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Cambridge Institute for Medical Research

 

The role of endoplasmic reticulum stress in disease

General audience summary: 
Proteins must be folded properly to function. If this becomes defective, cells experience stress and respond by clearing away these misfolded proteins for destruction. We are investigating how the response to this form a cellular stress is important in health and disease. Current projects in our group address a variety of lung diseases including mesothelioma, pulmonary hypertension, and pulmonary fibrosis.

Strategic CIMR themes: Protein Folding and Quality Control, Organelle Biology, Rare Genetic Diseases

Funding: Medical Research Council (MRC), Engineering and Physical Sciences Research Council (EPSRC), British Lung Foundation, Alpha1-Foundation, June Hancock Mesothelioma Research Fund

Research Group members: Joe Chambers, Jenny Dickens, Giulia Emanuelli, Joanna Obacz, Eimear Rutherford, Max Schwiening, Marie Shamseddin (visiting researcher), Elaine Soon, Haoyang Ying, Nikita Zubkov

Biography

Stefan studied medicine at the University of Cambridge as part of its MB/PhD Programme. After medical posts in Cambridge, London and Edinburgh, he undertook post-doctoral training in New York funded by the Wellcome Trust and as an MRC Clinician Scientist Fellow back in Cambridge. He established his own group in CIMR as an MRC Senior Clinical Research Fellow in 2012.  He is now Professor of Respiratory Science at the University of Cambridge and an Honorary Consultant Respiratory Physician at Addenbrooke’s and Royal Papworth Hospitals. His laboratory research focuses on the role of stress signalling in lung disease.  His clinical research focuses on pleural medicine, especially the genetics of pneumothorax. He is Director of the University of Cambridge MB/PhD Programme.

Research

The role of endoplasmic reticulum stress in disease

Studying the consequences of protein misfolding in the endoplasmic reticulum (ER), termed ER stress, particularly on cell growth and survival.

Proteins destined for secretion or for insertion into the cell membrane are first folded within the endoplasmic reticulum. The process of protein folding can become defective in many disease states such as hypoxia, malignancy and some forms of diabetes. When the level of misfolded proteins within the endoplasmic reticulum increases, the cell is said to experience ‘endoplasmic reticulum stress’.

We wish to understand the cellular consequences of endoplasmic reticulum stress, in particular its effects on tissue growth and cell survival. In doing so, we hope to identify targets for the development of novel therapies. During endoplasmic reticulum stress, protein biosynthesis is initially attenuated through phosphorylation of the translation initiation factor eIF2α by the kinase PERK.  Subsequent dephosphorylation of eIF2α following the induction of the phosphatase PPP1R15a (GADD34) restores protein translation. We previously discovered that this recovery of translation can contribute to the toxic effects of endoplasmic reticulum stress. This raises the exciting possibility that modulation of eIF2α phosphorylation may provide a useful target for the development of novel drugs to protect tissues from cell death.

 

 

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This movie shows CHO cell expressing YFP-Z-α1-antitrypsin subjected to serial blockface scanning electron microscopy. The surface of antitrypsin-containing inclusions were traced in 2D images and combined to generate a 3D projection by isosurface rendering with a surface area detail of 36nm. Distinct coloration of physically separated inclusions showed that many of these structures contacted one another, but inspection of the original 3View stack revealed that inclusion membrane contacts were almost never accompanied by evidence of inter-luminal connectivity.

Publications

Key publications: 

Ye S, Azad AA, Chambers JE, Beckett AJ, Roach L, Moorcroft SCT, Aslam Z, Prior IA, Markham AF, Coletta LP, Marciniak SJ* and Stephen Evans S* (2020). Exploring high aspect ratio gold nanotubes as cytosolic agents: structural engineering and uptake into mesothelioma cells. Small [in press]. *Joint senior authors

Chambers J.E., Kubankova M., Huber, R., López-Duart I, Avezov E., Bond P., Marciniak S.J.*, Kuimova, M.* (2018) An Optical Technique for Mapping Microviscosity Dynamics in Cellular Organelles. ACS Nano 12:4398-4407. *Joint senior authors

Malzer E., Dominicus C.S., Chambers J.E., Dickens J.A., Mookerjee S., Marciniak S.J. (2018).  The integrated stress response regulates BMP signalling through effects on translation.  BMC Biology 16:34 https://doi.org/10.1186/s12915-018-0503-x

van ‘t Wout E.F.A., van Schadewijk A., van Boxtel R., Dalton L.E., Clarke H.J., Tommassen J., Marciniak S.J.*, Hiemstra P.S.* (2015).  Virulence factors of Pseudomonas aeruginosa induce both the unfolded protein and integrated stress responses in airway epithelial cells.  PLoS Pathogens 11(6): e1004946. doi:10.1371/journal.ppat.1004946 *Joint senior authors

Chambers, J.E., Dalton, L.E., Clarke, H.J., Malzer, E., Dominicus, C.S., Patel, V., Moorhead, G.B.G., Ron, D., and Marciniak, S.J. (2015). Actin dynamics tune the integrated stress response by regulating eukaryotic initiation factor 2α dephosphorylation. eLIFE doi.org/10.7554/eLife.04872.

