Our primary research interests include studies of both somatically heritable and transient genetic changes in somatic cells that predispose to disease in humans. In addition, we are engaged in several large projects whose ultimate goal is the identification of genes that have major contributions to complex oligogenic disorders.
Loss of heterozygosity (LOH) for tumor suppressor genes in somatic cells frequently results in a recessive cellular phenotype that leads to cancer. We have studied the frequency and mechanisms of LOH in human heterozygotes and produced a heterozygous mouse model for investigation of LOH in different genetic backgrounds and after exposure to environmental agents. We have discovered that the major mechanisms for LOH in normal cells are mitotic recombination, followed by point mutation. Thus, we are investigating genes (e.g.. Tp53. Mlh1. Msh2) and environmental agents that may affect these processes. The mouse is an excellent model for this research due to the availability of many "knockouts" for genes that might affect LOH and our ability to deliver environmental agents, such as chemicals and radiation, in a precise manner.
Our group has also produced a knockout mouse model for APRT deficiency, which produces a human genetic disease (dihydroxyadenine urolithiasis) characterized by severe kidney stones and, in rare cases, chronic renal failure. We are comparing gene expression in mice with and without kidney stones in order to identify genes that are involved in early and late pathological changes. Thus far, the expression of several known and novel genes has been shown to increase or decrease with stone disease. We are investigating the expression of these genes in specific kidney cell types and correlating it with pathologic changes. Such studies may produce new targets for early pharmacologic intervention in the progression of kidney stone disease.
We are collaborating in several large, multidisciplinary projects whose goal is the identification and characterization of genes that make major contributions to complex human diseases such as alcoholism, opiate addiction, autism, schizophrenia and bipolar disorder. We are collecting blood and producing cell lines and DNA from large numbers of individuals in families with a high incidence of a specific disorder in an effort to find such genes.