Peripheral B Cell Receptor Editing

本提案详细介绍了B细胞发育生物学和免疫耐受研究的学术生涯发展的5年培训计划。PI与Fred Alt实验室一起研究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严谨的科学环境，开发尖端分子工具的专业知识。PI计划利用这些工具，当他成为一名独立的研究者，剖析B细胞免疫学临床相关问题的机制和分子基础。该PI目前是医学临床研究员，在Frederick Alt博士（导师）和Frank Austen博士（联合导师）的指导下进行研究。他的研究重点是B细胞亚群的特征，他最近发现免疫球蛋白轻链(Ig（）位点重排在肠系膜淋巴结B细胞中。在拟议的计划中，PI将表征这种外周编辑细胞群（目标1），并开发小鼠模型来研究这种Ig（基因座重排）活性与肠道环境的免疫耐受性（目标2）。在Aim 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，这一建议的结果将促进我们对B细胞发育机制、抗体特异性调节和DNA对V(D)J重排机制的可及性的调控的理解。此外，这些研究可能有助于理解过敏和/或炎症疾病过程中的外周B细胞受体编辑。导师是该领域的杰出科学家，拥有100多名已建立的学员，并完全专注于他目前的实验室项目。共同导师也是一位在超敏性疾病小鼠模型方面具有专长的杰出科学家，他将有助于候选人的职业发展。咨询委员会成员是非常杰出的、受人尊敬的免疫学家，他们也将监督该提案的进展，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协作环境中进行。私家医生还将受益于他所在机构的环境，即BWH的炎症和过敏性疾病研究科。这两个机构都致力于提供必要的资源和培训，以帮助首席研究员建立独立的职业生涯。如果我们的免疫系统不能产生耐受食物和“好”细菌，就会导致疾病。研究确定对这些实体的耐受机制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.