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Scleroderma Association of B.C. Research Program

The aim of the SABC Genome Research Project 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).

 

BASAK SAHIN

Basak has been involved with the SABC Research Project 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 Project HERE.

 

Summary of the SABC Research Project.

September 2022 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: If you recall, Dr. Boyang Zheng joined the SABC Research Program on 1 January 2021 as a postdoctoral fellow for one year on a part-time basis to work on the auto-antibody aspect of the Program with Drs. Dunne, Keen, and Ryerson. Dr. Zheng has been seeing patients through the rheumatology and scleroderma clinics at St. Paul’s Hospital.  He stayed on until March 2022 in a three-month extension of his fellowship and will continue to see patients for a private practice on locum (part-time) basis. He is also continuing his work on the manuscript noted below.

Follow @SABCResearch on Twitter and Facebook for progress and development updates. These social media handles were created in October 2020 and have  been providing communication on this SABC Research Program since.

Research Program Progress

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 Project 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 project 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.