- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03984227
New Signaling Pathway Targeting Systemic Lupus Erythematosus
Studying of New Signaling Pathway Targeting Systemic Lupus Erythematosus
Study Overview
Detailed Description
Antinuclear antibodies play a direct role in pathogenesis by forming immune complexes. These complexes can either deposit in the kidney or stimulate cytokine production. Dead and dying cells can fill the blood with a plentiful supply of immune complex components in lupus. So cell death is a critical issue in the pathway to auto-reactivity. Pyroptosis is a new member of cell death list. It combines the release of pro-inflammatory mediators and nuclear molecules in a way that could drive lupus. Nod-like receptor pyrins-3, caspase-1, IL-18, and IL-1β are commonly accepted markers of pyroptosis.
Gasdermin D was recently identified as the final pyroptosis executioner downstream of inflammasome activation, and may be an attractive drug target for many diseases. GSDMD is a member of the gasdermin protein family. It was identified as a caspase substrate. Under normal cellular conditions, the C-terminus of GSDMD auto-inhibits the pore-forming activity of the N-terminus. When extracellular signals associated with pyroptosis activate inflammasomes they subsequently cleave and activate caspases-1, -4, -5, and -11. Consequently, activated caspase-1 cleaves and separates the N- and C-terminals of GSDMD. Activated GSDMD forms nanoscopic pores in the cell membrane, leading to the release of proinflammatory materials and cell swelling.
Reactive oxygen species regulates the signaling pathways in response to the changes of the intracellular and extracellular environments. However, overproduction of ROS is toxic and lead to dysfunction of cell and tissue. Oxidative stress is increased in SLE. The increased ROS could promote the release of inflammatory related signaling factors, including nod-like receptor inflammasome and nuclear factor-κB. A recent study showed that inhibition of ROS generation suppressed pyroptosis of hematopoietic stem cells. It has been widely reported that NF-kB is a critical molecular switch for cellular response to oxidative stress. NF-kB exists in the form of dimer and has been demonstrated to be involved in the development and progression of various diseases associated with inflammation, apoptosis, and proliferation. A recent study showed that NF-kB is an essential transcription factor of GSDMD.
In the recent decades, increasing evidence have revealed the roles of epigenetic dysregulation, including microRNA, in the pathogenesis of SLE. MiRNAs is a class of short non-coding RNA approximately 21-25 nucleotides in length that plays important roles in many cellular processes by regulating gene expression. MiRNAs make up a novel class of post-transcriptional gene regulators By combining with the 3' noncoding region of target gene mRNA inducing their degradation or impairing their translation.
MiR-379-5p is located at delta-like 1 homolog-deiodinase, iodothyronine 3 genomic region on 14q32.31. The DLK1-DIO3 region contains 54 miRNAs that is associated with organ development and disease pathogenesis, especially carcinogenesis. Luciferase reporter assays showed that GSDMD was a direct target of miR-379-5p. The over-expression of miR-379-5p blocked the arsenite induced increases of GSDMD levels effect that were reversed by up-regulation of GSDMD.
Study Type
Enrollment (Anticipated)
Contacts and Locations
Study Contact
- Name: Eman R Mohamed, MD
- Phone Number: 01064006642
- Email: mervatragab224@gmail.com
Study Contact Backup
- Name: Manal A Mandour, PhD
- Phone Number: 088 041816
- Email: manal_mandour@aun.edu.eg
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Sampling Method
Study Population
Description
Inclusion Criteria:
- SLE diagnosed patients between (18- 60) years old will be enrolled.
Exclusion Criteria:
- Patients with known pre-existing immunological disorders.
- Patients with known pre-existing infection.
- clinical diagnosis of cancer.
- patients diagnosed with concomitant acute myocardial infarction.
Study Plan
How is the study designed?
Design Details
- Observational Models: Case-Control
- Time Perspectives: Retrospective
Cohorts and Interventions
Group / Cohort |
Intervention / Treatment |
---|---|
SLE patient group
SLE diagnosed patients between (18- 60) years old will be enrolled.
All participants should met at least four of the American College of Rheumatology criteria (Hochberg, 1997).
Disease activity will be assessed in accordance with the SLE Disease Activity Score (SLEDAI 2000 (SLEDAI-2K) (Ward et al., 2000).
|
quantitative real-time polymerase chain reaction
|
control group
The control group will include age and sex matched healthy volunteers
|
quantitative real-time polymerase chain reaction
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
determination of the expression levels of GSDMD, NF-kB and miR-379-5p in SLE group and Control group
Time Frame: 6 months
|
GSDMD, NF-kB and miR-379-5p expression levels will be measured using quantitative real time PCR
|
6 months
|
detection of the relationship between oxidative stress and pyroptosis
Time Frame: 6 months
|
correlation between oxidative stress and pyroptosis and detect if there is relationship between them
|
6 months
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Ghada M Ezzat, PhD, Department of Medical Biochemistry, Faculty of Medicine, Assiut University
- Principal Investigator: Marwa A Gaber, PhD, Department of Medical Biochemistry, Faculty of Medicine, Assiut University
Publications and helpful links
General Publications
- Basiorka AA, McGraw KL, Eksioglu EA, Chen X, Johnson J, Zhang L, Zhang Q, Irvine BA, Cluzeau T, Sallman DA, Padron E, Komrokji R, Sokol L, Coll RC, Robertson AA, Cooper MA, Cleveland JL, O'Neill LA, Wei S, List AF. The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype. Blood. 2016 Dec 22;128(25):2960-2975. doi: 10.1182/blood-2016-07-730556. Epub 2016 Oct 13.
- Dang Y, Wang X, Hao Y, Zhang X, Zhao S, Ma J, Qin Y, Chen ZJ. MicroRNA-379-5p is associate with biochemical premature ovarian insufficiency through PARP1 and XRCC6. Cell Death Dis. 2018 Jan 24;9(2):106. doi: 10.1038/s41419-017-0163-8.
- Li J, Xue J, Wang D, Dai X, Sun Q, Xiao T, Wu L, Xia H, Mostofa G, Chen X, Wei Y, Chen F, Quamruzzaman Q, Zhang A, Liu Q. Regulation of gasdermin D by miR-379-5p is involved in arsenite-induced activation of hepatic stellate cells and in fibrosis via secretion of IL-1beta from human hepatic cells. Metallomics. 2019 Feb 20;11(2):483-495. doi: 10.1039/c8mt00321a.
- Magna M, Pisetsky DS. The Role of Cell Death in the Pathogenesis of SLE: Is Pyroptosis the Missing Link? Scand J Immunol. 2015 Sep;82(3):218-24. doi: 10.1111/sji.12335.
- Shi G, Abbott KN, Wu W, Salter RD, Keyel PA. Dnase1L3 Regulates Inflammasome-Dependent Cytokine Secretion. Front Immunol. 2017 May 8;8:522. doi: 10.3389/fimmu.2017.00522. eCollection 2017.
Study record dates
Study Major Dates
Study Start (Anticipated)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- Systemic lupus erythematosus
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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