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Richard Lifton, MD, PhD of Yale University & Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension

Curator: Aviva Lev-Ari, PhD, RN

Article ID #118: Richard Lifton, MD, PhD of Yale University and Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension. Published on 3/3/2014

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SOURCE

http://www.bizjournals.com/sanfrancisco/prnewswire/press_releases/California/2013/12/13/NY33121

THE DISCOVERY

Laliotis 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

Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4.

Wilson FH¹, Kahle KT, Sabath E, Lalioti MD, Rapson AK, Hoover RS, Hebert SC, Gamba G, Lifton RP.

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LISTEN TO AUDIO TAPE by Prof. Richard Lifton

http://streaming.yale.edu/opa/podcasts/audio/schools/health_and_medicine/lifton_092007.mp3

Richard Lifton

Yale’s Richard Lifton is one of eight world-changing researchers whose work is celebrated during a program airing tonight (Jan. 27) on the Science Channel at 9 p.m. EST.

Lifton, Sterling Professor of Genetics and chair of the Department of Genetics, received a $3 million Breakthrough Prize in Life Sciences, created by top Silicon Valley entrepreneurs.

The Science Channel program features the Dec. 12 ceremony where Lifton and others received their prize. The festivities were hosted by actor Kevin Spacey and featured such celebrities as Conan O’Brien, Glenn Close, Rob Lowe, and Michael C. Hall, as well as tech leaders Mark Zuckerberg, Larry Page, Sergey Brin, Anne Wojcicki, Jimmy Wales, and Yuri Milner.

SOURCE

http://news.yale.edu/2014/01/27/tonight-lifton-honored-star-studded-ceremony

International Activity

• YALE-UCL Collaborative
  London, United Kingdom (2011)
  Dr. Lifton is on the Joint Strategy Committee for the Yale-UCL Collaborative, an alliance which will provide opportunities for high-level scientific research, clinical and educational collaboration across the institutions involved: Yale University, Yale School of Medicine, Yale-New Haven Hospital and UCL (University College London) and UCL Partners
• Transatlantic Network on Hypertension-Renal Salt Handling in the Control of Blood Pressure
  France (2007)
  Drs Hebert and Lifton will join leading researchers in Switzerland, France and Mexico in a transatlantic collaboration aimed at pinpointing the kidney’s role in high blood pressure.

Education & Training

M.D.

Stanford University (1982)

Ph.D.

Stanford University (1986)

Honors & Recognition

• 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

Research Interests

Molecular genetics of common human diseases

Research Summary

The common human diseases that account for the vast majority of morbidity and mortality in human populations are known to have underlying inherited components. Advances in human genetics have made the identification of genetic variants contributing to these traits feasible. Such identification promises to revolutionize the diagnostic and therapeutic approaches to these disorders. We have focused on cardiovascular and renal disease. To date, we have identified mutations underlying more than 20 human diseases; these include a host of diseases that define molecular determinants of hypertension, stroke and heart attack. We have gone on from these starting points to use biochemistry and animal models to define the physiologic mechanisms linking genotype and phenotype. These findings have provided new insight into normal and disease biology, are identifying new pathways underlying disease pathogenesis, and are identifying new targets for development of novel therapeutics.

Extensive Research Description

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. 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.

Selected Publications

PubMed Results: 10