Scleroderma Association of B.C. Research Program
Congratulations to the SABC Research Program team on their second publication.
Read our latest publication “Regulation of MicroRNA Expression in Scleroderma and Idiopathic Pulmonary Fibrosis: A Research Study” in the Undergraduate Research in Natural and Clinical Sciences Journal at Publication #2. A simplified version is included below.
This study investigated three proteins implicated in modification of microRNA expression using blood cells collected from healthy controls, patients with scleroderma, patients with undifferentiated connective tissue disease (UCTD) and patients with idiopathic pulmonary fibrosis. Were their any differences in these three proteins inside or outside of the nucleus that could be associated with the presence of scleroderma or idiopathic pulmonary fibrosis? If so, could the expression differences in proteins noted account for differences in microRNA expression? One of these proteins was found to have greater expression in the nucleus of controls compared to patients. Another protein was found to have greater expression outside the nucleus of controls compared to patients. No difference in expression either inside or outside of the nucleus was found for the third protein. Larger studies are needed to confirm this finding of dysregulation of microRNA pathways in patients with the future hope of delivering, using advanced technology, specific microRNAs to treat patients with scleroderma or idiopathic pulmonary fibrosis.
Congratulations to the SABC Research Program team.
Their current research has been published in the journal Scientific Reports. The article “Circulating cytokine levels in systemic sclerosis related interstitial lung disease and idiopathic pulmonary fibrosis” is available at Publication #1. A simplified version is included below.
The journal Scientific Reports on 24 April 2023 published an article by The SABC Research Program on a study of the differences in certain proteins called cytokines in people with either systemic scleroderma or interstitial lung disease, or both. The levels of 87 cytokines in blood plasma were compared with those of healthy individuals. No substantial association was found for any of the cytokines with changes in lung capacity over time, but four cytokines were found to be markedly different in patients compared to healthy individuals. One cytokine associated with ageing was increased two-fold in all patient groups. Another cytokine associated with tissue inflammation was increased eight-fold but only in patients with interstitial lung disease and was not increased in healthy individuals or patients with scleroderma but no lung involvement. A third cytokine associated with blood clotting was decreased in all patient groups compared to healthy individuals. Another cytokine was increased two-fold only in patients with the limited cutaneous form of scleroderma compared to healthy individuals. This fourth cytokine is associated with immune-cell migration into tissue and the promotion of fibrosis and may be a marker of milder forms of scleroderma. These results suggest there may be common and different reasons why people develop pulmonary fibrosis. Further research is needed. This study was funded by the Scleroderma Association of B.C. Scientific Reports is published by Springer Nature.
The aim of the SABC Genome Research Program is to identify biomarkers specific to people who have pulmonary fibrosis caused by systemic sclerosis (scleroderma). Being able to distinguish between pulmonary fibrosis that is idiopathic (of various or unknown origin) or the result of scleroderma will allow medical professionals to provide patients with an accurate diagnosis. Identifying reliable biomarkers also provides an opportunity to develop a functional cure; an ongoing treatment that corrects and prevents the disease from continuing to damage the affected organs (in this case, lungs).
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BASAK SAHIN Basak has been involved with the SABC Research Program since the beginning, as a research technician at the Molecular Phenotyping Core of UBC Centre for Heart Lung Innovation at St. Paul’s Hospital. Read Basak’s spotlight story on the SABC Research Program HERE. |
Summary of the SABC Research Program.
December 2023 Update
SABC funds and co-leads a research study that began recruiting scleroderma patients with and without interstitial lung disease (ILD) in July 2017. Blood samples have also been taken from patients with idiopathic pulmonary fibrosis (IPF) and undifferentiated connective tissue disease (UCTD) and both blood and skin samples have been taken from control participants. This research program is creating a firm foundation for intensive research to control lung and skin damage in patients with scleroderma and lung damage in patients with IPF, with the expectation of receiving future support from donations and, hopefully, research funding agencies. While the number of voluntary participants with uCTD are few at this time, it is expected that these patients will be helped too.
