Genetics of Autontibody Diversification

描述(由申请人提供)： 这项KO1建议的主要目标是让PI在分子生物学和遗传学领域获得足够的培训和专业知识，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来研究系统性红斑狼疮(SLE)对自身抗原的免疫反应。他的发表记录非常出色，证明他有潜力和素质发展成为一流的调查员。他已经组建了一个独立调查团队，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名具有竞争力的生物医学研究独立研究员。 风湿病和免疫科教授兼主任舒满福博士将担任主要导师。他在指导方面有出色的记录，并有大量资金使PI能够完成拟议的计划。该研究所的助理教授、该奖项的共同导师迈克尔·布朗博士已经成功地在老鼠身上绘制了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为PI提供帮助。南佛罗里达大学的加里·利特曼博士和西雅图弗吉尼亚·梅森医学中心的克里斯·阿梅亚博士将提供分子生物学和克隆方面的短期高强度培训。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进行必要的基本培训。弗吉尼亚大学医学院拥有一个互动的环境，拥有优秀的教员和研究设施。风湿病和免疫科已经在基础和临床研究中招募了几名独立的研究人员。该司得到医学院和内科的大力支持。因此，为国际和平研究所的进一步发展创造了良好的环境，该司和职业发展主席对他有着坚定的承诺。该建议提出了一种假设，即某些在免疫调节中重要的基因对SLE相关自身抗原的自身抗体多样化很重要。提出了两个具体的目标：(1)确定影响表位扩散的非MHC遗传位点；(2)确定影响表位扩散的非MHC遗传位点。为了证明在适当的遗传背景下，MHC II类基因决定了表位的传播。 该提案解决了自身免疫方面的一个重要问题，并将很好地作为一种培训工具，以实现国际和平协会所述的目标。

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.