Faculty
Beverly Davidson Ph.D.
Research in my laboratory is focused on inherited genetic diseases that cause central nervous system dysfunction, with a focus on (1) recessive, childhood onset neurodegenerative disease, in particular the lysosomal storage diseases such as the mucopolysaccharidoses and Battens disease; and (2) dominant genetic diseases for example the CAG repeat disorders, Huntington\'s disease and spinal cerebellar ataxia type I. Our research on childhood onset neurodegenerative diseases is focused on experiments to better understand the biochemistry and cellular trafficking of proteins deficient in these disorders, and to develop gene and cell-based medicines for therapy. Our gene therapy studies are focused on vector development, emphasizing the study of novel envelopes for cellular targeting of lentivirus vectors, or non-traditional capsid proteins for encapsidated vectors (AAV and adenovirus). In recent work we demonstrated that the application of these vectors to animal models of storage disease could reverse CNS deficits. Molecular correlates, examined using gene chip arrays, corroborated the beneficial effects of gene therapy. For cell based therapies, experiments are directed towards understanding the early signaling events required for differentiation of progenitor cell populations using microarray studies coupled with bioinformatics. The proteins revealed are then studied for their roles in development, and for their ability to induce differentiation of endogenous progenitor populations. Therapies for dominant disorders are an exciting challenge and require that the dominant disease allele be silenced. To approach this, we have developed vectors expressing small inhibitory RNA, or siRNA. These small RNAs lead to the degradation of the targeted sequence. We have shown that siRNA reduces expression of the target in cell culture models of CAG repeat diseases, leading to an improved phenotype. Current studies are determining the effectiveness of in vivo delivered siRNA to correct disease manifestations in relevant models.
Deborah V Dawson Ph.D., Sc.M.
My research interests focus on human genetic disorders, including both the development of new statistical methods for their investigation, and applied studies. My methodological research has included development of techniques in the areas of delayed onset disorders and correction for ascertainment bias, as well as approaches to problems in population immunogenetics, most recently as they relate to vaccine research. My applied work includes statistical genetic modeling of human disorders, and biostatistical modeling related to other clinical and epidemiologic studies. Modeling activities have focused on the genetics of the human major histocompatibility (HLA) complex, immune and inflammatory disorders (including autoimmune disorders and periodontal disease), and developmental disorders. The latter include studies of Fragile X syndrome, and genetic syndromes affecting teeth and bone. Other areas of application include studies related to craniofacial development, including longitudinal studies of normal development, and investigations of late onset disorders and of aging, including the genetics of longevity. More recent interests include the analysis of microarray data, meta-analytic assessment, and classification and risk assessment problems, particularly as they relate to genetic counseling.
Adam J Dupuy Ph.D.
Human cancers arise through a multi-step genetic process that involves the loss of tumor suppressor genes and activation of proto-oncogenes. However, it is challenging to identify the causal mutations amid the large number of genetic and epigenetic changes typically found in human tumors. Mouse models of human cancer have been useful in testing the contribution of specific mutations in oncogenesis. Unfortunately, single gene mouse models often do not translate well when compared to human cancer. It is thought that these models lack a sufficient number of mutations to generate aggressive tumors typically seen in human cancer patients. Insertional mutagenesis provides many advantages over single gene mouse models. The most common insertional mutagen used in mouse models of cancer is the murine leukemia virus. In these models, retroviral infection of hematopoietic cells leads to mutation when the provirus integrates into the host cell genome. Several rounds of retroviral infection followed by clonal expansion eventually leads to the development of leukemia/lymphoma in the mouse. This multi-step process is similar to what occurs in human cancer and produces tumors that are genetically heterogeneous. In retrovirally-induced tumors the provirus marks the site of mutation and provides a sequence tag that can be used to efficiently identify the mutated genes. Several labs have identified over 150 candidate cancer genes by cloning more than 2,000 proviral integrations sites from a variety of retrovirally-induced mouse models of leukemia and lymphoma (available at http://genome2.ncifcrf.gov/RTCGD). Unfortunately, retroviral infection of mice produces mammary and hematopoietic malignancies primarily. However, Sleeping Beauty (SB), an engineered cut-and-paste transposon system, has demonstrated activity in a variety of tissues in the mouse. The system consists of two parts—the transposase enzyme provided in trans and the DNA transposon vector. When these elements are present in the same cell, SB transposase binds to sites in the transposon and mediates excision from the donor site and integration to a random TA dinucleotide in the genome. Previous work has shown that transposons can generate de novo mutations when they integrated into the mouse genome. Recent work has modified the SB system as a somatic cell mutagen to induce tumor formation in mice. This work describes the first nonviral insertional mutagen capable of inducing tumors in vivo. In this regard, SB has several advantages over retroviruses in their ability to perform screens for cancer genes mainly because SB mutagenesis can be controlled by simply by regulating SB transposase expression. Current efforts are focused on generating tissue specific models of cancer in mice by directing transposase expression to specific sites in the mouse.