Chen, R., Rato, C., Yan, Y., Crespillo-Casado, A., Clarke, H.J., Harding, H.P., Marciniak, S.J.*, Read, R.J.*, and Ron, D.* (2015). G-actin provides substrate-specificity to eukaryotic initiation factor 2a holophosphatase. eLIFE doi.org/10.7554/eLife.04871. *Joint senior authors

Ordóñez A., Snapp E.L., Tan L., Miranda E., Marciniak S.J.*, Lomas D.A.* (2013) Endoplasmic reticulum polymers impair luminal protein mobility and sensitise to cellular stress in α1-antitrypsin deficiency. Hepatology 57: 2049-60. *Joint senior authors

Marciniak S.J., Garcia-Bonilla L., Hu J., Harding H.P., Ron D. (2006). Activation-dependent substrate recruitment by the eukaryotic translation initiation factor 2 kinase PERK. J Cell Biol. 172: 201-9.

Marciniak S.J, Yun CY, Oyadomari S, Novoa I, Zhang Y, Jungreis R, Nagata K, Harding HP, Ron D. (2004). CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 2004 18:3066-77.

Other publications: 

Bradley KL, Stokes CA, Marciniak SJ*, Parker LC*, Condliffe AM* (2020). The Role of Unfolded Proteins in Lung Disease. Thorax [in press] *Joint senior authors

Ye S#, Azad AA#, Chambers JE, Beckett AJ, Roach L, Moorcroft SCT, Aslam Z, Prior IA, Markham AF, Coletta LP, Marciniak SJ* and Stephen Evans S* (2020). Exploring high aspect ratio gold nanotubes as cytosolic agents: structural engineering and uptake into mesothelioma cells. Small [in press]. *Joint senior authors

Martinelli AW, Ingle T, Newman J, Nadeem I, Jackson K, Lane ND,18, Melhorn J, Davies HE, Rostron AJ, Adeni A, Conroy K, Woznitza N, Matson M, Brill SE, Murray J, Shah A, Naran R, Hare SS, Collas O, Bigham S, Spiro M, Huang MM, Iqbal B, Trenfield S, Ledot S, Desai S, Standing L, Babar J, Mahroof R, Smith I, Lee K, Tchrakian N, Uys S, Ricketts W, Patel ARC, Aujayeb A, Kokosi M, Wilkinson AJK & Marciniak SJ (2020). COVID-19 and Pneumothorax: A Multicentre Retrospective Case Series. Eur Respir J [epub ahead of print] (https://doi.org/10.1183/13993003.02697-2020).

Straková K; López-Andarias J, Jiménez-Rojo N, Chambers J, Marciniak SJ, Riezman H, Sakai N, Matile Stefan (2020) HaloFlippers:  A General Tool for the Fluorescence Imaging of Precisely Localized Membrane Tension Changes in Living Cells.  ACS Central Science [epub ahead of print] https://doi.org/10.1021/acscentsci.0c00666

Dell’Anno I, Barone E, Mutti L, Rassl DM, Marciniak SJ, Silvestri R, Landi S, Gemignani F (2020). Tissue expression of lactate transporters (MCT1 and MCT4) and prognosis of Malignant Pleural Mesothelioma. J Transl Med. 18, 341. https://doi-org.ezp.lib.cam.ac.uk/10.1186/s12967-020-02487-6

Emanuelli G, Nassehzadeh-Tabriz N, Morrell NW, Marciniak SJ (2020) The integrated stress response in pulmonary disease. Eur Respir Rev 29: 200184 doi.org/10.1183/16000617.0184-2020.

Hallifax RJ, McKeown E, Sivakumar P, Fairbairn I, Peter C, Leitch A, Knight M, Stanton A, Ijaz A, Marciniak S, Cameron J, Bhatta A, Blyth KG, Reddy R, Harris MC, Maddekar N, Walker S, West A, Laskawiec-Szkonter M, Corcoran JP, Gerry S, Roberts C, Harvey JE, Maskell N, Miller RF, Rahman NM. (2020) Ambulatory management of primary spontaneous pneumothorax: an open-label, randomised controlled trial. Lancet. 2020 396:39-49. doi: 10.1016/S0140-6736(20)31043-6.

