Peter A. Doris, Ph.D.
Professor & Deputy Director, Center for Human GeneticsPeter.A.Doris@uth.tmc.edu
Dr. Doris received his doctoral degree at the University of California and returned to his native England as a Medical Research Council post-doctoral fellow at Cambridge University and the University of Reading. He joined the Institute in the summer of 1997 and is appointed as Professor and Cullen Chair of Molecular Medicine in the Center for Human Genetics. His research focuses on mechanisms of common chronic cardiovascular disease including hypertension and the injury that it causes to the kidney and brain.
In spite of much progress, cardiovascular disease remains the leading cause of mortality and chronic disability in our society. High blood pressure (hypertension) is a major force creating cardiovascular disease by causing or exacerbating injury to the blood vessels (atherosclerosis), the heart (heart failure), the brain (stroke) and the kidney (progressive renal disease). The impact of these diseases on public health is often underappreciated. For example, progressive kidney disease resulting in insufficient renal function consumes nearly 7% of all US government Medicare spending (an amount equal to the annual budget of NASA) and causes as many deaths each year as breast and prostate cancer combined. There are no therapies that interrupt or prevent the course of this disease.
Part of the risk of cardiovascular disease is inherited. However, the inheritance is not simple and cannot be attributed to single genes. Furthermore, risk is partitioned between genes contributing to the damaging force (in the broad population this principally means those elevating blood pressure) and those contributing to response of the end organs to injury initiated by high blood pressure. The complex genetics have made uncovering the pathway of disease in humans very difficult. Part of this difficulty arises from the hypothesis-free nature of modern genetic inquiry into these diseases. Since genome-wide genetic studies and genome sequencing utilize only information about limited aspects of disease phenotype (e.g., blood pressure level, proteinuria, clinical occurrence of stroke) they are not informed by thorough investigation of the disease process, but by generalized outcomes of disease.
We use animal models of cardiovascular disease that resemble human disease in key ways: they arise from naturally occurring genetic variants; they involve the interactive effects of numerous genetic variants; and they produce disease outcomes highly similar to disease outcomes in humans. However, these models offer opportunities to study the disease process as it is developing, yielding insights that inform the application of genetic approaches and greatly enhancing their power.
Much work in our laboratory currently focuses on the role of genetic variation in the immune system as a pathway of disease. Hypertension activates inflammation in the end organs and this inflammation drives immune mechanisms. Immune activation includes mechanisms that 1) initiate pro-inflammatory immune responses and 2) serve to bring the inflammatory response to conclusion. We are developing evidence that genetic variation affects both elements of this process. In our animal models we can show how overriding the immune response with drugs protects against end organ injury. The laboratory has identified key genetic variants in immune signaling that affect the initiation of pro-inflammatory signaling by immunoglobulin, that controls the proliferation of immune cells, and that alter the calcium signaling pathways driving cytokine production.
- R.I. Dmitrieva, C.A. Hinojos, M. Grove, R.J. Bell, E. Boerwinkle, M. Fornage and P.A. Doris. Genome-wide identification of allelic gene expression in hypertensive rats. Circulation (Cardiovascular Genetics) 2:106-115, 2009
- Doris, P.A. The genetics of blood pressure and hypertension: the role of rare variants. Cardiovasc. Ther. 29:37-45, 2011.
- Bell, R., S.M.Herring, N. Gokul, M. Monita, M.L. Grove, E. Boerwinkle, P.A. Doris. High resolution identity by descent mapping uncovers the genetic basis for blood pressure differences between SHR lines. Circulation (Cardiovascular Genetics). 4:223-31, 2011
- Herring, S.M., N. Gokul, M. Monita, R. Bell, E. Boerwinkle, S.E. Wenderfer, M.C. Braun and P.A. Doris. The rat immunoglobulin locus is associated with serum IgG levels and albuminuria. J. Amer. Soc. Nephrol. 22:881-9, 2011.
- Braun, M.C. and P.A. Doris. Mendelian and trans-generational inheritance in hypertensive renal disease. Annals Medicine, 44:S65-73, 2012.
- Doris, P.A. Genetic susceptibility to hypertensive renal disease. Cell and Molecular Life Sciences, 69:3751-63, 2012.
- Mamenko, M, O. Zaika, P.A. Doris and Pochynyuk, O. Salt-dependent inhibition of ENaC-mediated sodium reabsorption in the aldosterone-sensitive distal nephron by bradykinin. Hypertension, 60:1234-41, 2012
- Braun, M.C. S.M. Herring, N. Gokul, M. Monita, R.J. Bell, S.E. Wenderfer and P.A. Doris. Hypertensive Renal Disease: Susceptibility And Resistance In Inbred Hypertensive Rat Lines. J. Hypertension 31:2050-2059, 2013.
- Mamenko, M, O. Zaika, M. Prieto, V. B. Jensen, P.A. Doris, L.G. Navar and O. Pochynyuk. Chronic Angiotensin II infusion drives excessive aldosterone-independent ENaC activation. Hypertension, 62:1111-22, 2013.
- Gonzalez-Garay, M.L., S.M. Cranford, M.C. Braun, and P.A. Doris. Diversity in the pre-immune immunoglobulin repertoire of SHR lines susceptible and resistant to end organ injury. Genes and Immunity, In Press