PAD2 and PAD4 in Citrullination, Autoantibodies, and Rheumatoid Arthritis

点击翻译按钮获取中文摘要

Project Summary/Abstract: Dr. Miriam Shelef is clinical instructor at the University of Wisconsin-Madison whose long- term professional goal is to become a clinician scientist, heading a productive research laboratory focused on the role of citrullinating enzymes in rheumatoid arthritis. She completed her MD and PhD at Columbia University College of Physician and Surgeons with graduate training in immunology and molecular biology. She completed internal medicine residency and rheumatology fellowship at the University of Wisconsin where she also received further training in cell motility and arthritis under the guidance of Dr. Anna Huttenlocher. She has published in top tier immunology journals and won several awards, which suggest future success. She is applying for a K08 to obtain the final piece training needed to successfully reach her goals. She will complete the aims of her K08 award at the University of Wisconsin, which is a top ranked university in terms of quality and breadth of research and research funding. She benefits from a collegial atmosphere and enthusiastic mentors. The UW provides all of the educational activities that she requires and is committed to the development of its junior faculty. Her department is extremely committed to her success and is providing protected time, research space, equipment, and sufficient research funds for the period of the K08. Additionally she has numerous core facilities and institutions to assist with her scientific and career needs. To get to her goal as a successful independent clinician scientist, she anticipates needing to (1) establish a well-organized, productive laboratory, (2) produce a body of work that informs on the role of PAD2 and PAD4 in rheumatoid arthritis and neutrophil function and provides the foundation for her research program (3), develop expertise in inflammatory arthritis, citrullination, and neutrophils, (4) improve skills in grant writing and submit a R01 level grant, and (5) strengthen research communication through oral presentations and publications. She will accomplish these aims with the assistance of her exceptional mentoring committee comprised of Dr. Anna Huttenlocher, an expert in cell motility and innate immunity, Dr. Molly Carnes, who is devoted to the advancement of women in science, and Dr. Alan Bridges, a well- published rheumatologist who is also Chief of Staff and the Veterans Hospital where Dr. Shelef will start her independent lab. Her research plan contains educational activities in laboratory management, leadership, grant writing, manuscript writing, mentoring, oral presentations, and training in experimental arthritis and neutrophil biology. Her research is focused on achieving a better understanding of rheumatoid arthritis (RA) with the goals of better treatments. RA is an inflammatory arthritis that affects almost 1% of Americans. Current therapies target specific immune cells, activation/proliferation of those cells, or inflammatory cytokines. Many people with RA do not respond to these treatments and suffer from permanent joint destruction and disability indicating a national need for better therapies. To design new therapies, novel components of RA pathophysiology must be targeted. Recent findings indicate that RA is not only an inflammatory arthritis, but a true autoimmune disease characterized by antibodies against citrullinated proteins. RA is thought to occur when low level inflammation, often in the lung, leads to local citrullination, followed by the development of anti- citrullinated protein antibodies (ACPAs), and ultimately TNF¿ production, inflammation, and RA. ACPAs are pathologic in and specific for RA, but citrullinated proteins, which increase in numerous inflammatory conditions, have an unclear role in RA, aside from becoming antigens for ACPAs. Dr. Shelef has novel preliminary data that TNF¿ can drive ACPA production instead of only the reverse as well as the first evidence that PAD4, one of the citrullinating enzymes, contributes to arthritis. Through this award, she will use transgenic mice, murine models of RA, ACPA multiplex arrays, a new citrulline detection probe, and other methods to determine if TNF¿ can drive ACPA production through lung inflammation, if both PAD4 and PAD2 are required for the production of ACPAs and arthritis development, and if PAD4 contributes to neutrophil function in ways that can contribute to chronic arthritis. The completion of these research aims would shed light on the role of citrullination in arthritis as well as open novel avenues of drug development involving citrullination.