Examining both the biomarker potential and functionality of exosomes from CF patient lung cells
Judith obtained a PhD from the RCSI in 2004, before undertaking postdoctoral training at the Scripps Research Institute, San Diego in new folding mechanisms in Cystic Fibrosis (CF). In 2011, she joined the University of California, San Diego as a faculty member before receiving an SFI award and returning to Ireland. In 2013, she became a a Principal investigator at the University College Dublin, where she set up a basic/translational research program focused on identifying new therapies and biomarkers in CF. Judith’s research areas include:
Judith now joins the RCSI and National Children’s Research Center as a Principal Investigator and Senior Lecturer in the Dept. of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland.
Dr Anne Trappe
Position: Postdoctoral Researcher
Deciphering the functional and clinical properties of exosomes in Cystic Fibrosis
Examining both the biomarker potential and functionality of exosomes from CF patient lung cells
Dissection of the PI3K/Akt/mTOR signalling pathway as a therapeutic target in Cystic Fibrosis.
We are currently conducting a long term ongoing research study looking at the evolution of infection and inflammation in the airways of children with cystic fibrosis (CF). Every year, children with CF undergo a procedure called a bronchoscopy. A small camera is inserted into the patients airways which allows us to look inside a patient’s lungs and identify any damage present. Biological samples such as bronchoalveolar lavage (BAL) fluid from the lung as well as urine, blood and samples from the throat and nose are taken during the procedure and stored in a specialised ‘biobank’ . We also collect some of the patient’s clinical information. SHIELD CF is in place across three sites; OLCH Crumlin, Tallaght hospital and University hospital Limerick. There are over 8000 samples in the biobank already and these have contributed to more than 25 peer reviewed publications, helping us to understand various different aspects of CF lung disease.
In recent years we have come to understand that a vast array of bacteria lives in our airways – even in healthy people. It has become clear that the interaction between the healthy and harmful bacteria in the lungs is complex. We are conducting a long term and very wide-ranging study in children with CF looking at how these bacteria vary over time and whether they are related to lung inflammation, changes in antibiotic use and lung function at school age.
Bronchoalveolar lavage fluid is collected when salt water is instilled temporarily in the lungs during a bronchoscopy procedure. It collects the proteins and bacteria from the lower airways that otherwise could not be collected. This is potentially a very useful test for clinical trials of new medications in children with CF, but there are several different approaches internationally to the way the test is performed. This multicentre study seeks to determine if different ways of handling and processing the fluid impact on its utility as a marker of lung pathology.
The purpose of the CUBS study is to see if we can find proteins or ‘biomarkers’ in the urine that will help us to identify lung disease in children with CF. Biomarkers are biological molecules found in blood, other body fluids, or tissues that can be indicative of a particular disease or abnormal process such as inflammation. Lots of substances that are produced in the body are excreted, at least partially, in the urine. This has been shown to be true of biomarkers of lung damage in people with lung diseases. In some instances, urinary biomarkers have been shown to correlate well with lung infection or lung damage. This is of significant interest to doctors looking after children with CF as the collection of urine is a painless and harmless procedure, urine is always accessible and it is an easy fluid to work with. In the first part of the study, parents of children with CF will collect urine on a regular basis for 3 months at home and sent it to our partner lab in the UK (Mologic) to allow us to determine what the ‘normal’ range is (parents keep a symptom diary so we could determine when the children were well or sick). In the second part of this study, we will match urine collected with the corresponding bronchoalveolar lavage (BAL) fluid collected as part of the SHIELD CF project. We are trying to determine if there are substances in urine which are typically present at the time that we see a marker of lung damage called neutrophil elastase (NE) in the lung fluid. Earlier detection of lung damage and earlier intervention could prevent or slow down the progression of lung disease in children with CF.
The presence of certain compounds called ‘proteases’ have been shown to be a risk factor for lung damage in children with CF. Proteases are enzymes that can degrade healthy lung tissue if present in abnormal amounts. There are lots of different types of proteases, and little is known about some of these in children with CF. It is not yet known if particular proteases are associated with infection or damage to the lungs. The study is designed to establish the degree and pattern of proteases in the lungs of preschool children with CF, and to determine if specific proteases are associated with either pulmonary infection or clinical disease parameters. This study might help us to discover meaningful tests in due course to determine whether harmful proteins are present in young babies and children with CF.
