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Richard P. Lifton |
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| Chairman Department of Genetics; Sterling Professor of
Genetics, Medicine and Molecular Biophysics and Biochemistry; Investigator, Howard Hughes Medical Institute |
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Molecular genetics of common human diseases.
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* National Academy of Sciences
* The Basic Science Prize, American Heart Association
* Homer Smith Award, American Society of Nephrology
* MSD International Award, International Society of Hypertension
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| The common human diseases that account for the vast majority of morbidity and mortality
in our society are known to have underlying inherited components. Rapid advances in molecular
genetics have led to a stage where identification of genetic variants contributing to these
common but complex traits is feasible. Such identification promises to revolutionize the
diagnostic and therapeutic approaches to these disorders.
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| Current Research: | |
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| Cardiovascular disease is the leading cause of death world-wide. Epidemiologic studies have
identified hypertension, high cholesterol, diabetes and smoking as major risk factors. By
investigation of rare families recruited from around the world that segregate single genes
with large effect, we have identified genes that contribute to these traits, putting a
molecular face on their pathogenesis. For example, we have identified mutations in 8 genes
that cause high blood pressure (hypertension) and another 8 that cause low blood pressure.
These mutations all converge on a final common pathway, the regulation of net salt reabsorption
in the kidney. These findings have established the key role of variation in renal salt
handling in blood pressure variation, and have led to changes in the approach to treatment
of this disease in the general population. They have also identified new therapeutic
targets that are predicted to have greater efficacy with reduced side effects. Finally,
they have identified new signaling pathways involved in the regulation of blood pressure
homeostasis. We have taken similar approaches to another common disease, osteoporosis, with
the identification of gain of function mutations in LRP5, a component of the Wnt signaling pathway,
in development of high bone density. This finding has led to intensive efforts to identify
small molecules that impact this pathway to protect against and/or reverse osteoporosis in
the general population. Ongoing studies use both emerging and novel approaches to identification
of genes that contribute to disease burden in the population, and to understanding the
pathways that link genes to disease.
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| Mutations that affect blood pressure in humans. A diagram of a nephron, the filtering
unit of the kidney, is shown. The molecular pathways mediating NaCl reabsorption in individual
renal cells along the nephron are shown, along with the pathway of the renin-angiotensin system,
a major regulator of renal salt reabsorption. Inherited diseases affecting these pathways are
indicated, with hypertensive disorders in red and hypotensive disorders in blue. From Lifton,
Gharavi, and Geller. Cell, 104:545-556, 2001.
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| Representative Publications: | |
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| Simon DB, Lu Y, Choate KA, Velazquez H, Al-Sabban E, Praga M, Casari G, Bettinelli A, Colussi G, Rodriguez-Soriano J, McCredie D,
Milford D, Sanjad S, Lifton RP. Paracellin-1, a renal tight junction protein required for paracellular Mg2+ reabsorption. Science, 285:103-106, 1999.
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| Geller DS, Farhi A, Pinkerton N, Fradley M, Moritz M, Spitzer A, Meinke G, Tsai TF, Sigler P, Lifton RP. Activating mineralocorticoid receptor
mutation in hypertension exacerbated by pregnancy. Science, 289:119-123, 2000.
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| Lifton RP, Gharavi A, Geller DS. Molecular mechanisms of human hypertension. Cell, 104:545-556, 2001.
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| Wilson FH, Disse-Nicodème S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, Gunel M, Milford DV, Lipkin GW, Achard JM, Feely MP,
Dussol B, Berland Y, Unwin RJ, Mayan H, Simon DB, Farfel Z, Jeunemaitre X, Lifton RP. Human Hypertension Caused by Mutations in
WNK Kinases. Science, 293:1107-1112, 2001.
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| Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP. High bone density due to a mutation in
LDL-receptor-related protein 5. New Engl J Med. 346:1513-1521, 2002.
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| Wilson FH, Hariri A, Farhi A, Zhao H, Peterson K, Toka HR, Nelson- Williams
C, Raja KM, Kashgarian M, Shulman GI, Scheinman SJ, Lifton RP. A cluster of
metabolic defects caused by mutation in a mitochondrial tRNA. Science,
306:1190-94, 2004.
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| Lalioti MD, Zhang J, Volkman HM, Kahle KT, Hoffmann, KE, Toka HR, Nelson-Williams C, Ellison, DH, Flavell, R, Booth, CJ, Lu Y,
Geller, DS, Lifton, RP. Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal
convoluted tubule. Nature Genetics, in press.
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| Contact Information: | | |
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