Dr. Peter A. Doris
The University of Texas Health Science Center at Houston
McGovern Medical School
Institute of Molecular Medicine
Research Center for Human Genetics
My laboratory studies the pathophysiology and genetics of high blood pressure and the mechanism by which it causes damage to organs. Much of our recent effort has been dedicated to the impact of hypertension on renal function, the role of oxidative stress in renal injury and the definition of a rat model of renal injury in hypertension for which we have also identified a closely-related hypertensive rat that resists injury. Along with advances in the resources available to perform genetic studies in the rat, we have created important opportunities to exploit these closely related lines to dissect the pathogenesis of renal injury in hypertension, its relationship with blood pressure and the involvement of immune mechanisms in disordered renal function and the relationship of this disease to other cardiovascular disease susceptibility. Our work has lead to the discovery that remarkable genetic variation occurs at the heavy chain locus of immunoglobulin across these two contrasting rat lines and that this variation has important functional implications for immunoglobulin and is associated with the emergence of renal injury. Our goal is to understand how this influence on renal injury occurs. We have obtained whole genome sequences for our contrasting rat strains which has lead us to uncover an important role for additional genetic variation in the immune system signaling pathway initiated by interaction of IgG with its receptor. Many elements of this signaling pathway genetically diverge across our injury-susceptible and -resistant lines and allow us to account for a large part of the risk of disease. Pharmacological modification of immune functions supports the role of this genetic variation showing that this pathway is druggable target to prevent progression of renal disease. We are also investigating the role of immunoglobulin as an agent of heritable phenotypes. Our studies indicate that genetic variation in our rats prevents the transmission of IgG from mother to progeny. This has prompted us to investigate further the role of the maternal uterine environment on disease risk in progeny and the role that IgG transmission plays in disease risk. Immunoglobulins possess important characteristics that may allow them to act to generate non-Mendelian traits. Like DNA, immunoglobulins function as memory molecules, endowing memory of prior antigen exposure. Immunoglobulins are also transmitted from parent to progeny and can have important effects on progeny traits that outlast the presence of the maternally-transmitted molecules.