BCL10-MALT1 protein-protein interaction in lymphocyte function and dysfunction

BCL10-MALT1 蛋白-蛋白相互作用在淋巴细胞功能和功能障碍中的作用

• 批准号: 10722751
• 负责人: Lisa M Maurer
• 金额: $ 17.32万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-12 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722751
• 关键词: Achievement; Affect; Animal Model; Antigen Receptors; Antigens; Authorship; Autoimmune; Award; B-Lymphocytes; BCL10 gene; Biochemistry; Bioinformatics; Biometry; Cells; Colitis; Complex; Development Plans; Disease; Disease model; Educational Status; Educational workshop; Environment; Event; Experimental Designs; Functional disorder; Goals; Grant; Growth; Immune; Immune System Diseases; Immunoglobulin Domain; Immunology; In Vitro; Inflammation; Inflammatory; K-Series Research Career Programs; Knowledge; Laboratories; Lymphocyte; Lymphocyte Activation; Lymphocyte Biology; Lymphocyte Function; Lymphocyte Subset; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Manuscripts; Mentors; Mentorship; Molecular; Mucosa- associated lymphoid tissue lymphoma translocation protein-1; Mus; Organ; Pathogenesis; Pathology; Patient-Focused Outcomes; Peptide Hydrolases; Phenotype; Physicians; Play; Positioning Attribute; Preparation; Production; Productivity; Proliferating; Protease Inhibitor; Protein Biochemistry; Proteomics; Psoriasis; Records; Regulatory T-Lymphocyte; Research; Role; Scientist; Seminal; Signal Transduction; Signaling Protein; T-Lymphocyte; T-Lymphocyte Subsets; Technical Expertise; Techniques; Therapeutic; Training; Transcriptional Activation; Universities; Work; Xenograft procedure; biomedical scientist; career; career development; cytokine; immune system function; improved; improved outcome; in vivo; in vivo Model; inhibitor; insight; lymphocyte proliferation; meetings; mouse model; murine colitis; pharmacologic; programs; protein complex; protein protein interaction; recruit; research and development; response; responsible research conduct; scaffold; skills; small molecule; systemic inflammatory response; transcription factor; transcriptomics

The goal of this career development award is for the applicant to gain knowledge and technical expertise in lymphocyte biology in order to advance our understanding of how the interaction between BCL10 and MALT1, two critically important lymphocyte signaling proteins, influences lymphocyte function and dysfunction. Knowledge gained during this career development award will provide new insights into the mechanism of interaction between BCL10 and MALT1 as well as the molecular pathogenesis of immune disorders associated with MALT1 dysregulation, including psoriasis and colitis. Experiments are designed with the ultimate goal of determining the therapeutic potential of targeting the BCL10-MALT1 protein-protein interaction in these inflammatory disorders. Specifically, the proposed studies will investigate how manipulation of the BCL10- MALT1 interaction affects MALT1 activity, proinflammatory lymphocyte signaling, and progression of psoriasis and colitis. The proposed experimental aims utilize sophisticated protein biochemistry techniques, in-depth in vitro analyses of lymphocyte function, robust in vivo models of inflammatory disease, and detailed bioinformatic analyses. The applicant has selected a mentor and co-mentor who have strong track records of both research mentorship and scientific achievement and who are therefore well positioned to provide expert guidance. Additionally, the applicant has constructed a career mentoring committee with expertise in developing small molecule protein-protein interaction inhibitors, in lymphocyte biology, and in the analysis of animal models of inflammatory disease. The applicant has also identified key collaborators with needed expertise in immune dysfunction in psoriasis and in biostatistics. The University of Pittsburgh provides a fantastic environment in which to launch an independent career as a productive biomedical scientist. The primary mentor and co-mentor are committed to guiding the applicant towards a highly successful career as a physician scientist via a formal program of scientific and professional milestone assessments. Key milestones emphasize the mastery of specific scientific techniques, the development of research mentoring skills, the transition to senior/corresponding authorship of scientific manuscripts and the preparation of the applicant to initiate her own independent laboratory program. The applicant’s career development plan was carefully crafted to take full advantage of the outstanding environment at University of Pittsburgh including graduate level course work in immunology and biochemistry, workshops and formal coursework in bioinformatics, didactics in murine models of disease, face- to-face career development workshops offered through the Office of Academic Career Development, and workshops in Responsible Conduct of Research. The applicant has identified opportunities to present her work locally as well as at national meetings. With full support of her mentor and co-mentor, the applicant is excited to pursue this training in order to launch her career as an independent scientist studying the influence of key protein- protein interactions in lymphocyte function and dysfunction at the University of Pittsburgh.

该职业发展奖的目标是让申请人获得以下领域的知识和技术专长： 淋巴细胞生物学，以加深我们对 BCL10 和 MALT1 之间如何相互作用的理解， 两种极其重要的淋巴细胞信号蛋白，影响淋巴细胞功能和功能障碍。 在此职业发展奖中获得的知识将为了解这一机制提供新的见解 BCL10 和 MALT1 之间的相互作用以及相关免疫疾病的分子发病机制 MALT1 失调，包括牛皮癣和结肠炎。实验的最终目标是 确定针对这些疾病中 BCL10-MALT1 蛋白-蛋白相互作用的治疗潜力 炎症性疾病。具体来说，拟议的研究将调查如何操纵 BCL10- MALT1 相互作用影响 MALT1 活性、促炎淋巴细胞信号传导和银屑病进展 和结肠炎。拟议的实验目标利用复杂的蛋白质生物化学技术，深入 淋巴细胞功能的体外分析、炎症性疾病的稳健体内模型以及详细的生物信息学 分析。申请人选择了一位在两项研究方面都有良好记录的导师和共同导师 指导和科学成就，因此谁有能力提供专家 指导。此外，申请人还建立了一个职业指导委员会，具有开发专业知识 小分子蛋白质-蛋白质相互作用抑制剂，用于淋巴细胞生物学和动物模型分析 炎症性疾病。申请人还确定了在免疫领域具有所需专业知识的关键合作者 银屑病和生物统计学功能障碍。匹兹堡大学提供了优越的环境 作为一名多产的生物医学科学家开启独立的职业生涯。主要导师和辅助导师 致力于引导申请人通过正式的医学科学家职业生涯取得高度成功 科学和专业的里程碑评估计划。关键里程碑强调对特定领域的掌握 科学技术、研究指导技能的发展、向高级/相应职位的过渡 科学手稿的作者身份以及申请人为启动自己的独立项目所做的准备 实验室计划。申请人的职业发展计划经过精心设计，以充分利用 匹兹堡大学的优越环境包括免疫学和研究生水平课程 生物化学、生物信息学讲习班和正式课程、小鼠疾病模型教学、面部 通过学术职业发展办公室提供的面对面职业发展研讨会，以及 负责任的研究行为研讨会。申请人已找到展示其作品的机会 地方和国家会议上。在导师和共同导师的全力支持下，申请人很高兴能够 接受这项培训是为了开始她作为一名独立科学家的职业生涯，研究关键蛋白质的影响- 匹兹堡大学淋巴细胞功能和功能障碍中的蛋白质相互作用。