Marciniak SJ & Johnson SR (2020). Pneumothorax and the biology of Birt-Hogg-Dubé syndrome. Thorax 75(6):442-443.

Rojas-Charry L., Calero-Martinez S, Morganti C, Morciano G, Hagel C, Marciniak SJ, Glatzel M, Pinton P, Park K, Sepulveda-Falla D. (2020). Susceptibility to cellular stress in PS1 mutant N2a cells is associated with mitochondrial defects and altered calcium homeostasis.  Sci Rep 10:6455. doi: 10.1038/s41598-020-63254-7.

Matsumoto K, Marciniak SJ (2020). The Importance of Genetic Factors in the Management of Spontaneous Pneumothorax.  Current Pulmonology Reports 9:47-55.

Boone PM, Scott RM, Marciniak SJ, Henske EP, Raby BA (2019). The genetics of pneumothorax. Am J Respir Crit Care Med. 199:1344-1357. doi: 10.1164/rccm.201807-1212CI.

Kubánková M, Chambers JE, Huber RG, Bond PJ, Marciniak SJ, Kuimova MK. (2019).  Linker length affects photostability of protein-targeted sensor of cellular microviscosity. Methods Appl Fluoresc. 7:044004. doi: 10.1088/2050-6120/ab481f.

Thiebaut AM, Hedou E, Marciniak SJ, Vivien D, Roussel BD (2019). The role of proteostasis in stroke: How ER stress and autophagy influence the neuronal outcome. Front Neurosci. doi: 13:637. 10.3389/fnins.2019.00637.

Patel V, Bidault G, Chambers JE, Carobbio S, Everden AJT, Garcés C, Dalton LE, Gribble FM, Vidal-Puig A & Marciniak SJ (2019).  Inactivation of Ppp1r15a minimises weight gain and insulin resistance during caloric excess in female mice. Sci Rep 9:2903 doi.org/10.1038/s41598-019-39562-y.

Marciniak SJ. (2019). Endoplasmic reticulum stress: a key player in human disease. FEBS J. 286:228-231. doi: 10.1111/febs.14740.

Dickens J.A., Malzer E., Chambers J.E. Marciniak S.J. (2018). Pulmonary endoplasmic reticulum stress: Scars, Smoke and Suffocation.  FEBS J 286:322-341doi: 10.1111/febs.14381.

Holcman D, Parutto P, Chambers JE, Fantham M, Young LJ, Marciniak SJ, Kaminski CF, Ron D, Avezov E. (2018). Single particle trajectories reveal active endoplasmic reticulum luminal flow. Nat Cell Biol 20:1118-1125 doi: 10.1038/s41556-018-0192-2.

Chambers JE, Dickens JA, Marciniak SJ (2018). Measuring the effects of α1-antitrypsin polymerisation on the structure and biophysical properties of the endoplasmic reticulum. Biol Cell 69:851-860 doi: 10.1111/boc.201800023.

Segeritz C-P, Rashid ST, Cardoso de Brito M, Serra Paola M, Ordonez A, Morell C, Kaserman JE, Madrigal P, Hannan N, Gatto L, Tan L, Wilson AA, Lilley K, Marciniak SJ, Gooptu B, Lomas DA, Vallier L (2018). hiPSC hepatocyte model demonstrates the role of unfolded protein response and inflammatory networks in α1-antitrypsin deficiency.  J Hepatol. S0168-8278(18)32113-5. doi: 0.1016/j.jhep.2018.05.028.

Lim R., Marciniak S.J., Marcadier J., Rassl D., Mitchell P.D. (2018). Time is of the essence: a young man with recurrent pneumothorax and cavitating lung lesions. Ann. Am. Thor. Soc. 15: 988-991.

Chambers J.E., Kubankova M., Huber, R., López-Duart I, Avezov E., Bond P., Marciniak S.J.*, Kuimova, M.* (2018) An Optical Technique for Mapping Microviscosity Dynamics in Cellular Organelles. ACS Nano 12:4398-4407. *Joint senior authors

Malzer E., Dominicus C.S., Chambers J.E., Dickens J.A., Mookerjee S., Marciniak S.J. (2018).  The integrated stress response regulates BMP signalling through effects on translation.  BMC Biology 16:34 https://doi.org/10.1186/s12915-018-0503-x

Scott R.M., Henske E.P., Raby B., P.M., Rusk R.A., Marciniak S.J. (2018).  Familial pneumothorax – towards precision medicine. Thorax 73:270-276.

Marciniak S.J. (2017).  Endoplasmic reticulum stress in lung disease.  Eur. Respir. Rev. 26: 170018 [https://doi.org/10.1183/16000617.0018-2017].

