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William J. Pavan, Ph.D.

Senior Investigator, Genetic Disease Research Branch
Head, Genomics, Development and Disease Section
Director, Intramural Training Office

Scientific Summary

The Genomics, Development and Disease Section (GDDS; originally called the Mouse Embryology Section) was established in 1994 on the foundation that transformative and translational discoveries will be revealed through the application of advanced genetic and genomic approaches to the study of mouse genetic mutants that model human disease traits. The section uses a wide array of genomic tools along with the genetic manipulation of model systems to discover genome function and to dissect gene regulatory pathways in development and disease.

The main areas of research interest are the genetics of pigmentation and its diseases and the lysosomal storage disease Niemann-Pick disease, type C (NPC). With the ultimate goal of annotating human genome function with an emphasis on understanding and treating human diseases, Dr. Pavan's work is focused on transformative research that will provide insights into mammalian developmental pathways, disease pathology and therapeutic interventions.

Modified Melanocyte StainingThis approach has been highly successful. Dr. Pavan's section has discovered critical genetic components needed for normal development and/or postnatal homeostasis in 20 mouse mutant strains, with over half of these being instructive regarding orthologous human diseases. In 1998, Dr. Pavan's section discovered that mutations of the HMG-box transcription factor SOX10 result in neural crest stem cell defects in mice that accurately model enteric nervous system deficiencies offile://msgr_image/?msgr_image#2051524096 Hirschsprung (HSCR) disease and melanocyte deficiencies of Waardenburg (WS) syndrome.  Subsequently, germline SOX10 mutations were identified in individuals with WS-HSCR disease. Next, the GDDS worked with the NHGRI genomics and embryology core facilities to develop technologies to further examine the transcriptional target genes of SOX10 in stem cell biology and explore SOX10's relationship to other HSCR and WS disease genes.  

In 1997, Dr. Pavan's group used a mouse mutant that modeled the neurodegenerative and associated cholesterol and glycolipid storage defects of NPC to discover the underlying molecular defect in the protein NPC1 that was responsible for the disease traits. They went on to use this information to reveal that the orthologous human gene NPC1 is also mutated in individuals with NPC.  Further animal modeling studies demonstrated neuronal-targeted expression of NPC1 rescued neurodegenerative disease, essential information for designing therapeutic interventions.

Modified Melanocyte StainingMore recently, the Pavan group has further explored these pathways in development and disease as well as developed genetic screens to identify additional disease pathway components. Routinely they have occupied the forefront of research innovation by using high-risk modifier screens to identify major modifiers of primary genetic defects.  They have expanded understanding of SOX10's contribution to human disease by demonstrating that somatic mutations of the SOX10 melanocyte stem cell transcriptional regulatory pathway are present in human melanoma, the most lethal form of skin cancer in the United States that is increasing in incidence worldwide.

These findings led to the hypothesis that altering SOX10 levels in melanoma may alter melanomagenesis. To identify SOX10 modulatory factors, they used comparative genomic sequencing analyses and zebrafish transgenic technologies to reveal cis-acting genomic elements that regulate SOX10 expression. To identify SOX10 target genes, they built genomic resources to interrogate transcriptional regulatory pathways in development and melanoma, integrating ChIP-seq, in vivo modeling, computational analyses and machine learning to identify a predictive sequence vocabulary involved in melanocyte gene expression. To identify trans-acting components that synergize with SOX10 stem cell function and thus may be targets for intervention in melanoma procession, they established a SOX10-sensitized genetic screen.

From this screen, nine mutant loci were identified that targeted multiple biological pathways; examples included identification of a role for the exon junction complex in stem cell maintenance and DNA integrity, discovery that NRG1/ERBB3 pathway activation is required in order to retain stem cell fate and it is again re-activated during human melanoma progression, and analysis of RPS7 mutations that resulted in expansion of the repertoire of RPS-associated phenotypes of Diamond-Blackfan anemia to include CNS and morphological traits. The Pavan group's NPC work has continued in a multi-lab effort aimed at developing and assessing effective NPC treatment strategies.  This has involved collaborations with the NIH's National Chemical Genomics Center to identify candidate therapeutic compounds via high-throughput screens, its Therapeutics for Rare and Neglected Diseases program to bridge the gaps between basic discoveries and clinical trials, and NIH Clinical Center physicians for identification of biomarkers and bioassays as well as evaluation of compounds in NPC disease patients. They have also collaborated in establishment of a natural history study to identify screening criteria and biomarkers for use in gauging therapeutic interventions.

Current studies in the GDDS focus on transformative research that will simultaneously reveal new details of development and disease pathways and also provide candidate pathways for evaluation in human therapeutic interventions. The group continues to further examine the links between melanocyte development and melanoma by identifying modifiers of SOX10 in adult melanocyte stem cells and melanoma, and by examining SOX10's role in genome regulation. These studies include identification of in vivo genetic modifiers of hair graying, a novel model for study of MCSC that will allow discovery of genetic pathways that impact adult MCSC and may have far-reaching impact towards understanding adult stem cells, regeneration medicine, and melanoma research, since pathways utilized to maintain MCSC may also be involved in stem cell properties of melanoma cells. They are analyzing chromatin modifications of target genes using ChIP-seq analyses in studies that utilize genetic manipulations, such as loss- and gain-of-function SOX10 alleles, and candidate pharmacological interventions.  In addition, they are collaborating with an international consortium to assemble a cohort of HSCR disease patients who will be evaluated for microbiome changes associated with enterocolitis, which occurs at a rate of 30 percent in HSCR patients and is the major morbidity associated with this neurocristopathy. Identification of altered HSCR microbiome populations may provide a means of early prognosis and potential therapeutic management.

The group continues to identify compounds for treatment of NPC and assess these compounds in animal models with the goal of translating this information into clinical trials at the NIH. Collectively, these future studies are designed to utilize the most current genomic technologies in combination with mouse models to facilitate effective disease therapy.

Genomics, Development and Disease Section Members

Stacie Loftus, Ph.D., Associate Investigator
Dawn Watkins-Chow, Ph.D., Biologist
Julie Cronin, M.S., Biologist
Denise Larson, B.A., Biologist
Melissa Harris, Ph.D., Postdoctoral Fellow
Temesgen Fufa, Ph.D., Postdoctoral Fellow
Laura Baxter, Ph.D., Biologist
Arturo Incao, D.V.M., Biologist

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Posted: January 6, 2016