Patients with systemic lupus erythematosus (SLE) and the related antiphospholipid syndrome (APS) are predisposed to life-threatening thrombotic events. Neutrophils, and in particular neutrophil extracellular traps (NETs), have recently been linked to both active SLE and thrombosis. The possibility that NETs might be an important trigger of thrombosis in autoimmune disease patients has not, however, been rigorously evaluated. This award will play a critical role in helping me achieve my long-term career goals, which include: (1) becoming an expert in SLE and APS pathogenesis, especially the interplay between innate immune responses and thrombosis, (2) establishing a career as an independent investigator at a leading medical research institution, and (3) mentoring and fostering the development of trainees. These objectives will be reached by incorporating both a strong mentorship environment and a formal instructional plan. The plan focuses on specific scientific and career development goals. Mentorship Environment: I am currently a Clinical Lecturer in the Division of Rheumatology at the University of Michigan. I will become a tenure-track Assistant Professor on January 1, 2014. With this promotion, my time will be protected for research with just one-half day of clinic per week. Further, as is detailed in the Letter of Institutional Support, substantial start-up funds will be provided to support my research activities. Over the past two years, I have received strong training from Dr. Mariana Kaplan as an immunologist. In this proposal, I am seeking support for a significantly new research endeavor, as I turn my attention to the pathologic thrombosis inherent to systemic autoimmune diseases such as SLE. Dr. David Pinsky, an expert in cardiovascular medicine and the interplay between inflammation and thrombosis, will be my primary research mentor going forward. Formal Instruction: My scientific goals include: (1) applying models of neutrophil activation and thrombosis to the rheumatic diseases, (2) working effectively and efficiently with patient samples, and (3) mechanistically studying platelet signaling and activation. Basic science coursework will be through several centers at the University of Michigan including the Center for Statistical Consultation and Research, the Flow Cytometry Core, and the Center for Live Cell Imaging. I also plan to regularly attend the intensive Symposium on Hemostasis, held biennially in Chapel Hill, NC. Equally important are my career development goals, which include: (1) improving written and oral communication skills, (2) developing IRB proposals for research on human subjects, and (3) enriching my mentoring skills. Specific instructional programs and courses will be utilized including the Michigan Institute for Clinical and Health Research, IRBMED, the Program for Education and Evaluation in Responsible Research and Scholarship, and the Undergraduate Research Opportunity Program. Research: Globally, I plan to explore the hypothesis that exaggerated NET formation is an important mediator of pathologic thrombosis in SLE and APS patients.
Aim 1 will study the role of antiphospholipid antibodies (the hallmark of APS, and also frequently found in SLE) in activating neutrophils to release NETs.
Aim 2 will explore the extent to which SLE platelets interact with neutrophils to promote NET formation.
Aim 3 will build on the human studies of Aims 1 and 2 by testing the importance of neutrophils and platelets in animal models of autoimmune-mediated thrombosis and vascular damage.

Public Health Relevance

Systemic lupus erythematosus and the related antiphospholipid syndrome are potentially devastating autoimmune diseases that preferentially target African Americans and women of childbearing age. These diseases not only result in severe damage to vital organs such as the kidneys, but also predispose to many types of cardiovascular disease, including abnormal and life-threatening blood clotting. The training provided by this award will uniquely position me at the intersection of these fields, studying the role of autoimmunity in blood clotting and cardiovascular disease.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Clinical Investigator Award (CIA) (K08)
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Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Mancini, Marie
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Knight, Jason S; Mazza, Levi F; Yalavarthi, Srilakshmi et al. (2018) Ectonucleotidase-Mediated Suppression of Lupus Autoimmunity and Vascular Dysfunction. Front Immunol 9:1322
Woods, Robert J; Reyes, Emmanuel J; Knight, Jason S (2018) Histoplasma Tenosynovitis Revealed by Fungal Culture in a Patient Treated with Infliximab. J Rheumatol 45:284-285
Meng, He; Yalavarthi, Srilakshmi; Kanthi, Yogendra et al. (2017) In Vivo Role of Neutrophil Extracellular Traps in Antiphospholipid Antibody-Mediated Venous Thrombosis. Arthritis Rheumatol 69:655-667
Wang, Hui; Wang, Qian; Wang, Jintao et al. (2017) Proprotein convertase subtilisin/kexin type 9 (PCSK9) Deficiency is Protective Against Venous Thrombosis in Mice. Sci Rep 7:14360
Jackson, William G; Oromendia, Clara; Unlu, Ozan et al. (2017) Recurrent thrombosis in patients with antiphospholipid antibodies and arterial thrombosis on antithrombotic therapy. Blood Adv 1:2320-2324
Vreede, Andrew P; Bockenstedt, Paula L; Knight, Jason S (2017) Antiphospholipid syndrome: an update for clinicians and scientists. Curr Opin Rheumatol 29:458-466
Mor-Vaknin, Nirit; Saha, Anjan; Legendre, Maureen et al. (2017) DEK-targeting DNA aptamers as therapeutics for inflammatory arthritis. Nat Commun 8:14252
Kazzaz, Nayef M; Wilson, Allecia M; Kado, Ruba et al. (2017) A 37-Year-Old Man With Primary Antiphospholipid Syndrome Presenting With Respiratory Distress and Worsening Toe Ischemia. Arthritis Care Res (Hoboken) 69:1253-1259
Knight, Jason S; Meng, He; Coit, Patrick et al. (2017) Activated signature of antiphospholipid syndrome neutrophils reveals potential therapeutic target. JCI Insight 2:
Grenn, Robert C; Yalavarthi, Srilakshmi; Gandhi, Alex A et al. (2017) Endothelial progenitor dysfunction associates with a type I interferon signature in primary antiphospholipid syndrome. Ann Rheum Dis 76:450-457

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