Cystic fibrosis is a common inherited life threatening disease which is particularly common in Ireland. People with CF have a mutation in a gene that produces a protein called cystic fibrosis transmembrane conductance protein or CFTR. CFTR regulates the movement of salt in and out of cells. When CFTR doesn’t work well the result is thick, sticky mucus in the respiratory, digestive and reproductive systems, and inability to fight lung infections. Medications have now been designed to specifically target the CFTR protein. These are called CTR modulators. One such modulator is Orkambi, which has recently been approved to treat children over 6 years in Ireland. In this study we are using a new type of specialised lung function technique called ‘multiple breath washout’ (MBW) to look at the lung function of children aged 6-11 years with CF. Children will undergo MBW and a new form of low dose CT scanning called ‘spirometrically controlled CT’ before they commence on Orkmabi. In the first study of its kind in the world, we will be working with colleagues in Rotterdam, London and Cincinnati to assess the effects of Orkambi on the lung structure and lung function of these Irish children for two years following commencement of Orkambi in a real world setting.
The introduction of promising new medications to treat the basic defect in people with CF holds great promise to improve the survival and health of our patients with CF. New CF treatment such as Orkambi are currently only available for CF patients with the most common mutations. Furthermore only individuals with common or well-recognised mutations are being recruited to clinical trials of these new investigational medications. There are likely to be a significant group of children and adults with rarer mutations who may be left behind, with no prospect of having new drugs licensed for use in these people. What is required here is a patient specific ‘test’ to determine whether an individual may benefit from treatment with a given drug. The purpose of this research is to create a repository or “bank” of a type of stem cell called “induced pluripotent stem cells” or iPSCs. Stem cells are special kinds of cells that can renew themselves. Under certain experimental conditions, iPSCs can be directed to grow into any type of tissue or organ. In the case of this study, we are working with colleagues in RCSI and Boston University to develop a special type of lung cell which can readily be used to determine whether the child’s own lung cells may respond to new CF drugs. Ultimately, we would like to develop a test that can be offered to all patients with cystic fibrosis, particularly those with rare mutations not currently able to avail of approved drugs, to determine whether or not they will respond to a given drug.
Understanding early lung disease in CF is an international focus to try and tailor treatment to slow or prevent decline in lung function. In Ireland, we currently have limited capacity to formally assess early lung disease in this group. In recent years, there has been a move towards closer monitoring and active treatment in younger patients with CF, in an effort to improve long term survival. Lung Clearance Index (LCI) is a lung function measurement performed using the multiple breath washout (MBW) method. The MBW technique is an effort independent, low-risk, non-invasive procedure performed on spontaneously breathing children. The LCI is a value that is used to indicate the performance of the lungs, particularly the smaller airways. LCI is much more sensitive than other established tests for CF lung disease and can be performed in younger children. It is therefore a very helpful test for doctors looking after children with CF. We have recently acquired the equipment for MBW testing (N2) and wish to validate the test in a population of healthy Irish children and in children with CF, both when well and unwell and to compare our results with established values using this equipment. We are working with our colleage Dr Barry Linnane in Limerick, who has been using this device for a number of years.
The list of publications below is automatically derived from MEDLINE/PubMed. As a result, there may be incorrect or missing publications.