Hello from the Research Team: Dr. Tillie-Louise Hackett joined the SABC Research Group in December 2023. Dr Hackett is a Professor in the Department of Anesthiology, Pharmacology and Therapeutics at UBC. Since 2014, Prof. Hackett has served as the Director of the James C. Hogg Lung Tissue Biobank at the Heart and Lung Institute (HLI) of St. Paul’s Hospital.
Our undergraduate co-op student Ms. Raveen Badyal finished her work with us as a research assistant at the end of December 2023. Ms. Badyal will commence thesis research in scleroderma towards an MSc degree at UBC with Dr. Tillie-Louise Hackett and Dr. James Dunne as supervisor and co-supervisor, respectively, in January 2024. Ms. Badyal will be receiving financial support from the SABC Research Program for two years as she studies the structure of lung and skin lesions from scleroderma patients and explores cell culture response of two novel small-molecule drugs in blocking fibrosis of lung cells derived from patients with scleroderma.
Under the joint supervision of Dr. Amrit Singh of the Computational Biology Lab (CBL) and Dr. James Dunne, postgraduate fellow Dr. Young Woong Kim is telecommuting out of Edmonton and working on a half-time basis on the metabolite analysis, for which the lab work was done in Edmonton by The Metabolomics Innovation Centre at the University of Alberta.
Mr. Brandon Kohlen and Ms. Gaea Buenaventura have joined the team on a part-time basis to help out Ms. Badyal in the laboratory.
Follow @SABCResearch on X (formerly known as Twitter) and Facebook or Instagram for progress and development updates.
Research Program Progress
| Dec 2023 | miRNA module: Ninety-two DNA samples were delivered to Canada’s Michael Smith Genome Science Centre (GSC) for sequencing on 14 December 2023 and passed GSC quality control on 20 December 2023. Results should be available by the end of the first quarter of 2024. Ms. Raveen Badyal continued to work on the in vitro experiment to assess the inhibition of fibrosis in normal lung and skin cells by a novel small-molecule drug. |
| circRNA, lncRNA & mRNA module: The abstract on possible small RNA pathways for differentiating early and severe forms of scleroderma submitted for poster presentation by Drs. Keen and Dunne at the 8th World Scleroderma Congress in Prague, 14-16 March 2024, was accepted on 1 December 2023. | |
| DNA modulation module: After more in-depth bioinformatic computations were completed in late October 2023, a further joint meeting with the Kobor lab in mid-December led to the co-authoring in late December of a draft abstract to be submitted by the 15 January 2024 deadline for consideration for presentation during the 2024 Congress of the European Alliance of Associations for Rheumatology in Vienna (Austria), 12 – 15 June 2024. The analysis to be presented shows advanced aging (so-called hyper-aging), detected by assessing DNA methylation, as a feature of scleroderma and interstitial lung disease. | |
| Sep 2023 | Ms. Raveen Badyal started work over the summer on an in vitro experiment to assess the inhibition of fibrosis in normal lung and skin cells by a novel small-molecule drug. Preliminary results were presented by an oral presentation in Jul 2023 and then a poster presentation in Aug 2023, both at the Centre for Heart Lung Innovation. |
| circRNA, lncRNA & mRNA module: With the assistance of high school graduate, Mr. Alykhan Rajan, who worked as a summer student for the Research Program, Dr. Keen was able to prepare and submit an abstract for consideration for presentation to the 8th World Scleroderma Congress in Prague (Czech Republic), occurring 14 – 16 March 2024. The submitted abstract discusses possible molecular pathways, for early and severe forms of scleroderma, developed from the discovery of and then the confirmatory analyses of (completed in Oct 2022) long non-coding, circular, and messenger RNA. | |
| DNA modulation module: Assessment of the massive preliminary bioinformatic computational analysis on DNA-methylation was conducted at a joint meeting with the Kobor lab in early Sep 2023. The assessment led to the decision for more in-depth bioinformation computations to be completed by the end of Oct 2023. DNA-methylation has been implicated in defects of the process of normal replacement of cells. | |
| Jun 2023 | miRNA module: The manuscript of our undergraduate co-op student Ms. Raveen Badyal as lead author on microRNA modifiers was accepted on 15 Mar 2023 subject to major revisions and an improved version was published on 20 Jun 2023 in the Undergraduate Research in Natural Sciences and Technology (URNCST) Journal. The article can be found online here: https://doi.org/10.26685/urncst.442. |
