The research goals of my laboratory group involve the utilization of genetic approaches to the identification of mechanistic bases of human disease pathology and the utilization of this knowledge to develop effective strategies for intervention in human disease. Our efforts are focused in three major disease areas: trinucleotide repeat disorders particularly Huntington's disease (HD), cancer and cardiovascular disease.

Huntington's Disease: Our current research goals include identifying modifier genes which are responsible for variation in age of onset for HD. Prospective studies on extended HD families demonstrate that, other than the length of the CAG repeat sequence, modifier genes contribute significantly to determining the age of onset for HD. We are currently pursuing genetic linkage and association studies designed to identify these genes. In parallel, we are carrying out studies to identify genes which contribute to the timing of disease onset in mouse model systems for HD. We have also developed a series of model systems for the pathological effects of expanded polyglutamine repeats in Huntington's disease. Using these systems we have achieved the following goals: 1. Developed genetic suppressors of the pathological effects of expanded polyglutamines and assessed the mode of action of these suppressors 2. Isolated small molecules which inhibit the pathological effects of expanded polyglutamines. 3. Identified a pathway to pathology which involves transcriptional disregulation and the inhibition of histone deacetylase activities. Our current goals are focused on the identification and development of small molecules which show promise for therapeutic intervention in HD.

Cancer: We have focused on several cancers including Wilms tumor and glioblastoma, in which analysis of genetic alterations in germline DNA or in specific tumors identify pathways of particular significance to tumorigenesis.

Wilms tumor: Our laboratory has been very active in the study of the WT1 tumor suppressor gene demonstrating its key role in tumorigneesis and kidney and urogeneital development. Most recently, we have focues on the role of the WT1 gene in hematopoiesis. WT1 has been utilized a marker and proposed as a target for therapy for leukemia. We studied murine hematopietic cells in which the WT1 gene has been inactivated by homologous recombination. We have found that cells lacking WT1 show deficits in hematopoietic stem cell function. We are currently exploring the impact of compromise to WT1 function on both normal and leukemic cells with the goal of gaining further understanding of the utility of WT1 as a marker and a target in therapy for leukemia.

Glioblastoma: We have focused on the receptor tyrosine kinase, c-Ros, which we have shown to be activated in a novel manner in glioblastoma. Through the characterization of a microdeletion on 6q22 in a glioblastoma, c-Ros can be activated via fusion to a novel Golgi apparatus-associated protein, Fig. The fused protein product (Fig-Ros) displays intrinsic kinase activity and is a potent oncogene. The transforming potential of the Fig-Ros fusion product resides in its ability to interact with and become localized to the Golgi apparatus. We are currently exploring the mechanisms by which a Golgi localized activated oncogene can cause cell transformation, and are initiating studies to identify small molecules which may serve as probes for Ros function in glioblastoma and the basis for possible therapeutic intervention for this tumor.

Cardiovascular disease: We are currently taking two major approaches to identifying genes which are significant contributors to cardiovascular disease. One approach involves population based association studies in which we are testing the association of specific SNP genotypes and haplotypes to cardiovascular disease and associated phenotypes. Our second approach involves proteomic analysis in a mouse model system. These studies currently focus on a mouse model for the cardiac pathology observed in myotonic dystrophy, We have utilized a proteomic approach including two dimensional gel electrophoresis and mass spectrometry to identify polypeptides which are altered in mobility in the hearts of mice deficient in the DMPK protein kinase, a gene whose expression is compromised in myotonic dystrophy and whose absence causes significant cardiac pathology in mice which lack this kinase. The goal of these studies is to determine the pathway to cardiac pathology which begins with the absence of function of the DMPK kinase and through this understanding elucidate the signaling pathways involving the DMPK kinase. Our further goal is to generalize this approach to other mouse models of cardiac pathology.