Owen M. Woodward
HSFI, Room 565
University of Virginia, B.A. in Biology with Highest Distinction
University of Washington, PhD in Zoology
Johns Hopkins University School of Medicine, Research Fellow in Physiology
My work has come to focus on the complicated workings of the human kidney and understanding how genetic mutations lead to disease, describing the physiological mechanism, and finding possible therapies.
ABCG2, Hyperuricemia, and gout
Urate (uric acid) handling and secretion in humans and the great apes is unique among mammals; we have lost the function of the urate oxidase (uricase) enzyme, the enzyme responsible for metabolizing urate into allantoin. The loss of uricase appears to be adaptive in humans, however it puts humans at risk for retaining too much urate (hyperuricemia), which can lead to gout, kidney disease, hypertension, metabolic disorders and cardiovascular disease. Yet, until recently the transporters responsible for urate secretion and absorption remained mostly unknown.
Recently, we discovered that ABCG2 is a novel urate transporter, perhaps the most important secretion mechanism for uric acid in humans, and identified a loss of function mutation that causes hyperuricemia and gout. Importantly the mutation is common, carried by almost a billion people, putting them at increased risk for hyperuricemia, gout, and possibly hypertension and other metabolic diseases. Most recently, we have gained an understanding of how this mutation causes dysfunction in ABCG2 and have used this new understanding to find small molecules that can correct the defect, a proof of principal that new small molecule therapy may be possible for hyperuricemia and gout.
ROMK and hypertension
I am working with PA Welling to better our understanding of how the function of the important renal K+ channel, ROMK, is regulated in the renal tubule. ROMK is known to be regulated by the WNK kinases, kinases that can carry mutations that cause familial hyperkalemic hypertension. What is not known is the mechanistic connection between the WNK kinases and the surface expression of ROMK, but recent work by Dr. Welling has shown that the WNKs may specifically regulate ROMK endocytosis and therefore its degradation. All of the relevant players are not yet known and our work hopes to indentify the remaining parts of the regulatory pathway, an effort bent at finding new and better ways to treat hypertension.
Lab Techniques and Equipment:
Our work uses many different tools, all focused on understanding the physiology of the human kidney. We use genetic studies to find disease causing mutations and test the mutant protein’s function with radioactive transport assays, patch clamp studies, two electrode voltage clamp, live cell imaging, and FRET. And finally we use mouse models to gain a better understanding of how mutant proteins fit into the whole animal physiology.
1. Woodward, O.M.
(2015) ABCG2: The Molecular mechanisms of urate secretion and gout
. Am J Physiol Renal Physiol. 2015 Jul 1:ajprenal.00242.2015. doi: 10.1152/ajprenal.00242.2015. [Epub ahead of print]
2. Woodward, O.M.†,
Tukaye, D.N., Cui, J., Greenwell P., Constantoulakis, L.M., Parker B.S., Rao, A., Kottgen, M., Maloney P.C., and Guggino, W.B. (2013) Gout causing Q141K mutation in ABCG2 leads to instability of the nucleotide binding domain and can be corrected with small molecules
. Proc Natl Acad Sci USA.
110(13):5223-5228 (†Corresponding Author)
3. Anna Köttgen, Eva Albrecht, Alexander Teumer, Veronique Vitart, Jan Krumsiek, Claudia Hundertmark, Giorgio Pistis, Daniela Ruggiero, Conall M O’Seaghdha, Toomas Haller, Qiong Yang, Toshiko Tanaka, Andrew D Johnson, Zoltán Kutalik, Albert V Smith, Julia Shi, Maksim Struchalin, Rita PS Middelberg, Morris J Brown, Angelo L Gaffo, Nicola Pirastu, Guo Li, Caroline Hayward, Tatijana Zemunik, Jennifer Huffman, Loic Yengo, Jing Hua Zhao, Ayse Demirkan, Mary F Feitosa, Xuan Liu, Giovanni Malerba, Lorna M Lopez, Pim van der Harst, Xinzhong Li, Marcus E Kleber, Andrew A Hicks, Ilja M Nolte, Asa Johansson, Federico Murgia, Sarah H Wild, Stephan JL Bakker, John F Peden, Abbas Dehghan, Maristella Steri, Albert Tenesa, Vasiliki Lagou, Perttu Salo, Massimo Mangino, Lynda M Rose, Terho Lehtimäki, Owen M. Woodward,
Yukinori Okada, et al. (2013) Genome-wide association analyses identify 18 new loci associated with serum urate concentrations
. Nature Genetics.
4. Cebotaru L, Woodward O.M.,
Cebotaru V, Guggino WB. (2013) Transcomplementation by a truncation mutant of CFTR enhances Delta F508 processing through a biomolecular interaction
. J Biol Chem.
Mar 5. [Epub ahead of print]
5. Woodward, O.M.
and Guggino, W.B. (2012) Anion channels of the human kidney, in Seldin and Geibesh’s The Kidney: Physiology and Pathophysiology
. Fifth edition. Academic Press, New York.
6. Woodward, O.M.,
Kottgen, A., and Kottgen, M. (2011) ABCG transporters and disease
. FEBS J.
Sep; 278(18): 3215-25.
7. Tin A*, Woodward OM*,
Kao WH, Liu CT, Lu X, Nalls AM, Shriner D, Semmo M, Akylbekova EL, Wyatt SB, Hwang SJ, Yang Q, Zonderman AB, Adeyemo A, Palmer C, Meng Y, Reilly MP, Shlipak MG, Siscovick DS, Evans MK, Rotimi CN, Flessner MF, Köttgen M, Cupples LA, Fox CS, and Köttgen A (2011) Genome-wide Association Study for Serum Urate Concentrations and Gout among African Americans Identifies Genomic Risk Loci and a Novel URAT1 Loss-of-Function Allele
. Hum Mol Genet.
Oct 15;20(20): 4056-68 (*equal contribution)
8. Woodward, O.M.,
Li, Y.,Yu, S., Greenwell, P., Wodarczyk, C., Boletta, A., Guggino, W.B., and Qian, F. (2010) Identification of a Polycystin-1 cleavage product, P100, that regulates store operated Ca2+ entry through interactions with STIM1
. PLoS ONE
. 5(8): e12305. PMCID: PMC2925899
9. Woodward, O.M.,
Kottgen, A., Coresh, J., Boerwinkle, E., Guggino, W.B., and Kottgen, M. (2009) Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout
. Proc Natl Acad Sci USA
. 106(25):10338-42. PMCID: PMC2700910
10. Li, Y., Santoso, N.G., Yu, S., Woodward, O.M.,
Qian, F., Guggino, W.B. (2009) Polycystin-1 interacts with IP3R to modulate intracellular Ca2+ signaling, with implications for polycystic kidney disease
. J Biol Chem
. 284(52):36431-41. PMCID: PMC2794759