PAD2 and PAD4 in Citrullination, Autoantibodies, and Rheumatoid Arthritis

简介(申请人提供)：米里亚姆·谢里夫博士是威斯康星大学麦迪逊分校的临床讲师，他的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酶在类风湿关节炎中的作用的富有成效的研究实验室。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生和风湿病研究员的工作，在那里她还在Anna Huttenlocher博士的指导下接受了细胞运动性和关节炎的进一步培训。她曾在顶级免疫学杂志上发表文章，并获得了几个奖项，这些奖项预示着她未来的成功。她正在申请K08，以获得成功实现目标所需的最后一块训练。她将在威斯康星大学完成K08奖项的目标，这所大学在研究和研究资金的质量和广度方面都是一流的大学。她受益于大学的氛围和热情的导师。华盛顿大学提供了她所需要的所有教育活动，并致力于其初级教员的发展。她的部门非常致力于她的成功，并为K08期间提供受保护的时间、研究空间、设备和足够的研究资金。此外，她还拥有许多核心设施和机构来帮助满足她的科学和职业需要。为了实现她作为一名成功的独立临床科学家的目标，她预计需要(1)建立一个组织良好、富有成效的实验室，(2)制定一系列工作，介绍PAD2和PAD4在类风湿性关节炎和中性粒细胞功能中的作用，并为她的研究计划提供基础(3)发展炎症性关节炎、瓜氨酸和中性粒细胞方面的专业知识，(4)提高拨款撰写技能并提交R01级拨款，以及(5)通过口头陈述和出版物加强研究交流。她将在她杰出的指导委员会的帮助下实现这些目标，委员会成员包括细胞运动学和先天免疫专家安娜·哈滕罗彻博士、致力于提高女性科学地位的莫莉·卡恩斯博士和出版广泛的风湿病专家兼办公厅主任艾伦·布里奇斯博士，以及退伍军人医院，谢里夫博士将在那里开始她的独立实验室。她的研究计划包括实验室管理、领导力、拨款撰写、手稿撰写、指导、口头报告以及实验关节炎和中性粒细胞生物学培训等教育活动。她的研究重点是更好地了解类风湿性关节炎(RA)，目标是更好的治疗。RA是一种炎症性关节炎， 影响了近1%的美国人。目前的治疗方法是针对特定的免疫细胞、这些细胞的激活/增殖或炎性细胞因子。许多RA患者对这些治疗没有反应，并遭受永久性关节破坏和残疾，这表明全国需要更好的治疗方法。要设计新的治疗方法，必须有针对性地研究RA病理生理学的新成分。最近的研究结果表明，类风湿关节炎不仅是一种炎症性关节炎，而且是一种真正的自身免疫性疾病，其特征是抗瓜氨酸蛋白抗体。RA被认为是当低水平的炎症(通常在肺部)导致局部瓜氨酸化，随后产生抗瓜氨酸蛋白抗体(ACPA)，最终产生肿瘤坏死因子�，炎症和类风湿性关节炎。ACPA在RA中具有病理性和特异性，但在许多炎症条件下增加的瓜氨酸蛋白除了成为ACPA的抗原外，在RA中的作用尚不清楚。谢里夫博士有新的初步数据表明，肿瘤坏死因子�可以推动酸性磷酸酶的产生，而不仅仅是相反，而且首次有证据表明，瓜氨酸酶之一的PAD4有助于关节炎。通过这个奖项，她将利用 转基因小鼠、类风湿关节炎小鼠模型、酸性磷酸酶复合阵列、新型瓜氨酸检测探针和其他方法，以确定肿瘤坏死因子�是否可以通过肺部炎症来推动酸性磷酸酶的产生，Pad4和Pad2是否都是ACPA产生和关节炎发展所必需的，以及Pad4是否以导致慢性关节炎的方式促进中性粒细胞功能。这些研究目标的完成将阐明瓜氨酸化在关节炎中的作用，以及涉及瓜氨酸化的药物开发的开放的新途径。

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.