Jonathan Stamler

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Jonathan S. Stamler
Jonathan Stamler.jpg
Jonathan Stamler in his laboratory
Born
Jonathan Solomon Stamler

(1959-06-23) June 23, 1959 (age 62)
Wallingford, Oxfordshire, England
NationalityAmerican
Alma mater
Known forIdentification of S-nitrosylation as a protein post-translational modification, characterizing its regulatory enzymes, and defining its physiological and disease relevance
Awards
  • Pew Scholar
  • HHMI Investigator
  • Outstanding Investigator Award in Basic Science (American Federation for Medical Research Foundation)
  • Korsemyer Award (ASCI Award; finalist)
  • Ewing Marion Kauffman Innovator
  • Coulter Translational Partnership Research Award
  • American Heart Association Distinguished Scientist Award
Scientific career
Fields
Institutions

Jonathan Solomon Stamler (born June 23, 1959) is an English-born American physician and scientist. He is known for his discovery of protein S-nitrosylation, the addition of a nitric oxide (NO) group to cysteine residues in proteins, as a ubiquitous cellular signal to regulate enzymatic activity and other key protein functions in bacteria, plants and animals, and particularly in transporting NO on cysteines in hemoglobin as the third gas in the respiratory cycle.[1][2][3]

Early life and education[]

Stamler was born in Wallingford, England on June 23, 1959 [4] to a British father and American mother, and lived in multiple countries (United Kingdom, Switzerland, Israel, United States) as a youth due to his father's global career. He played on the Israeli national (under 18) tennis team.

He graduated with a bachelor's degree from Brandeis University in 1981, and earned his M.D. degree from Icahn School of Medicine at Mount Sinai in 1985.[4] His residency and fellowship training in pulmonary medicine and in cardiovascular medicine was at Brigham and Women’s Hospital at Harvard Medical School.[4]

Career and research[]

Academic appointments[]

Stamler was appointed Assistant Professor in Medicine at Harvard Medical School in 1993, and Associate Professor then Professor in Medicine at Duke University School of Medicine in 1993 and 1996, respectively, with recognition as the George Barth Geller Professor for Research in Cardiovascular Diseases in 2004.[4] He was an Investigator with the Howard Hughes Medical Institute from 1997 to 2005.[4][5] In 2009, Stamler became Robert S. and Sylvia K. Reitman Family Foundation Distinguished Chair in Cardiovascular Innovation and Professor of Medicine, Professor of Biochemistry and founding Director of the Institute for Transformative Molecular Medicine at Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center.[4][6] In 2012, Stamler founded and became Director of the Harrington Discovery Institute at University Hospitals Cleveland Medical Center, and in 2016 was named Harrington Discovery Institute President.[4][7][8] He is a founder of the Harrington Project, a tripartite collaboration among non-profit and for-profit organizations to shepherd laboratory discovery through translation and into biotechnology commercialization and approved therapy.[4]

Research[]

At the start of Stamler's research career, nitric oxide (NO) gas recently had been identified as a signaling molecule that mediated control of blood pressure.[9] NO gas released from blood vessel endothelial cells travels into surrounding vascular smooth muscle cells to vasodilate arteries (thereby decreasing blood pressure) by binding to the heme cofactor in the enzyme soluble guanylyl cyclase to produce cyclic guanosine monophosphate (cGMP) that activates the cGMP-dependent protein kinase to phosphorylate proteins regulating muscle contraction, among other targets.[10]

NO gas is unsuited to widespread signaling throughout the body. Its actions cannot be controlled and it exhibits high affinity binding to the hemes in red blood cell hemoglobin, whose vast quantity should prevent NO activity from traversing the bloodstream.[10] Furthermore, most biological actions that were being discovered for NO were not mediated by guanylyl cyclase/cGMP.[11] Stamler would provide a general mechanism to explain NO function in biology, which requires redox-activation of NO to allow its conjugation to all main classes of proteins, and would thereby establish the prototypic redox-based cellular signaling mechanism in biology.