| Cytokine & Antibody Module: On 24 April 2023, the revised article with postdoctoral fellow Dr. Boyang Zheng on 87 cytokines was published by the journal Scientific Reports and can be read at the following online location: https://rdcu.be/daAJ5. | |
| DNA modulation module: The massive bioinformatic computational analysis on DNA-methylation was completed on 14 Jun 2023. Assessment of these results will not be available until the next quarterly report. | |
| Mar 2023 | Cytokine & Antibody Module: On 23 February, the revised article with postdoctoral fellow Dr. Boyang Zheng on 87 cytokines was submitted to the journal Scientific Reports. On 8 March 2023, the Editor of Scientific Reports, confirmed that the revised article was accepted without any further changes required. |
| DNA modulation module: By early March, our collaborating laboratory had completed the biochemical analysis of DNA-methylation from existing blood samples. Research then moved to the bioinformatic or data-analysis phase. With quality control checks completed at the end of March on the samples, the massive bioinformatic computational analysis started with results expected no earlier than mid-June. | |
| Dec 2022 | miRNA module: Work continued on the manuscript of undergraduate student Ms. Raveen Badyal as lead author on microRNA modifiers. |
| Cytokine & Antibody module: In mid-November, the article with postdoctoral fellow Dr. Boyang Zheng on 87 cytokines was accepted for publication subject to acceptable major revisions by the publisher Springer Nature in its journal Scientific Reports. The revisions were completed by mid-December. |
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| circRNA, lncRNA & mRNA module: By late October, in-depth biomolecular analysis of six mRNA’s, four lncRNA’s, and two circRNA’s by a collaborating laboratory was completed. |
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| Metabolomics module: The results for a second set of approximately 2,000 metabolites detected in samples of circulating blood from patients and controls were available mid-October. Dr. Kevin Keen presented at a research seminar on 14 October 2022 at the Centre for Heart Lung Innovation at St. Paul’s Hospital on a small subset of metabolites that are thought to be important in regular replacement of skin and lung tissue in patients with scleroderma, interstitial lung disease, or both. |
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| DNA modulation module: Core Laboratory staff were busy in the month of October preparing samples for shipment in November 2022 to another collaborating laboratory for analysis of DNA-methylation from existing blood samples. DNA-methylation is also implicated in defects of normal replacement of cells. |
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| Sep 2022 | Work continued on the accepted manuscript proposal with Ms. Raveen Badyal, the undergraduate student and lead author. In late September, a collaborating laboratory began preparations for the confirmatory, time-consuming, in-depth biomolecular analysis of the mRNAs, lncRNAs, and circRNAs previously identified. In late August, another collaborating laboratory provided the results of the first 2,000 metabolites detected in circulating blood from patients and controls. The results for a second set of approximately 2,000 metabolites are expected by mid-October 2022. It is expected that a small subset of metabolites that are important in regular replacement of skin and lung tissue will be detected in these samples. By late October, processing of blood samples by St. Paul’s Core Laboratory is expected to be completed for the detection of DNA-telomere shortening that is thought to be responsible for defects in the normal replacement of cells in skin and lung tissues. Core Lab staff were busy in the month of October preparing samples for shipment to a collaborating laboratory for analysis of DNA-methylation from existing blood samples. DNA-methylation is also implicated in defects of normal replacement of cells. |
| Jun 2022 | Dr. Zheng virtually presented an abstract, poster and video on the results of 87 cytokines in circulating blood from controls, scleroderma patients with ILD and IPF patients on June 1 at the 2022 Annual European Congress of Rheumatology in Copenhagen, Denmark. The abstract can be viewed at the “Annals of the Rheumatic Diseases”. With an undergraduate student as lead author, a manuscript proposal was accepted by a scientific journal on 21 April. Additional laboratory work was completed in May. The manuscript draft was completed by the end of June. Data was received on 2 May from the collaborating laboratory analyzing expression of long noncoding, messenger, and circular RNA. Six mRNA’s, four lncRNA’s, and two circRNA’s had been identified with respect to skin and lung damage in scleroderma and lung damage in IPF. These have been selected for confirmatory laboratory analysis. Laboratory staff were busy in the month of June preparing samples for shipment to two collaborating laboratories for metabolomic analysis and DNA analysis of blood samples. |
