Peripheral B Cell Receptor Editing

该提案详细介绍了一个为期5年的培训计划，用于B细胞发育生物学和免疫耐受研究的学术生涯的发展。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严格的科学环境来开发尖端分子工具的专业知识。PI计划在成为独立研究者后利用这些工具来剖析B细胞免疫学中临床相关问题的机制和分子基础。PI目前是医学临床研究员，在Frederick Alt博士（导师）和Frank Austen博士（共同导师）的指导下进行研究。他的研究重点涉及B细胞亚群的特征，他最近发现，重新排列肠系膜淋巴结B细胞中的免疫球蛋白λ轻链（IG（）位点。在拟定计划中，PI将表征该外周编辑细胞群体（目标1），并开发小鼠模型以研究该IG（基因座重排活性与肠道环境免疫耐受性相关）（目标2）。在目标3中，他将继续研究阐明免疫球蛋白轻链基因重排调控的分子机制。总之，从这个建议的结果将促进我们的理解的机制，B细胞的发展，抗体特异性调制和调节的DNA可及性V（D）J重排机制。此外，这些研究可能有助于理解过敏性和/或炎症性疾病过程中的外周B细胞受体编辑。导师是该领域的杰出科学家，拥有100多名受训人员，并完全专注于他目前的实验室计划。共同导师也是一位杰出的科学家，在过敏性疾病的小鼠模型方面具有专业知识，他将帮助候选人的职业发展。咨询委员会成员都是非常杰出的、受人尊敬的免疫学家，他们也将监督这项提案的进展，并在预定的会议和非正式会议上对方法和结果的解释提出批评。这项研究将在波士顿儿童医院免疫疾病研究所/细胞和分子医学项目的高度合作环境中进行。PI还将受益于他的家乡机构的环境，BWH的炎症和过敏性疾病研究部门。这两个机构都致力于提供必要的资源和培训，以帮助主要调查员建立独立的职业生涯。我们的免疫系统未能发展耐受性食物和“好”细菌导致疾病。确定对这些实体的耐受机制的研究对于设计预防和治疗食物过敏和炎症性肠病的新疗法至关重要。

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.