Specially, Stamler recognized that NO can be redox-activated to bind to thiol groups, including those of free cysteine residues present in most proteins, by conversion to nitrosonium ion (NO+), to form an S-nitrosothiol (SNO) that is no longer subject to inactivation by heme and provides a means to stabilize and regulate NO bioactivity. Stamler then demonstrated that SNO modification of proteins, which he coined 'S-nitrosylation' to denote a signaling function, can regulate enzyme activity by modifying active site or allosteric site cysteines.[12][13] He went on to show that protein S-nitrosylation is a widespread mechanism for NO to be carried by proteins, including by hemoglobin, but also for regulating essentially all main classes of proteins: enzymes, transcription factors, receptors, G proteins, protein kinases, ion channels and micro RNA processing machinery.[1][14] That is, NO in the form of an SNO is a cellular signal that acts through post-translational modification of target proteins, akin to protein phosphorylation or ubiquitination.[15] At this time, approximately 7000 proteins have been reported to be nitrosylated.[16]

In addition to proteins, Stamler demonstrated that low molecular weight metabolic thiols (e.g., glutathione, coenzyme A) also can be S-nitrosylated under physiological conditions and can act as carriers of NO bioactivity,[17][18][19] and he identified the first endogenous SNOs.[17][20] He further demonstrated that specific enzymes convert NO to SNO (S-nitrosothiol synthases), transfer S-nitrosyl (SNO) groups to specific residues in proteins (transnitrosylases), and remove specific SNO groups from low-molecular weight or protein thiols (S-nitrosothiol reductases).[18][21][22]

Stamler's studies have identified numerous physiological and pathophysiological roles for protein S-nitrosylation and its regulation, demonstrating that SNO-based activity accounts for many physiological actions originally attributed to NO gas and to vasodilator drugs such as nitroglycerin, as well mediating previously unknown actions. Notable examples include inhibition of apoptosis, skeletal muscle contractility, the fight-or-flight response (cardiac response to adrenergic stimulation), regulation of gene expression, neuroprotection, and development and discovery of red blood cell mediated vasodilation.[15][23] His work has established that hemoglobin in red blood cells not only carries oxygen and carbon dioxide to support cellular respiration, but also carries NO as an S-nitrosothiol that is critical for autoregulation of blood flow through tissue microcapillaries. Thus, the respiratory cycle may be viewed as a 3-gas system (O2/NO/CO2) where oxygen delivery to tissue by hemoglobin is linked to oxygen-dependent R- and T-state conformational changes of hemoglobin to load NO on cysteine 93 of beta-globin in high oxygen and to deliver this SNO to dilate blood vessels in low oxygen.[1][2][3][14][24][25][26] The SNO-hemoglobin content of RBCs is low in multiple clinical conditions, including pulmonary hypertension, COPD, vascular disease and sickle cell disease, which impairs vasodilation by RBCs. For example, the ability of hemoglobin to undergo conformation-dependent S-nitrosylation is impaired in red blood cells from sickle cell disease patients, impairing vasodilation (subserving microcirculatory blood flow and tissue oxygen delivery) beyond that caused by red blood cell sickling.[27][28] Further, since hemoglobin S-nitrosylation is rapidly lost upon blood storage, the lack of S-nitrosylation within stored red blood cells limits the effective oxygen delivery capability of transfused blood, which can be improved by treating stored red blood cells to replace lost SNO.[29][30][31]

But hemoglobin is only one example where aberrant S-nitrosylation may contribute to disease. Accumulated evidence has demonstrated that S-nitrosylation of proteins plays important roles in many diseases, from heart failure to cancer to neurodegenerative disease.[32][33][34][35] Stamler’s studies have shown that SNO dysregulation is important in asthma,[36][37] pulmonary hypertension,[38] heart failure,[39][40] diabetes,[41] kidney injury,[42][43] and infectious diseases,[44][45] and he has worked to create therapeutic interventions to alleviate these dysfunctions that are in preclinical and clinical development.