| Mar 2022 | A revised abstract was submitted and accepted on 31 March 2022 for presentation by electronic poster with a 4-minute video by Dr. Zheng. These will be released to attendees at the 2022 Annual European Congress of Rheumatology to be held 1 – 4 June 2022 (online and in-person) in Copenhagen, Denmark. Confirmation of receipt of the submission of the abstract’s corresponding article manuscript for peer review by a biomedical journal was confirmed on 28 March. One of our undergraduate students has continued working to visualize and confirm, by a different biochemical pathway, a potential biomarker discovered in the first miRNA analysis. Poster presentations of this research were made in August 2021 and March 2022. Shipment of samples for an analysis of long noncoding RNA and circular RNA occurred in February 2022. We are awaiting the results from the collaborating laboratory. |
| Dec 2021 | Statistical review of the second miRNA plate of 92 blood samples was completed and no quality control issues were detected, so analysis of this second confirmatory cohort will proceed. One of our summer students was back to continue her work with the Western blot analysis of three potential biomarkers from blood samples. Planning and sampling selection has concluded for an analysis of long noncoding RNA and circular RNA. |
| Sep 2021 | BC Genome Sciences Centre released the results of the second miRNA to the research team on 20 Jul 2021, a tad late for analysis during the summer. Our summer student working on the Western blot analyses was able to present interim results at a summer-student research conference at St. Paul’s Hospital at the end of August. Dr. Dunne and laboratory staff wrapped up their developmental work with the two biomarkers. |
| Jun 2021 | The second plate of 92 samples for miRNA analysis was submitted to the BC Genome Sciences Centre on 20 April 2021. In May 2021, two undergraduate research assistants joined the Research Program fulltime for the summer to help with database consolidation (needed for Dr. Zheng’s research) and Western blot analyses. Since the end of March, Dr. Dunne and the laboratory staff were working on finding optimal dilutions for two potential biomarkers discovered from the initial miRNA analysis. |
| Mar 2021 | In February 2021, Dr. Keen completed the biostatistical analysis of the biomarker laboratory results obtained before the holiday break in December 2020. The second biomarker laboratory work and biostatistical analysis are planned for early in the second quarter of 2021. Preparation of the samples for the confirmatory miRNA analysis were completed before the end of March 2021. These will be processed by the BC Genome Sciences Centre hopefully in April 2021 so that the bioinformatic and biostatistical analyses can be completed, or at least preliminary results, by the end of June 2021. |
| Dec 2020 | Work continued for continuation of human-participant approval by UBC/Providence and UNBC Research Ethics Boards for the Program and the Scleroderma Biobank at St. Paul’s Hospital in Vancouver. Laboratory prepwork begun for two new biomarker analyses using banked blood samples. The laboratory and bioinformatic analyses for one of these two sub-projects was completed before the holiday break. Blood samples for the miRNA confirmatory cohort for PCR cross-validation were mostly completed but halted due to a global shortage of pipette tips needed for PCR analysis of he COVID-19 virus and its variants of concern. |
| Sep 2020 | Preparation of blood samples for the miRNA confirmatory cohort continued as was preparation of samples for the PCR cross-validation. The results from the analysis of blood samples performed by the Mitogen Advanced Diagnostics Laboratory were accepted during the last week of September 2020. A decision was made to engage on a part-time basis, through existing research funding, a rheumatologist graduating from McGill University to serve as a postdoctoral fellow beginning in January 2021. |