|Useckaite Z, Ward MP, Trappe A, Reilly R, Lennon J, Davage H, Matallanas D, Cassidy H, Dillon ET, Brennan K, Doyle SL, Carter S, Donnelly S, Linnane B, McKone EF, McNally P, Coppinger JA, 2020 Jun, Increased extracellular vesicles mediate inflammatory signalling in cystic fibrosis. Thorax, DOI: 10.1136/thoraxjnl-2019-214027|
|Shields S, Conroy E, O'Grady T, McGoldrick A, Connor K, Ward MP, Useckaite Z, Dempsey E, Reilly R, Fan Y, Chubb A, Matallanas DG, Kay EW, O'Connor D, McCann A, Gallagher WM, Coppinger JA, 2019 May 3, Correction: BAG3 promotes tumour cell proliferation by regulating EGFR signal transduction pathways in triple negative breast cancer. Oncotarget, DOI: 10.18632/oncotarget.26920|
|Shields S, Conroy E, O'Grady T, McGoldrick A, Connor K, Ward MP, Useckaite Z, Dempsey E, Reilly R, Fan Y, Chubb A, Matallanas DG, Kay EW, O'Connor D, McCann A, Gallagher WM, Coppinger JA, 2018 Mar 20, BAG3 promotes tumour cell proliferation by regulating EGFR signal transduction pathways in triple negative breast cancer. Oncotarget, DOI: 10.18632/oncotarget.24590|
|Reilly R, Mroz MS, Dempsey E, Wynne K, Keely SJ, McKone EF, Hiebel C, Behl C, Coppinger JA, 2017 Aug 9, Targeting the PI3K/Akt/mTOR signalling pathway in Cystic Fibrosis. Sci Rep, DOI: 10.1038/s41598-017-06588-z|
|Gaffney PM, Imai DM, Clifford DL, Ghassemian M, Sasik R, Chang AN, O'Brien TD, Coppinger J, Trejo M, Masliah E, Munson L, Sigurdson C, 2014, Proteomic analysis of highly prevalent amyloid A amyloidosis endemic to endangered island foxes. PLoS One, DOI: 10.1371/journal.pone.0113765|
|Chiang WC, Kroeger H, Sakami S, Messah C, Yasumura D, Matthes MT, Coppinger JA, Palczewski K, LaVail MM, Lin JH, 2015 Aug, Robust Endoplasmic Reticulum-Associated Degradation of Rhodopsin Precedes Retinal Degeneration. Mol Neurobiol, DOI: 10.1007/s12035-014-8881-8|
|Pasillas MP, Shields S, Reilly R, Strnadel J, Behl C, Park R, Yates JR 3rd, Klemke R, Gonias SL, Coppinger JA, 2015 Jan, Proteomic analysis reveals a role for Bcl2-associated athanogene 3 and major vault protein in resistance to apoptosis in senescent cells by regulating ERK1/2 activation. Mol Cell Proteomics, DOI: 10.1074/mcp.M114.037697|
|Choi S, Kelber J, Jiang X, Strnadel J, Fujimura K, Pasillas M, Coppinger J, Klemke R, 2014 Feb 1, Procedures for the biochemical enrichment and proteomic analysis of the cytoskeletome. Anal Biochem, DOI: 10.1016/j.ab.2013.10.025|
|Coppinger JA, Hutt DM, Razvi A, Koulov AV, Pankow S, Yates JR 3rd, Balch WE, 2012, A chaperone trap contributes to the onset of cystic fibrosis. PLoS One, DOI: 10.1371/journal.pone.0037682|
|Jang CY, Coppinger JA, Yates JR 3rd, Fang G, 2011 Apr 29, Mitotic kinases regulate MT-polymerizing/MT-bundling activity of DDA3. Biochem Biophys Res Commun, DOI: 10.1016/j.bbrc.2011.04.004|
|Jang CY, Coppinger JA, Yates JR 3rd, Fang G, 2010 Mar 5, Phospho-regulation of DDA3 function in mitosis. Biochem Biophys Res Commun, DOI: 10.1016/j.bbrc.2010.01.115|
|Koulov AV, LaPointe P, Lu B, Razvi A, Coppinger J, Dong MQ, Matteson J, Laister R, Arrowsmith C, Yates JR 3rd, Balch WE, 2010 Mar 15, Biological and structural basis for Aha1 regulation of Hsp90 ATPase activity in maintaining proteostasis in the human disease cystic fibrosis. Mol Biol Cell, DOI: 10.1091/mbc.e09-12-1017|
|Minamide LS, Maiti S, Boyle JA, Davis RC, Coppinger JA, Bao Y, Huang TY, Yates J, Bokoch GM, Bamburg JR, 2010 Feb 19, Isolation and characterization of cytoplasmic cofilin-actin rods. J Biol Chem, DOI: 10.1074/jbc.M109.063768|
|Liu GH, Guan T, Datta K, Coppinger J, Yates J 3rd, Gerace L, 2009 Nov, Regulation of myoblast differentiation by the nuclear envelope protein NET39. Mol Cell Biol, DOI: 10.1128/MCB.00684-09|