Examining the hemoglobins of microbes and the parasitic worm Ascaris, Stamler found that these ancient forms of hemoglobin either eliminate NO enzymatically (bacteria and yeast) or utilize it to eliminate oxygen from its anaerobic environment (Ascaris), showing that the primordial function of hemoglobin was in NO processing not oxygen transport.[46][47][48][49] Stamler also identified trans-kingdom SNO signaling (operating between species as a general language between microbiota and animal host), since microbiota that produce NO can lead to widespread protein S-nitrosylation in a Caenorhabditis elegans host with profound genetic and physiological consequences.[23] Stamler also identified an enzymatic mechanism of nitroglycerin bioactivation to produce NO bioactivity, thus solving a longstanding mystery (i.e., the generation of NO from nitroglycerin was awarded a Nobel Prize in 1998, but how was not understood) and he demonstrated how nitroglycerin tolerance develops during therapy.[50]

Other activities[]

Stamler is a co-founder of multiple biotechnology companies focused on improving health through modifying S-nitrosylation or its physiological targets, including several that have had public offerings, and he has also licensed additional discoveries to large pharma. [4]

References[]

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  2. ^ a b Blakeslee, Sandra (1997-07-22). "What Controls Blood Flow? Blood". The New York Times. Retrieved 2019-01-11.
  3. ^ a b Saunders, Fenella (1997-01-01). "The NO & SNO Cycle". www.discovermagazine.com. Retrieved 2019-01-11.
  4. ^ a b c d e f g h i Jonathan Stamler curriculum vitae (PDF), retrieved 2019-01-11
  5. ^ "Jonathan S. Stamler". hhmi.org/. Howard Hughes Medical Institute. Retrieved 2019-01-11.
  6. ^ "Director of Institute for Transformative Molecular Medicine, Inaugural Robert S. and Sylvia K. Reitman Family Foundation Distinguished Chair in Cardiovascular Innovation Announced". case.edu. Case Western Reserve University. 2009-09-17. Retrieved 2019-01-11.
  7. ^ Zeitner, Brie (2012-02-29). "Jonathan Stamler named director, Bob Keith to head drug development of Harrington project". The Plain Dealer.
  8. ^ Rosenblum, Jonah (2016-02-11). "Stamler gains 'genius' tag as Harrington Discovery Institute director". Cleveland Jewish News. Retrieved 2019-01-11.
  9. ^ "1998 Nobel Prize in Medicine or Physiology". Nobel Foundation. Retrieved 2019-01-11.
  10. ^ a b Murad, Ferid (1994). "The nitric oxide-cyclic GMP signal transduction system for intracellular and intercellular communication". Recent Prog Horm Res. 49: 239–248. doi:10.1016/b978-0-12-571149-4.50016-7. ISBN 9780125711494. PMID 7511827.
  11. ^ Garg, UC; Hasid, A (August 1990). "Nitric oxide-generating vasodilators inhibit mitogenesis and proliferation of BALB/C 3T3 fibroblasts by a cyclic GMP-independent mechanism". Biochem Biophys Res Commun. 171 (1): 474–479. doi:10.1016/0006-291x(90)91417-q. PMID 1697465.
