Role of mitochondria in SLE and its cardiovascular complications
Ended Project Grant Awarded Last action
- Award ID
- R01HL158606
- Recipient
-
University Of Washington UEI HD1WMN6945W6 Part of University Of Washington
- Awarding agency
-
National Heart Lung and Blood Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $5,791,731
Award facts
- Assistance listing
- 93.837 Cardiovascular Diseases Research
- Completion date
- Funding
-
- $5,182,806.00 Federal
- $608,925.00 Non-federal
- Place of performance
- Seattle, WA 98109, USA
Award details come from USAspending.gov.
Description
- Abstract
- Upon cellular death, cells release damaged mitochondria, contributing to local inflammation. The overall aims of the present study are to investigate how mitochondria are cleared to avoid evoking an aberrant immune response, and to determine if autoantibodies targeting mitochondrial proteins have clinical utility in assessing development of thrombosis in patients with systemic lupus erythematosus (SLE). The premise of the study is that SLE patients have impaired clearance of mitochondria, promoting development of mitochondrial antibodies, inflammation and organ damage, including thrombosis. To investigate this we have three main aims. The first aim investigates how mitochondrial extrusion promotes autoimmunity towards mitochondrial protein antigens, attempting to define the exact target of novel main mitochondrial autoantibody, AMA-17, the processes involved in exposing the autoantigen in vitro, as well as potential therapeutic targets, e.g. mitochondrial ROS, involved in generating AMA-17 in vivo. The second aim investigates how anti-mitochondrial antibodies partake in thrombosis development. Using a large longitudinal SLE cohort (n=500), followed over 10 years, we will determine the capacity of AMA-17 to associate with and/or predict development of venous thrombosis. Affinity-purified AMA-17 antibodies will be tested for platelet activation and thrombus formation in vitro using flow cytometry, aggregometry and a cutting-edge model of engineered microvessels, as well as in vivo using a novel model of antibody-mediated venous thrombosis developed by DR. Knight. Finally, in aim 3, we will investigate underlying mechanisms involved in clearance of mitochondria, with an emphasis on the role of complement C1Q and C3 to facilitate silent clearance. These studies will be done both in vitro using select isolated complement components, as well as in vivo using unique C1Q and C3 deficient mice. Outcome measures include phagocytosis, cytokine production, and net formation. Downstream signaling pathways involved in mitochondrial-mediated inflammation will be identified using mass spectrometry-based phosphoproteomics. In all, our study aims at identifying fundamental mechanisms regulating inflammation, thrombosis and autoimmunity in the context of human disease, with an emphasis on the role of the complement system in silent removal of mitochondria. We expect the proposed research to provide novel therapeutic targets disrupting the inflammatory and immunogenic properties of mitochondria, applicable for many diseases, including SLE and rheumatoid arthritis, as well as identify prognostic mitochondrial- derived biomarkers enabling early and preventive treatment of venous thrombosis.
Transactions
| Action | Federal | Non-federal | Date |
|---|---|---|---|
| Amendment | $524,401 | $0 | |
| Amendment | $565,466 | $0 | |
| Amendment | $587,228 | $0 | |
| Amendment | $587,228 | $0 | |
| Amendment | $545,854 | $0 | |
| Amendment | $545,854 | $0 | |
| Amendment | $608,925 | $0 | |
| Amendment | $608,925 | $0 | |
| Original award | $608,925 | $608,925 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Bloodworks | $45,250 | |
| Institute For Systems Biology | $45,750 | |
| Regents Of The University Of Michigan | -$52,601 | |
| Institute For Systems Biology | -$3,995 | |
| Institute For Systems Biology | $45,750 | |
| Regents Of The University Of Michigan | $22,502 | |
| Bloodworks | $45,250 | |
| Karolinska Institutet | $75,144 | |
| Regents Of The University Of Michigan | $60,528 | |
| Bloodworks | $43,893 |
Quick answers
Who received award R01HL158606?
R01HL158606 was awarded to University Of Washington by National Heart Lung and Blood Institute (National Institutes of Health) on August 25, 2021.
How much is award R01HL158606 worth?
$5,791,731 has been obligated on R01HL158606: $5,182,806 in federal funding and $608,925 in non-federal funding.
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