PAD2 and PAD4 in Citrullination, Autoantibodies, and Rheumatoid Arthritis

PAD2 和 PAD4 在瓜氨酸化、自身抗体和类风湿关节炎中的作用

• 批准号: 9235228
• 负责人: Miriam Anne Shelef
• 金额: $ 14.74万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-05 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9235228
• 关键词: Acute; Address; Adhesions; Affect; American; Antibodies; Antibody Formation; Antigen-Antibody Complex; Antigens; Arginine; Arginine deiminase; Arthritis; Autoantibodies; Autoimmune Diseases; Award; Biology; Cells; Chemotaxis; Chronic; Citrulline; Clinical; Collagen-Induced Arthritis; Communication Research; Core Facility; Data; Deposition; Detection; Development; Doctor of Philosophy; Educational Activities; Enzymes; Equipment; Experimental Arthritis; Faculty; Fellowship; Foundations; Functional disorder; Funding; Future; Gene Expression; Generations; Goals; Grant; Histones; Human; Immune; Immune Cell Activation; Immunology; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Arthritis; Institution; Internal Medicine; Joints; Journals; K/BxN model; Laboratories; Laboratory Research; Leadership; Light; Lung; Lung Inflammation; Manuscripts; Mentors; Methods; Modeling; Molecular Biology; Mollies; Mus; Natural Immunity; Oral; Pain; Pathologic; Pathology; Pathway interactions; Peritonitis; Physicians; Process; Production; Proteins; Publications; Publishing; Recruitment Activity; Regulation; Research; Residencies; Resistance; Respiratory Burst; Rheumatoid Arthritis; Rheumatology; Role; Science; Scientist; Severities; Surgeon; T-Cell Activation; T-Lymphocyte; TNF gene; Testing; Thioglycolates; Time; Training; Transgenic Mice; Universities; Veterans Hospitals; Wisconsin; Woman; Writing; adaptive immunity; career; cell motility; citrullinated protein; college; cytokine; design; disability; drug development; educational atmosphere; extracellular; improved; in vivo; inhibitor/antagonist; instructor; joint destruction; macrophage; mouse model; neutrophil; novel; novel therapeutics; overexpression; programs; public health relevance; rheumatologist; skills; success; targeted treatment

DESCRIPTION (provided by applicant): 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 wel as open novel avenues of drug development involving citrullination.

描述（由申请人提供）：Miriam shelf博士是威斯康星大学麦迪逊分校的临床讲师，其长期职业目标是成为一名临床科学家，领导一个专注于瓜氨酸化酶在类风湿关节炎中的作用的高效研究实验室。她在哥伦比亚大学内科和外科医学院完成了医学博士和博士学位，并接受了免疫学和分子生物学的研究生培训。她在威斯康星大学完成了内科住院医师和风湿病学奖学金，在那里她还在Anna Huttenlocher博士的指导下接受了细胞运动和关节炎的进一步培训。她曾在顶级免疫学期刊上发表文章，并获得多个奖项，这预示着她未来的成功。她正在申请一把K08，以获得成功实现目标所需的最后一件训练。她将在威斯康星大学（University of Wisconsin）完成K08奖的目标。威斯康星大学在研究质量、广度和研究经费方面都名列前茅。她受益于学院的氛围和热情的导师。西澳大学提供了她所需要的所有教育活动，并致力于其初级教师的发展。她的部门非常致力于她的成功，并为K08期间提供了受保护的时间、研究空间、设备和充足的研究资金。此外，她还有许多核心设施和机构来协助她的科学和职业需求。为了实现她作为一名成功的独立临床医生科学家的目标，她预计需要(1)建立一个组织良好、富有成效的实验室，(2)完成一系列关于PAD2和PAD4在类风湿关节炎和中性粒细胞功能中的作用的工作，并为她的研究计划提供基础(3)，发展炎症性关节炎、瓜氨酸化和中性粒细胞方面的专业知识，(4)提高拨款写作技能并提交R01水平的拨款。(5)通过口头报告和出版物加强研究交流。她将在她的杰出指导委员会的帮助下实现这些目标，该委员会由细胞运动和先天免疫专家Anna Huttenlocher博士、致力于女性科学进步的Molly Carnes博士和发表过大量文章的风湿病学家Alan Bridges博士组成，他也是退伍军人医院的参谋长，shelf博士将在退伍军人医院开设她的独立实验室。她的研究计划包括实验室管理、领导能力、拨款写作、手稿写作、指导、口头报告以及实验性关节炎和中性粒细胞生物学方面的培训。她的研究重点是更好地了解类风湿关节炎（RA），目标是更好地治疗。类风湿性关节炎是一种炎性关节炎