  12. ^ Stamler, JS; Simon, DI; Osborne, JA; Mullins, ME; Jaraki, O; Michel, T; Singel, DJ; Loscalzo, J (1992-01-01). "S-nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds". Proc Natl Acad Sci U S A. 89 (1): 444–448. Bibcode:1992PNAS...89..444S. doi:10.1073/pnas.89.1.444. PMC 48254. PMID 1346070.
  13. ^ Stamler, JS; Simon, DI; Jaraki, O; Osborne, JA; Francis, S; Mullins, M; Singel, D; Loscalzo, J (1992-09-01). "S-nitrosylation of tissue-type plasminogen activator confers vasodilatory and antiplatelet properties on the enzyme". Proc Natl Acad Sci U S A. 89 (17): 8087–8091. Bibcode:1992PNAS...89.8087S. doi:10.1073/pnas.89.17.8087. PMC 49861. PMID 1325644.
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  15. ^ a b Hess, DT; Stamler, JS (2012-02-10). "Regulation by S-nitrosylation of protein post-translational modification". J Biol Chem. 287 (7): 4411–4418. doi:10.1074/jbc.R111.285742. PMC 3281651. PMID 22147701.
  16. ^ Stomberski, C; Hess, DT; Stamler, JS (2018-04-01). "Protein S-Nitrosylation: Determinants of Specificity and Enzymatic Regulation of S-Nitrosothiol-Based Signaling". Antioxidants & Redox Signaling. 30 (10): 1331–1351. doi:10.1089/ars.2017.7403. PMC 6391618. PMID 29130312.
  17. ^ a b Gaston B, Reilly J, Drazen JM, Fackler J, Ramdev P, Arnelle D, Mullins ME, Sugarbaker DJ, Chee C, Singel DJ, Loscalzo J, Stamler JS (1993). "Endogenous nitrogen oxides and bronchodilator S-nitrosothiols in human airways". Proc Natl Acad Sci U S A. 90 (23): 10957–10961. Bibcode:1993PNAS...9010957G. doi:10.1073/pnas.90.23.10957. PMC 47900. PMID 8248198.
  18. ^ a b Benhar, M; Forrester, MT; Stamler, JS (October 2009). "Protein denitrosylation: enzymatic mechanisms and cellular function". Nat Rev Mol Cell Biol. 10 (10): 721–732. doi:10.1038/nrm2764. PMID 19738628.
  19. ^ Anand P, Hausladen A, Wang YJ, Zhang GF, Stomberski C, Brunengraber H, Hess DT, Stamler JS (2014). "Identification of S-nitroso-CoA reductases that regulate protein S-nitrosylation". Proc Natl Acad Sci U S A. 111 (52): 18572–18577. Bibcode:2014PNAS..11118572A. doi:10.1073/pnas.1417816112. PMC 4284529. PMID 25512491.
  20. ^ Stamler JS, Jaraki O, Osborne J, Simon DI, Keaney J, Vita J, Singel D, Valeri CR, Loscalzo J (1992). "Nitric oxide circulates in mammalian plasma primarily as an S-nitroso adduct of serum albumin". Proc Natl Acad Sci U S A. 89 (16): 7674–7677. Bibcode:1992PNAS...89.7674S. doi:10.1073/pnas.89.16.7674. PMC 49773. PMID 1502182.
  21. ^ Seth D, Hess DT, Hausladen A, Wang L, Wang YJ, Stamler JS (2018). "A Multiplex Enzymatic Machinery for Cellular Protein S-nitrosylation". Mol Cell. 69 (3): 451–464.e6. doi:10.1016/j.molcel.2017.12.025. PMC 5999318. PMID 29358078.
  22. ^ "New Nitric Oxide-Converting Enzymes Discovered". genengnews.com. Mary Ann Liebert Inc. 2018-01-19.
  23. ^ a b Seth, P; Hsieh, PN; Jamal, S; Wang, L; Gygi, SP; Jain, MK; Coller, J; Stamler, JS (2019-02-21). "Regulation of MicroRNA Machinery and Development by Interspecies S-Nitrosylation". Cell. 176 (5): 1014–1025. doi:10.1016/j.cell.2019.01.037. PMC 6559381. PMID 30794773.
  24. ^ Stamler, JS; Jia, L; Eu, JP; McMahon, TJ; Demchenko, IT; Bonaventura, J; Gernert, K; Piantadosi, CA (1997-06-27). "Blood flow regulation by S-nitrosohemoglobin in the physiological oxygen gradient". Science. 276 (5321): 2034–2037. doi:10.1126/science.276.5321.2034. PMID 9197264.