|Jang CY, Coppinger JA, Seki A, Yates JR 3rd, Fang G, 2009 May 1, Plk1 and Aurora A regulate the depolymerase activity and the cellular localization of Kif2a. J Cell Sci, DOI: 10.1242/jcs.044321|
|Zhu H, Coppinger JA, Jang CY, Yates JR 3rd, Fang G, 2008 Dec 1, FAM29A promotes microtubule amplification via recruitment of the NEDD1-gamma-tubulin complex to the mitotic spindle. J Cell Biol, DOI: 10.1083/jcb.200807046|
|Steiniger SC, Coppinger JA, Krüger JA, Yates J 3rd, Janda KD, 2008 Dec, Quantitative mass spectrometry identifies drug targets in cancer stem cell-containing side population. Stem Cells, DOI: 10.1634/stemcells.2008-0397|
|Zhao WM, Coppinger JA, Seki A, Cheng XL, Yates JR 3rd, Fang G, 2008 Sep 9, RCS1, a substrate of APC/C, controls the metaphase to anaphase transition. Proc Natl Acad Sci U S A, DOI: 10.1073/pnas.0709227105|
|Seki A, Coppinger JA, Jang CY, Yates JR, Fang G, 2008 Jun 20, Bora and the kinase Aurora a cooperatively activate the kinase Plk1 and control mitotic entry. Science, DOI: 10.1126/science.1157425|
|Jang CY, Wong J, Coppinger JA, Seki A, Yates JR 3rd, Fang G, 2008 Apr 21, DDA3 recruits microtubule depolymerase Kif2a to spindle poles and controls spindle dynamics and mitotic chromosome movement. J Cell Biol, DOI: 10.1083/jcb.200711032|
|Seki A, Coppinger JA, Du H, Jang CY, Yates JR 3rd, Fang G, 2008 Apr 7, Plk1- and beta-TrCP-dependent degradation of Bora controls mitotic progression. J Cell Biol, DOI: 10.1083/jcb.200712027|
|Coppinger JA, Maguire PB, 2007, Insights into the platelet releasate. Curr Pharm Des, DOI: 10.2174/138161207781662885|
|Coppinger JA, O'Connor R, Wynne K, Flanagan M, Sullivan M, Maguire PB, Fitzgerald DJ, Cagney G, 2007 Jun 1, Moderation of the platelet releasate response by aspirin. Blood, DOI: 10.1182/blood-2006-07-038539|
|Coppinger J, Fitzgerald DJ, Maguire PB, 2007, Isolation of the platelet releasate. Methods Mol Biol, DOI: 10.1385/1-59745-214-9:307|
|Wang X, Venable J, LaPointe P, Hutt DM, Koulov AV, Coppinger J, Gurkan C, Kellner W, Matteson J, Plutner H, Riordan JR, Kelly JW, Yates JR 3rd, Balch WE, 2006 Nov 17, Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell, DOI: 10.1016/j.cell.2006.09.043|
|McRedmond JP, Park SD, Reilly DF, Coppinger JA, Maguire PB, Shields DC, Fitzgerald DJ, 2004 Feb, Integration of proteomics and genomics in platelets: a profile of platelet proteins and platelet-specific genes. Mol Cell Proteomics, DOI: 10.1074/mcp.M300063-MCP200|
|Coppinger JA, Cagney G, Toomey S, Kislinger T, Belton O, McRedmond JP, Cahill DJ, Emili A, Fitzgerald DJ, Maguire PB, 2004 Mar 15, Characterization of the proteins released from activated platelets leads to localization of novel platelet proteins in human atherosclerotic lesions. Blood, DOI: 10.1182/blood-2003-08-2804|
|du Laney TV, Cherry RS, Coppinger JA, Truskey GA, 1992 Nov-Dec, Altered distribution of mitochondria and actin fibers in 3T3 cells cultured on microcarriers. Biotechnol Prog, DOI: 10.1021/bp00018a600|
|Funding Agency:||Science Foundation of Ireland|
|Project Title:||Characterising Hsp90 signalling in Cystic Fibrosis|
|Start Date/End Date:||2013-2017|
|Funding Agency:||National Children’s Research Centre Fund|
|Project Title:||Dissecting the role of exosomes in Cystic Fibrosis|
|Start Date/End Date:||2017-2020|
|Name:||Professor Jonathan Lin|
|Institution:||University of California San Diego|
|Name:||Professor William Balch|
|Institution:||The Scripps Research Institute|
|Name:||Professor Deborah Penque|
|Institution:||National Institute of Health, Lisbon|
|Name:||Professor Christian Behl|
|Institution:||University of Mainz|
|Name:||Professor Stephen Keely|
|Institution:||Royal College of Surgeons in Ireland|
|Name:||Professor Paul McNally|
|Institution:||Our Lady’s Children’s Hospital|