of a large-scale haplotype mapping project to identify genes responsible for chronic debilitating spontaneous diseases. We are also collaborating with Dr. Paul Schofield (Cambridge U.) and Beth Sundberg (The Jackson Laboratory) to expand Pathbase by developing a subdirectory, Skinbase, that describes mutant mice with skin, hair, and nail abnormalities, including information on normal anatomic structures, coordinated with the assistance of a medical specialist to use terms familiar to both veterinarians and physicians.
Training programs for veterinarians and physicians interested in mouse research and pathology continue both here at The Jackson Laboratory as well as off campus. Dr. Thomas Chase, working in Dr. Leonard Shultz's laboratory, is currently on our NIH T32 training grant for veterinarians. Dr. Seymour (see above) completed her work on the T32 training grant and was awarded an NIH K08 Mentored Clinical Scientist grant. We hold an annual week-long training course for pathologists (Pathology of Mouse Models for Human Diseases). Dr. Sundberg conducted a series of minicourses on mouse pathology and mouse databases at Northwestern U., Purdue U., the University of Illinois, and many others are being planned.