  25. ^ Zhang, R; Hess, DT; Qian, Z; Hausladen, A; Fonseca, F; Chaube, R; Reynolds, JD; Stamler, JS (2015-05-19). "Hemoglobin βCys93 is essential for cardiovascular function and integrated response to hypoxia". Proc Natl Acad Sci U S A. 112 (20): 6425–6430. Bibcode:2015PNAS..112.6425Z. doi:10.1073/pnas.1502285112. PMC 4443356. PMID 25810253.
  26. ^ Paddock, Catherine (2015-04-13). "Study shows blood cells need nitric oxide to deliver oxygen". Medical News Today. Healthline Media UK. Retrieved 2019-01-11.
  27. ^ Pawloski, JR; Hess, DT; Stamler, JS (2005-02-15). "Impaired vasodilation by red blood cells in sickle cell disease". Proc Natl Acad Sci U S A. 102 (7): 2531–2536. Bibcode:2005PNAS..102.2531P. doi:10.1073/pnas.0409876102. PMC 548996. PMID 15699345.
  28. ^ Leary, Warren E (1996-04-23). "Findings Intrigue Sickle Cell Experts". The New York Times. Retrieved 2019-01-11.
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  30. ^ Reynolds, JD; Bennett, KM; Cina, AJ; Diesen, DL; Henderson, MB; Matto, F; Plante, A; Williamson, RA; Zandinejad, K; Demchenko, IT; Hess, DT; Piantadosi, CA; Stamler, JS (2013-07-09). "S-nitrosylation therapy to improve oxygen delivery of banked blood". Proc Natl Acad Sci U S A. 110 (28): 11529–11534. Bibcode:2013PNAS..11011529R. doi:10.1073/pnas.1306489110. PMC 3710799. PMID 23798386.
  31. ^ Park, Alice (2007-10-08). "Why Banked Blood Goes Bad". Time. Retrieved 2019-01-11.[dead link]
  32. ^ Foster MW, McMahon TJ, Stamler JS (2003). "S-nitrosylation in health and disease". Trends Mol Med. 9 (4): 160–168. doi:10.1016/S1471-4914(03)00028-5. PMID 12727142.
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  34. ^ Nakamura, T; Lipton, SA (2017-12-01). "'SNO'-Storms Compromise Protein Activity and Mitochondrial Metabolism in Neurodegenerative Disorders". Trends Endocrinol Metab. 28 (12): 879–892. doi:10.1016/j.tem.2017.10.004. PMC 5701818. PMID 29097102.
  35. ^ Reis, AKCA; Stern, A; Monteiro, HP (2019-04-05). "S-nitrosothiols and H2S donors: Potential chemo-therapeutic agents in cancer". Redox Biol. 27: 101190. doi:10.1016/j.redox.2019.101190. PMC 6859576. PMID 30981679. 101190.
  36. ^ Gaston, B; Sears, S; Woods, J; Hunt, J; Ponaman, M; McMahon, T; Stamler, JS (1998-05-02). "Bronchodilator S-nitrosothiol deficiency in asthmatic respiratory failure". Lancet. 351 (9112): 1317–1319. doi:10.1016/S0140-6736(97)07485-0. PMID 9643794.
  37. ^ Que, LG; Liu, L; Yan, Y; Whitehead, GS; Gavett, SH; Schwartz, DA; Stamler, JS (2005-06-10). "Protection from experimental asthma by an endogenous bronchodilator". Science. 308 (5728): 1618–1621. Bibcode:2005Sci...308.1618Q. doi:10.1126/science.1108228. PMC 2128762. PMID 15919956.
  38. ^ McMahon TJ, Ahearn GS, Moya MP, Gow AJ, Huang YC, Luchsinger BP, Nudelman R, Yan Y, Krichman AD, Bashore TM, Califf RM, Singel DJ, Piantadosi CA, Tapson VF, Stamler JS (2005). "A nitric oxide processing defect of red blood cells created by hypoxia: deficiency of S-nitrosohemoglobin in pulmonary hypertension". Proc Natl Acad Sci U S A. 102 (41): 14801–14806. Bibcode:2005PNAS..10214801M. doi:10.1073/pnas.0506957102. PMC 1253588. PMID 16203976.
