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, Tgfb2, 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.

Another area of interest is cell signaling mediated by low molecular mass phospholipase A2 (PLA2) enzymes. We have identified two new PLA2 genes in humans and rodents and have shown that they are part of a complex locus containing one other PLA2 gene. The expression of these genes is developmentally regulated and specific to certain cell types. Our studies suggest involvement of the novel PLA2 in diseases such as asthma and skin disorders. Further studies are aimed at understanding the complex biology involving these enzymes.

	Linkage and linkage disequilibrium of evoked EEG oscillations with CHRM2 receptor gene polymorphisms: implications for human brain dynamics and cognition. Jones KA, Porjesz B, Almasy L, Bierut L, Goate A, Wang JC, Dick DM, Hinrichs A, Kwon J, Rice JP, Rohrbaugh J, Stock H, Wu W, Bauer LO, Chorlian DB, Crowe RR, Edenberg HJ, Foroud T, Hesselbrock V, Kuperman S, Nurnberger Jr J, O'Connor SJ, Schuckit MA, Stimus AT, Tischfield JA, Reich T, Begleiter H. Int J Psychophysiol. 2004 Jul;53(2):75-90.
	Expression of FACIT collagens XII and XIV during bleomycin-induced pulmonary fibrosis in mice. Tzortzaki EG, Tischfield JA, Sahota A, Siafakas NM, Gordon MK, Gerecke DR. Anat Rec. 2003 Dec;275A(2):1073-80.
	Impaired expression of an organic cation transporter, IMPT1, in a knockout mouse model for kidney stone disease. Tzortzaki EG, Yang M, Glass D, Deng L, Evan AP, Bledsoe SB, Stambrook PJ, Sahota A, Tischfield JA. Urol Res. 2003 Aug;31(4):257-61. Epub 2003 Jul 11.
	Gender- and age-dependent changes in kidney androgen protein mRNA expression in a knockout mouse model for nephrolithiasis. Tzortzaki EG, Glass D, Yang M, Evan AP, Bledsoe SB, Stambrook PJ, Sahota A, Tischfield JA. J Histochem Cytochem. 2002 Dec;50(12):1663-9.