Genetics of Autontibody Diversification

描述（由申请人提供）： 本KO1提案的主要目的是使PI获得分子生物学和遗传学领域的充分培训和专业知识，以解决自身免疫性疾病中的重要问题。PI在免疫化学和细胞免疫学方面训练有素，并开发了实验小鼠模型系统，以研究系统性红斑狼疮（SLE）对自身抗原的免疫反应。他的出版记录是杰出的，并提供证据表明，他有潜力和质量，发展成为一个一流的调查。他已组建了一个独立调查小组，以帮助他实现所述的短期目标。这段时间的进一步培训将确保他发展成为一个有竞争力的生物医学研究的独立调查员。 博士风湿免疫学系主任舒满福教授将担任主要导师。他在指导和大量资金方面有着出色的记录，使PI能够完成拟议的计划。该部门的助理教授和该奖项的共同导师Michael Brown博士成功地绘制了小鼠中的NKC区域。他在提案中使用的许多方法方面都有专业知识。此外，一组分子生物学和遗传学领域的顾问将帮助PI。南佛罗里达大学的加里利特曼博士和位于西雅图的弗吉尼亚梅森医学中心的克里斯阿米亚博士将提供分子生物学和克隆方面的短期密集培训。PI将在大学和其他地方参加一系列经过深思熟虑的课程，以确保在分子遗传学和生物信息学方面获得所需的基本培训。弗吉尼亚大学医学院拥有一个互动的环境，拥有优秀的教师和研究设施。流变学和免疫学部门在基础和临床研究方面招募了几名独立的研究人员。该科得到医学院和内科学系的大力支持。因此，PI进一步发展的环境非常好，该司和主席对他的职业发展做出了坚定的承诺。该提案解决了这样一个假设，即某些基因在免疫调节中的重要性对于SLE相关自身抗原的自身抗体多样化是重要的。提出了两个具体目标：（1）确定影响表位扩展的非MHC遗传位点，和（2）。证明在适当的遗传背景下，MHC II类基因决定表位扩散。 该提案解决了自身免疫的一个重要问题，并将作为培训工具，以实现PI规定的目标。

DESCRIPTION (provided by applicant): The main objective of this KO1 proposal is for the PI to obtain sufficient training and expertise in the areas of molecular biology and genetics to address important questions in autoimmune disorders. The PI is well trained in immunochemistry and cellular immunology and has developed experimental mouse model systems to study immune responses to autoantigens in systemic lupus erythematosus (SLE). His publication record is outstanding and provides evidence that he has the potential and the quality to develop into a first-rate investigator. He has assembled a team of independent investigators to help him to achieve the stated short-term objective. This period of further training will ensure him to develop into a competitive independent investigator in biomedical research. Dr. Shu Man Fu, Professor and Chief of the Division of Rheumatology and Immunology will serve as the primary mentor. He has an outstanding record in mentoring and significant funding to enable the PI to complete the proposed program. Dr. Michael Brown, Assistant professor in the Division and the co-mentor of the award has successfully mapped the NKC region in the mouse. He has the expertise in many of the approaches used in the proposal. In addition, a group of consultants in the areas of molecular biology and genetics will help the PI. Dr. Gary Litman of the University of South Florida and Dr. Chris Amemiya of the Virginia Mason Medical Center at Seattle will provide intense short period of training in molecular biology and cloning. A well thought-out series of courses at the University and elsewhere will be attended by the PI to ensure the needed basic training in molecular genetics and bioinformatics. The University of Virginia School of Medicine has an interactive environment with outstanding faculty and research facilities. The Division of Rheumatology and Immunology has recruited several independent investigators in both basic and clinical research. The Division is well supported by the Medical School and the Department of Internal Medicine. Thus the environment is outstanding for the further development of the PI and there is strong commitment to him from the Division and the Chair for career development. The proposal addresses the hypothesis that certain genes important in immunoregulation are important for autoantibody diversification to SLE-related autoantigens. Two specific aims are proposed: (1) To define non- MHC genetic loci influencing epitope spreading, and (2). To demonstrate that under an appropriate genetic background, MHC Class II genes dictate epitope spreading. The proposal addresses a significant issue in autoimmunity and will serve well as a training vehicle to obtain the stated goals by the PI.