Crespillo-Casado A., Chambers J.E., Fischer P., Marciniak S.J., Ron D. (2017). PPP1R15A-mediated dephosphorylation of eIF2α is unaffected by Sephin1 or Guanabenz. eLIFE. 10.7554/eLife.19893.

Nikolić M.Z. & Marciniak S.J. (2017).  Familial Pneumothorax.  Respiratory Disease in Practice 25: 8-11.

Dickens J.A., Ordóñez A., Chambers J.E., Beckett A.J., Patel V., Malzer E., Dominicus C.S., Bradley J., Peden A.A., Prior I.A., Lomas D.A., Marciniak S.J. (2016).  The endoplasmic reticulum remains functionally connected by vesicular transport after its fragmentation in cells expressing Z-α1-antitrypsin.  FASEB J 30: 4083-4097.

Greene C, Marciniak S.J., Teckman J., Ferrarotti I., Brantly M., Lomas D.A., Stoller J., McElvaney N.G. (2016) Alpha-1-antitrypsin deficiency. Nat. Rev. Dis. Primers.  2: 16051. doi: 10.1038/nrdp.2016.51.

Marciniak S.J., Ordóñez A., Dickens J.A., Chambers J.E., Patel V., Dominicus C.S., Malzer E. (2016). New concepts in α1-antitrypsin deficiency disease mechanisms.  Ann. Am. Thor. Soc. 13(S4): S289-S296.

Fra A., Cosmi F., Ordoñez A., Berardelli R., Perez J., Guadagno N.A., Corda L., Marciniak S.J., Lomas D.A., Miranda E. (2016). Polymers of Z-α1-antitrypsin are secreted in cell models of disease. Eur. Respir. J. 47:1005-9.

Ulbrich L., Favaloro F.L., Trobiani L., Marchetti V., Patel V., Pascucci T., Comoletti D., Marciniak S.J., De Jaco A. (2016). Autism associated R451C mutation in Neuroligin 3 leads to the activation of the unfolded protein response in a PC12 Tet-On inducible system. Biochem J. 473:423-34.

Rintoul R.C., Rassl R.M., Gittins J., Marciniak S.J.; MesobanK collaborators. (2016). MesobanK UK: an international mesothelioma bioresource. Thorax 7: 380-2.

Chambers J.E., Dalton L.E., Subramanian D.N., Gooptu B., Balan A., Park S-P., Holden S., Marciniak S.J. (2015). Spontaneous pneumothorax can be associated with TGFBR2 mutation. Eur. Respir. J. 46: 1832-1835.

Moriconi C., Ordóñez A., Lupo G., Gooptu B., Irving J., Noto R., Martorana V., Manno M., Timpano V., Guadagno N., Lucy D., Marciniak S.J., Lomas D, Miranda E. (2015) Interactions between N-linked glycosylation and polymerisation of neuroserpin within the endoplasmic reticulum. FEBS J.  282:4565-79.

van ‘t Wout E.F.A., van Schadewijk A., van Boxtel R., Dalton L.E., Clarke H.J., Tommassen J., Marciniak S.J.*, Hiemstra P.S.* (2015).  Virulence factors of Pseudomonas aeruginosa induce both the unfolded protein and integrated stress responses in airway epithelial cells.  PLoS Pathogens 11(6): e1004946. doi:10.1371/journal.ppat.1004946 *Joint senior authors

Chambers, J.E., Dalton, L.E., Clarke, H.J., Malzer, E., Dominicus, C.S., Patel, V., Moorhead, G.B.G., Ron, D., and Marciniak, S.J. (2015). Actin dynamics tune the integrated stress response by regulating eukaryotic initiation factor 2α dephosphorylation. eLIFE doi.org/10.7554/eLife.04872.

Chen, R., Rato, C., Yan, Y., Crespillo-Casado, A., Clarke, H.J., Harding, H.P., Marciniak, S.J.*, Read, R.J.*, and Ron, D.* (2015). G-actin provides substrate-specificity to eukaryotic initiation factor 2a holophosphatase. eLIFE doi.org/10.7554/eLife.04871. *Joint senior authors

Nikolic M.Z., Lok L.S.C., Mattishent K., Barth S., Yung B., Cummings N., Wade D., Vali Y., Chong K., Wilkinson A., Mikolasch T., Brij S., Jenkins H.S., Kamath A., Pasteur M., Hopkins T., Wason J., Marciniak S.J. (2015) Non-interventional statistical comparison of BTS and ACCP guidelines for size and severity in primary pneumothorax. Eur. Respir. J. 45: 1731-4.