  39. ^ Hayashi, H; Hess, DT; Zhang, R; Sugi, K; Gao, H; Tan, BL; Bowles, DE; Milano, CA; Jain, MK; Koch, WJ; Stamler, JS (2018-05-03). "S-Nitrosylation of β-Arrestins Biases Receptor Signaling and Confers Ligand Independence". Mol Cell. 70 (3): 473–487. doi:10.1016/j.molcel.2018.03.034. PMC 5940012. PMID 29727618.
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  41. ^ Qian, Q; Zhang, Z; Orwig, A; Chen, S; Ding, WX; Xu, Y; Kunz, RC; Lind, NRL; Stamler, JS; Yang, L (2018-02-01). "S-Nitrosoglutathione Reductase Dysfunction Contributes to Obesity-Associated Hepatic Insulin Resistance via Regulating Autophagy". Diabetes. 67 (2): 193–207. doi:10.2337/db17-0223. PMID 29074597.
  42. ^ Zhou, HL; Zhang, R; Anand, P; Stomberski, CT; Qian, Z; Hausladen, A; Wang, L; Rhee, EP; Parikh, SM; Karumanchi, SA; Stamler, JS (2019-01-10). "Metabolic reprogramming by the S-nitroso-CoA reductase system protects against kidney injury". Nature. 565 (7737): 96–100. Bibcode:2019Natur.565...96Z. doi:10.1038/s41586-018-0749-z. PMC 6318002. PMID 30487609.
  43. ^ "Re-programming the body's energy pathway boosts kidney self-repair". medicalexpress.com. Science X. 2018-11-28. Retrieved 2019-01-11.
  44. ^ de Jesús-Berríos M, Liu L, Nussbaum JC, Cox GM, Stamler JS, Heitman J (2003). "Enzymes that counteract nitrosative stress promote fungal virulence". Curr Biol. 13 (22): 1963–1968. doi:10.1016/j.cub.2003.10.029. PMID 14614821.
  45. ^ Elphinstone RE, Besla R, Shikatani EA, Lu Z, Hausladen A, Davies M, Robbins CS, Husain M, Stamler JS, Kain KC (2017). "S-Nitrosoglutathione Reductase Deficiency Confers Improved Survival and Neurological Outcome in Experimental Cerebral Malaria". Infect Immun. 85 (9): e00371-17. doi:10.1128/IAI.00371-17. PMC 5563579. PMID 28674030.
  46. ^ Hausladen, A; Gow, AJ; Stamler, JS (1998-11-24). "Nitrosative stress: metabolic pathway involving the flavohemoglobin". Proc Natl Acad Sci USA. 95 (24): 14100–14105. Bibcode:1998PNAS...9514100H. doi:10.1073/pnas.95.24.14100. PMC 24333. PMID 9826660.
  47. ^ Liu, L; Zeng, M; Hausladen, A; Heitman, J; Stamler, JS (2000-04-25). "Protection from nitrosative stress by yeast flavohemoglobin". Proc Natl Acad Sci USA. 97 (9): 4672–4676. Bibcode:2000PNAS...97.4672L. doi:10.1073/pnas.090083597. PMC 18291. PMID 10758168.
  48. ^ Minning, DM; Gow, AJ; Bonaventura, J; Braun, R; Dewhirst, M; Goldberg, DE; Stamler, JS (1999-09-30). "Ascaris haemoglobin is a nitric oxide-activated 'deoxygenase'". Nature. 401 (6752): 497–502. Bibcode:1999Natur.401..497M. doi:10.1038/46822. PMID 10519555.
  49. ^ Blakeslee, Sandra (1999-10-05). "Thanks to a 'Horrible Worm,' New Ideas on Hemoglobin". The New York Times. Retrieved 2019-01-11.
  50. ^ Chen, Z; Zhang, J; Stamler, JS (2002-06-11). "Identification of the enzymatic mechanism of nitroglycerin bioactivation". Proc Natl Acad Sci USA. 99 (12): 8306–8311. doi:10.1073/pnas.122225199. PMC 123063. PMID 12048254.

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