Peripheral B Cell Receptor Editing

外周 B 细胞受体编辑

• 批准号: 8082810
• 负责人: Duane R. Wesemann
• 金额: $ 13.71万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8082810
• 关键词: Address; Advisory Committees; Allergic; Allergic Disease; Antibody Repertoire; Antibody Specificity; Antigens; Autoantigens; Autoimmune Process; B-Cell Activation; B-Cell Development; B-Lymphocytes; Bacteria; Binding; Biological Assay; Bone Marrow; Boston; Cell surface; Cells; Clinical; Commit; Committee Members; Critiques; DNA; DNA Sequence Rearrangement; Data; Development; Developmental Biology; Disabled Persons; Disease; Environment; Failure; Food; Food Hypersensitivity; Frequencies; Gene Rearrangement; Genetic Recombination; Home environment; Hypersensitivity; Immature Bone; Immune System Diseases; Immune Tolerance; Immune system; Immunization; Immunoglobulin Genes; Immunoglobulin Light Chain Genes; Immunoglobulins; Immunologist; Immunology; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Institutes; Institution; Laboratories; Life; Light; Light-Chain Immunoglobulins; Location; Maintenance; Mature B-Lymphocyte; Mediating; Medicine; Mentors; Mesentery; Methods; Microbe; Modeling; Molecular; Molecular Medicine; Nonhomologous DNA End Joining; Pediatric Hospitals; Peripheral; Physiological; Play; Population; Prevention therapy; Process; Program Development; Receptors, Antigen, B-Cell; Regulation; Regulatory Element; Research; Research Personnel; Resources; Role; Schedule; Scientist; Signal Transduction; Specificity; Surface Immunoglobulins; T-Lymphocyte; Testing; Toll-like receptors; Training; Training Programs; V(D)J Recombination; career; career development; clinically relevant; design; enhancing factor; in vivo; insight; lymph nodes; meetings; microbial; mouse model; programs; receptor; research study; tool

This proposal details a 5 year training program for the development of an academic career in the study of B cell developmental biology and immune tolerance. The PI has joined the laboratory of Fred Alt to study B cell receptor editing and the regulation of immunoglobulin light chain rearrangement, and plans to utilize the rigorous scientific environment in the Alt to develop expertise in cutting edge molecular tools. The PI plans to then utilize these tools as he becomes an independent investigator to dissect the mechanistic and molecular underpinnings of clinically relevant problems in B cell immunology. The PI is currently a Clinical Fellow in Medicine conducting research under the direction of Dr. Frederick Alt (mentor) and Dr. Frank Austen (co-mentor). His research focus involves the characterization of a subpopulation of B cells that he recently found to rearrange the immunoglobulin lambda light chain (Ig() locus in mesenteric lymph node B cells. In the proposed plan, the PI will characterize this population of peripheral editing cells (Aim 1) and develop mouse models to investigate this Ig( locus rearrangement activity with respect to immunological tolerance to the gut environment (Aim 2). In Aim 3, he will pursue studies to elucidate the molecular mechanisms involved in regulation of immunoglobulin light chain gene rearrangements. Together, results from this proposal will advance our understanding of the mechanisms of B cell development, antibody specificity modulation and regulation of DNA accessibility to V(D)J rearrangement machinery. Moreover, these studies may aid the understanding of peripheral B cell receptor editing in allergic and/or inflammatory disease processes. The mentor is an eminent scientist in the field with over 100 established trainees and is fully focused on his current laboratory program. The co-mentor is also an eminent scientist with expertise in mouse models of hypersensitivity diseases who will aid in the candidates career development. Advisory committee members are exceptionally outstanding, respected immunologists who will also oversee the progress of this proposal and provide critique on the methods and interpretation of results at scheduled meetings and informally. The research will take place within the highly collaborative environment of the Immune Disease Institute/Program for Cellular and Molecular Medicine at the Children's Hospital Boston. The PI will also benefit from the environment of his home institution, the Inflammation and Allergic Diseases Research Section at BWH. Both of these institutions are committed to providing the necessary resources and training to help the primary investigator establish an independent career. Failure of our immune system to develop tolerance food and "good" bacteria leads to disease. Studies to determine the mechanism of tolerance to these entities will be critical to designing new therapies for prevention and treatment of food allergy and inflammatory bowel disease.

该建议详细介绍了一项为期5年的培训计划，以开发B细胞发育生物学和免疫耐受性研究的学术生涯。 PI已加入Fred Alt的实验室，研究B细胞受体编辑和免疫球蛋白轻链重排的调节，并计划利用ALT中严格的科学环境来开发尖端分子工具方面的专业知识。 PI计划随后使用这些工具，因为他成为独立研究者，以剖析B细胞免疫学中临床相关问题的机械和分子基础。 PI目前是医学临床研究员，在Frederick Alt博士（Mentor）和Frank Austen博士（Co-Contor）的指导下进行研究。 His research focus involves the characterization of a subpopulation of B cells that he recently found to rearrange the immunoglobulin lambda light chain (Ig() locus in mesenteric lymph node B cells. In the proposed plan, the PI will characterize this population of peripheral editing cells (Aim 1) and develop mouse models to investigate this Ig( locus rearrangement activity with respect to immunological tolerance to the gut environment (Aim 2在AIM中，他将进行研究，以调节免疫球蛋白轻链基因重排，该提议的结果将提高我们对B细胞发展的机制的理解和/或炎症性疾病过程。该联合学者还是一位杰出的科学家，在高敏疾病的老鼠模型中具有专业知识，这些疾病将有助于候选人职业发展。咨询委员会成员是异常出色的，受人尊敬的免疫学家，他们还将监督该提案的进展，并就计划会议和非正式的结果的方法和解释提供批评。该研究将在波士顿儿童医院的免疫疾病研究所/细胞和分子医学计划的高度协作环境中进行。 PI还将受益于他的家庭机构的环境，BWH的炎症和过敏性疾病研究部分。这两个机构都致力于提供必要的资源和培训，以帮助主要研究人员建立独立的职业。免疫系统未能发展耐受性食物和“好”细菌会导致疾病。确定对这些实体的耐受性机制的研究对于设计新疗法以预防和治疗食物过敏和炎症性肠病至关重要。