Ordóñez A., Pérez J., Tan L., Dickens J.A., Motamedi-Shad N., Irving J.A., Haq I., Ekeowa U., Marciniak S.J., Miranda E., Lomas D.A. (2015) A single-chain variable fragment intrabody prevents intracellular polymerisation of Z-α1-antitrypsin while allowing its antiproteinase activity.  FASEB J. 29:2667-78.

Tan L., Perez J., Mela M., Miranda E., Burling K.A., Rouhani F.N., DeMeo D.L., Haq I., Irving J.A., Ordonez A., Dickens J.A., Brantly M., Marciniak S.J., Alexander G., Gooptu B., Lomas D.A., (2015) Characterising the association of latency with α1-antitrypsin polymerisation using a novel monoclonal antibody.  Int J Biochem Cell Biol. 58:81-91.

van ‘t Wout E.F.A., van Schadewijk A., Lomas D.A., Stolk J, Marciniak S.J., Hiemstra P.S. (2015). Function of monocytes and monocyte-derived macrophages in α1-antitrypsin deficiency. Eur. Respir. J. 45: 3654-376.

Khabirova E., Moloney A., Marciniak S.J., Williams J., Lomas D.A., Oliver S.G., Favrin G., Sattelle D.B., Crowther D.C. (2014).  The TRiC/CCT Chaperone Is Implicated in Alzheimer's Disease Based on Patient GWAS and an RNAi Screen in Aβ-Expressing Caenorhabditis elegans.  PLoS One. 2014 Jul 31;9:e102985. doi: 10.1371/journal.pone.0102985.

Jama G.M., Scarci M., Bowden J., & Marciniak S.J. (2014) Palliative treatment for symptomatic malignant pericardial effusion. Interact Cardiovasc Thorac Surg 19: 1019-26.

Clarke H.J., Chambers J.C., Liniker E. & Marciniak S.J. (2014).  Endoplasmic reticulum stress in malignancy.  Cancer Cell 25: 563-573.

van Galen P, Kreso A, Mbong N, Kent DG, Fitzmaurice T, Chambers JE, Xie S, Laurenti E, Hermans K, Eppert K, Marciniak SJ, Goodall JC, Green AR, Wouters BG, Wienholds E, Dick JE. (2014).  The unfolded protein response governs integrity of the haematopoietic stem-cell pool during stress. Nature. 510: 268-72.

Chambers J.E. & Marciniak S.J. (2014).  Cellular Mechanisms of Endoplasmic Reticulum Stress Signaling in Health and Disease. 2. Protein misfolding and ER stress. Am J Physiol Cell Physiol. 307:C657-C670.

van ‘t Wout E.F.A., Hiemstra P.S., Marciniak S.J. (2014).  The Integrated Stress Response in Lung Disease.  Am. J. Respir. Cell Mol. Biol.  50: 1005-9.

van ‘t Wout E.F.A., Dickens J.A., van Schadewijk A., Haq I., Kwok H.F., Ordóñez A., Murphy G., Stolk J., Lomas D.A., Hiemstra P.S., Marciniak S.J. (2014). Increased ERK signalling promotes inflammatory signalling in primary airway epithelium expressing Z α1-antitrypsin.  Hum. Mol. Gen. 23:929-41.

Tan L., Dickens J.A., DeMeo D.L., Miranda E., Perez J., Rashid S.T., Day J., Ordoñez A., Marciniak S.J., Haq I., Barker A.F., Campbell E.J., Eden E., McElvaney N.G., Rennard S.I., Sandhaus R.A., Stocks J.M., Stoller J.K., Strange C., Turino G., Rouhani F.N., Brantly M. & Lomas D.A.  (2014).  Circulating polymers in α1-antitrypsin deficiency.  Eur. Respir. J. 43: 150-4.

Marciniak S.J. & Lomas D.A. (2014). Genetic susceptibility. (COPD themed issue) Clin Chest Med 35: 29-38.

Adolph T.E., Tomcza M.F., Niederreiter L., Ko H-J, Böck J., Martinez-Naves E, Glickman J.N., Tschurtschenthaler M., Hartwig J., Hosomi S., Flak M.B., Cusick J.L., Kohno K., Iwawaki T., Billmann-Born S., Bharti R., Lucius R., Kweon M-N., Marciniak S.J., Choi A., Hagen S.J., Schreiber S., Rosenstiel P., Kaser A., Blumberg R.S. (2013) Paneth cells as a site of origin for intestinal inflammation.  Nature 503: 272-6.