| Aug 2020 | Biostatistical analysis was completed for cytokines for the first miRNA cohort. The remainder of the cytokine samples represents a historical cohort from approximately one decade ago and this required going back to archived electronic and paper records to confirm disease status. Preparation of blood samples for PCR analysis for a second confirmatory batch of samples was commenced. |
| Jul 2020 | Blood samples from 337 participants were prepared and shipped to Eve Technologies for biomolecular analysis of circulating cytokines, which was received at month’s end. Available blood samples continued to be prepared for next next generation sequencing of miRNA molecules in the confirmation cohort. |
| Jun 2020 | Decision to pursue peer review and publication in a biomedical journal regarding the diagnostic panel created with known micro-RNA (miRNA) molecules. Preparation and submission of an application to Providence Health Care Research Institute to resume tissue collection to complete the verification cohort. Creation of a co-authorship partnership with Dr. Marvin Fritzler at the University of Calgary for biomolecular analyses of circulating cytokines and factors to be conducted at Mitogen Advanced Diagnostics Laboratory. Planning for resumption of biomolecular processing for the Program by the core research laboratory at St. Paul’s Hospital. |
| May 2020 | Preparation and cost quote for next generation sequencing of miRNA molecules in the confirmation cohort. |
| Apr 2020 | Identification of target biomolecular pathways for inflammation and calcinosis for miRNA’s in the diagnostic panel of known miRNA’s and plans for supporting laboratory analyses. |
| Mar 2020 | Recruitment and sample preparation for verification cohort of miRNA-sequencing and PCR analyses has been placed on hold due to Covid-19. Biostatistical analysis of existing miRNA and clinical data, however, is continuing. |
| Feb 2020 | Bioinformatic verification of PCR lab analysis. |
| Jan 2020 | Polymerase chain reaction (PCR) lab analysis for biochemical pathway predicted by known-miRNA sequencing. |
| Dec 2019 | Approval from University-Industry Liaison Office to publish results for known miRNA’s in medical literature and encouragement to pursue patent protection for novel miRNA’s. |
| Oct 2019 | Invention disclosure to UBC, UNBC, and PCH for known miRNA. |
| Aug 2019 | Completion of differential expression analysis of known and unknown miRNA sequences in blood, skin, and cultured skin-fibroblasts. |
| Feb 2019 | Completion of QC assessment for last third of the samples and QC examination for pilot study of fourth tissue. |
| Nov 2018 | Completion of QC assessment for first two-thirds of the samples. |
| Jul 2018 | miRNA sequence data downloaded for one-third of the samples and quality control (QC) checks started by the scientific team members. |
| May 2018 | Frozen tissue samples from three tissue types transferred to the BC Genome Sciences Centre for sequencing. |
| Apr 2018 | Extraction of micro-RNA (miRNA) from tissue types. |
| Dec 2017 | Skin tissue growth completed. |
| Nov 2017 | Collection of blood and skin tissue samples completed and stored in The Scleroderma Biobank at St. Paul’s Hospital in Vancouver. |
| Jul 2017 | Commence collection of blood and skin tissues from study participants. |
This proof-of-concept study is to discover miRNA sequences and their impact on biochemical processes at the cellular level with the goal of targeted therapeutic interventions to correct the disturbed cycle of regeneration in heart, lung, and skin tissues in scleroderma and lung tissue in IPF. This study is important for the approximately 15,604 Canadians with scleroderma and the approximately 7,045 Canadians with IPF (as confirmed by CT, biopsy, or bronchoscopy). Discovering which miRNA sequences are too low or too high and correcting these imbalances could lead to effective treatment of skin damage in patients with scleroderma and treatment of lung damage in patients with IPF only and in patients with both scleroderma and ILD.
SABC has been behind this program since 2017. Your donations do make a difference in contributing to research that otherwise would not even be considered for funding for these two orphan diseases.
The research team brings together experts in respirology, rheumatology, bioinformatics, and genetical statistics to uniquely tackle this challenge. The team is led by SABC President Rosanne Queen, Beth Miller, Drs. James Dunne and Kevin Keen. Drs. Chris Ryerson and Pearce Wilcox round out the scientific research team. Both Rosanne and Beth participate on the leadership team to keep us informed on the progress of this SABC-funded research program and to ensure the interests of patients and their families are at the forefront.