Kruppa A.J., Ott S., Chandraratna D.S., Irving J.A., Page R.M., Speretta E., Camargo L.M., Marciniak S.J.*, Lomas D.A.*, Crowther D.C.* (2013).  Suppression of Aβ toxicity by puromycin-sensitive aminopeptidase is independent of its proteolytic activity.  Biochim Biophys Acta. 1832: 2115-2126. *Joint senior authors

Roussel BD, Newton TM, Malzer E, Simecek N, Haq I, Thomas SE, Burr ML, Lehner PJ, Crowther DC, Marciniak S.J.* & Lomas DA* (2013).  Sterol metabolism regulates neuroserpin polymer degradation in the absence of the unfolded protein response in the dementia FENIB.  Hum Mol. Gen. 22: 4616-26. *Joint senior authors

Malzer E, Szajewska-Skuta M, Dalton L.E., Thomas S.E., Hu N., Skaer H., Lomas D.A., Crowther D.C., & Marciniak S.J. (2013) Coordinate regulation of eIF2a phosphorylation by dPPP1R15 and dGCN2 is required during Drosophila development.  J. Cell Sci. 126: 1406-1415.

Long L, Yang X, Southwood M, Lu J, Marciniak S.J., Dunmore B.J. & Morrell N.W. (2013) Chloroquine Prevents Progression of Experimental Pulmonary Hypertension via Inhibition of Autophagy and Lysosomal Bmpr-II Degradation. Circ Res. 122: 1159-1170.

Thomas S.E., Malzer E, Ordoñez A, Dalton L.E., van ‘t Wout EFA, Liniker E, Crowther DC, Lomas DA & Marciniak S.J. (2013) p53 and translation attenuation regulate distinct cell cycle checkpoints during ER stress. J Biol Chem 288: 7606-17.

Dalton LE, Clarke HJ, Knight J, Lawson MH, Wason J, Lomas DA, Howat WJ, Rintoul RC, Rassl DM & Marciniak S.J. (2013) The endoplasmic reticulum stress marker CHOP predicts survival in malignant mesothelioma. Br J Cancer 108: 1340-7.

Roussel B.D., Kruppa A.J., Miranda E., Crowther D.C., Lomas D.A. and Marciniak S.J. (2013) Endoplasmic reticulum dysfunction in neurological disease. Lancet Neurol 12:105-18.

Hilliard NJ, Marciniak SJ, Babar JL, Balan A. (2013) Evaluation of secondary spontaneous pneumothorax with multidetector CT.  Clin Radiol. 68: 521-8.

Ordóñez A., Snapp E.L., Tan L., Miranda E., Marciniak S.J.§*, Lomas D.A.* (2013) Endoplasmic reticulum polymers impair luminal protein mobility and sensitise to cellular stress in α1-antitrypsin deficiency. Hepatology 57: 2049-60. *Joint senior authors §Corresponding author

Klionsky D.J. et al. (2012) Guidelines for the use and interpretation of assays for monitoring autophagy.  Autophagy 8: 445-544.

Dalton L.E., Healey E., Irving J. & Marciniak S.J. (2012).  Phosphoproteins in stress-induced disease.  Prog Mol Biol Transl Sci 106: 189-221

Yusa K, S. Rashid T, Strick-Marchand H, Varela I, Liu P-Q, Paschon DE, Miranda E, Ordóñez A, Hannan N, Rouhani F, Darche S, Alexander G, Marciniak SJ, Hasegawa M, Fusaki N, Holmes MC, Di Santo JP, Lomas DA, Bradley A and Vallier L (2011) Targeted gene correction of a1-antitrypsin deficiency in induced pluripotent stem cells. Nature 478: 391-394.

Irving JA, Ekeowa UI, Belorgey D, Haq I., Gooptu B., Miranda E., Perez J, Roussel R.D., Ordonez A, Dalton L.E., Thomas S.E., Marciniak SJ, Parfrey H, Chilvers E, Teckman JH, Alam S, Mahadeva R, Rashid ST, Vallier L & David A. Lomas (2011). The Serpinopathies: Studying Serpin Polymerization In Vivo.  Methods Enzymol. 501: 421-466.

Thomas SE, Dalton L, Malzer E, Marciniak SJ (2011).  Unraveling the story of protein misfolding in diabetes mellitus.  World J Diabetes. 2:114-8.

Hopkins T.G., Maher E., Reid E. & Marciniak SJ. (2011) Recurrent pneumothorax. Lancet 377: 1624.

Jahn TR, Malzer E, Roote J, Vishnivetskaya A, Imarisio S, Giannakou M, Panser K, Marciniak S, Crowther DC.  (2011) Modeling Serpin Conformational Diseases in Drosophila melanogaster.  Methods Enzymol. 499: 227-58.

Ekeowa U.I., Marciniak S.J., & Lomas D.A. (2011). a1-antitrypsin deficiency and inflammation. Expert Rev. Clin. Immunol. 7: 243-52.

Roussel B.D., Irving J.A., Ekeowa U.I., Belorgey D., Haq I., Ordóñez A., Kruppa A.J., Duvoix A., Rashid S.T., Crowther D.C., Marciniak S.J., Lomas D.A. (2011) Unravelling the twists and turns of the serpinopathies. FEBS J. 278: 3859-67.

Belorgey D., Irving J.A., Ekeowa U.I., Freeke J., Roussel B.D., Miranda E., Pérez J., Marciniak S.J., Crowther D.C., Michel C.H. & Lomas D.A. (2011). Characterisation of serpin polymers in vitro and in vivoMethods 53: 255-266.

Liu B., Moloney A., Meehan S., Morris K., Thomas S.E., Serpell L.C., Hider R., Marciniak S.J., Lomas D.A., & Crowther D.C. (2011). Iron Promotes The Toxicity Of Amyloid Beta Peptide By Impeding Its Ordered Aggregation. J Biol. Chem. 286: 4248-56.

Malzer E., Daly M.L., Moloney A., Sendall T.J., Thomas, S.L. Ryder E., Ryoo H.D., Crowther D.C., Lomas, D.A. & Marciniak S.J. (2010). Impaired tissue growth is mediated by checkpoint kinase 1 (CHK1) in the integrated stress response.  J. Cell Sci. 123: 2892-2900.

Rashid S.T., Corbineau S., Hannan N., Marciniak S.J., Miranda E., Alexander G., Huang-Doran I., Ahrlund-Richter L., Skepper J., Griffin J., Semple R., Weber A. Lomas D.A. & Vallier L. (2010). Modeling inherited metabolic disorders of the liver with human induced pluripotent stem cells.  J Clin. Invest. 120: 3127-36.

Miranda E., Pérez J., Ekeowa U.I., Hadzic N., Kalsheker N., Gooptu B., Portmann B., Belorgey D., Hill M., Chambers S., Teckman J., Alexander G.J., Marciniak S.J. & Lomas D.A. (2010). A novel monoclonal antibody to characterize pathogenic polymers in liver disease associated with a1-antitrypsin deficiency.  Hepatology 52: 1078-88.

Marciniak S.J. & Lomas (2010). a1-Antitrypsin deficiency and autophagy. N Engl J Med. 363:1863-1864.

Marciniak S.J. & Ron D. (2010).  The Unfolded Protein Response in Lung Disease.  Proc. Am. Thor. Soc. 7:356-362.

Thomas S.E , Dalton L.E., Daly M.L., Malzer E., & Marciniak S.J. (2010) Diabetes as a disease of endoplasmic reticulum stress. Diabetes Metab Res Rev. 26: 611-21.

Kröger H., Miranda E., MacLeod I., Pérez J., Crowther D.C.,  Marciniak S.J.*§ & Lomas D.A.* (2009).  ERAD and autophagy cooperate to degrade polymerogenic mutant serpins. J Biol. Chem. 284: 22793-802. *Joint senior authors §Corresponding author

Davies M.J., Miranda E., Kaufman R.J., Marciniak S.J.* & Lomas D.A.* (2009). Neuroserpin polymers activate NF-B by a calcium-signalling pathway that is independent of the unfolded protein response.  J Biol. Chem. 284: 18202-9.  *Joint senior authors

Ekeowa U.I., Gooptu B., Belorgey D., Hägglöf P., Karlsson-Li S,. Miranda E., Pérez J., MacLeod I., Kroger H., Marciniak S.J., Crowther D.C. & Lomas D.A. (2009). a1-Antitrypsin deficiency, chronic obstructive pulmonary disease and the serpinopathies.  Clin Sci. 116: 837-50.

Marciniak S.J. & Lomas D.A. (2009). What can naturally occurring mutations tell us about the pathogenesis of COPD?  Thorax 64: 359-364.

Marciniak S.J. & Lomas D.A. (2008).  Intracellular serpins, firewalls and tissue necrosis.  Trends Cell Biol.  18:45-47.

Marciniak S.J. (2008). Mesothelioma in older people.  CME Geriatric Medicine 10: 47-50.

Marciniak S.J. & Ron D. (2006). Endoplasmic reticulum stress signalling in disease. Physiol Rev. 86: 1133-49.

Marciniak S.J., Garcia-Bonilla L., Hu J., Harding H.P., Ron D. (2006). Activation-dependent substrate recruitment by the eukaryotic translation initiation factor 2 kinase PERK. J Cell Biol. 172: 201-9.

Pereira R.C., Stadmeyer L., Marciniak S.J., Ron D., Canalis E. (2006). C/EBP homologous protein is necessary for normal ost­eoblastic function. J Cell Biochem. 97:633-640.

Harding HP, Zhang Y, Khersonsky S, Marciniak S, Scheuner D, Kaufman RJ, Javitt N, Chang YT, Ron D. (2005). Bioactive small molecules reveal antagonism between the integrated stress response and sterol-regulated gene expression. Cell Metab. 2:361-71.

Silva R.M., Ries V., Oo T.F., Yarygina O., Jackson-Lewis V., Ryu E.J., Lu P.D., Marciniak S.J., Ron D., Przedborski S., Kholodilov N., Greene L.A., Burke R.E. (2005).  CHOP/GADD153 is a mediator of apoptotic death in substantia nigra dopamine neurons in an in vivo neurotoxin model of parkinsonism. J Neurochem. 95:974-8.

Marciniak S.J, Yun CY, Oyadomari S, Novoa I, Zhang Y, Jungreis R, Nagata K, Harding HP, Ron D. (2004). CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 2004 18:3066-77.

Lu P.D., Jousse C., Marciniak S.J., Zhang Y., Novoa I., Scheuner D., Kaufman R.J., Ron D., Harding H.P. (2004). Cytoprotection by pre-emptive conditional phosphorylation of translation initiation factor 2. EMBO J. 23:169-79.

Daniil Z., Gilchrist F.C., Marciniak S.J., Pantelidis P., Goldstraw P., Pastorino U. & du Bois R.M. (2000). The effect of lung biopsy on lung function in diffuse lung disease. Eur. Respir. J. 16:67-73.

Marciniak S.J. & Edwardson J.M. (1996). Association of nucleoside diphosphate kinase with pancreatic zymogen granules; effects of local GTP generation on granule membrane characteristics. Biochem. J. 316: 99-106.

Edwardson J.M. & Marciniak S.J. (1995). Molecular mechanisms in exocytosis. J. Memb. Biol. 146: 113-122.

Lee E.G., Marciniak S.J., MacLean C.M. & Edwardson J.M. (1994). Pancreatic plasma membranes: promiscuous partners in membrane fusion. Biochem. J. 298: 599-604.

MacLean C.M., Marciniak S.J., Hall D.V. & Edwardson J.M. (1993). Involvement of a phosphoprotein on the zymogen granule membrane in the control of regulated exocytosis in the exocrine pancreas. J. Cell Sci. 106: 663-670.

Marciniak S.J., Plumpton C., Barker P.J., Huskisson N.S. & Davenport A.P. (1992). Localization of immunoreactive endothelin and proendothelin in the human lung. Pulm. Pharm. 5: 175-182.

Teaching and Supervisions

Teaching: 
Research supervision: 

Current PhD students

  • Eimear Rutherford
  • Haoyang Ying
  • Nikita Zubkov
  • Max Schwiening

 

Previous Graudate students

  • PhD Heike Kroger
  • PhD Elke Malzer
  • PhD Sally Thomas
  • PhD Jenny Dickens
  • PhD Hanna Clarke
  • PhD Vruti Patel
  • PhD Caia Dominicus

 

  • MPhil Marie-Louise Daly
  • MPhil Nicolas Piton
  • MPhil Elizabeth Liniker
  • MPhil Nikita Zhubkov
  • MPhil Ahmad Hilder
  • MPhil Alexandra Ekvik

Other Professional Activities

  • Professor of Respiratory Science, University of Cambridge
  • Directorate Research Lead, Addenbrooke’s Hospital: Allergy, Infection & Inflammation
  • Honorary Consultant Respiratory Physician, Addenbooke’s Hospital
  • Honorary Consultant Respiratory Physician, Royal Papworth Hospital
  • MB/PhD Programme Director, University of Cambridge
  • Elected Member (2020-2023) - European Respiratory Society (ERS) Assembly 3 – Long Range Planning Committee (Basic & Translational Sciences)
  • British Lung Foundation (BLF) Research Panel
  • Member of NIHR Translational Research Collaboration for Inflammatory Respiratory Diseases Steering Committee Meeting
  • MKMRF/BLF Mesobank National Mesothelioma Tissue Bank steering committee
Professor of Respiratory Science

Contact Details

sjm20@cam.ac.uk
Office phone: 01223 762660
PA: Anne Francis af640@medschl.cam.ac.uk
Cambridge Institute for Medical Research (CIMR), University of Cambridge School of Clinical Medicine, The Keith Peters Building, Cambridge Biomedical Campus, Hills Rd
Cambridge
CB2 0XY
Takes PhD students
Available for consultancy

Affiliations

Classifications: 
Departments and institutes: 
Person keywords: 
ER stress, unfolded protein response (UPR), integrated stress response (ISR) Respiratory medicine: alpha1-antitrypsin deficiency, mesothelioma, pneumothorax, pulmonary fibrosis, pulmonary hypertension
College: 
St Catharine's College