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.

这一职业发展奖的目标是让申请者获得知识和技术专长 淋巴细胞生物学为了促进我们对Bcl10和MALT1之间的相互作用的理解， 两个至关重要的淋巴细胞信号蛋白，影响淋巴细胞的功能和功能障碍。 在这个职业发展奖中获得的知识将为我们提供对 Bcl10和MALT1的相互作用及其相关免疫疾病的分子发病机制 患有MALT1失调，包括牛皮癣和结肠炎。设计实验的最终目标是 确定靶向Bcl10-MALT1蛋白-蛋白相互作用的治疗潜力 炎症性疾病。具体地说，拟议的研究将调查如何操纵BCL10- MALT1相互作用影响MALT1活性、促炎症淋巴细胞信号转导和银屑病进展 还有结肠炎。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，炎症性疾病的体内模型，以及详细的生物信息学 分析。申请人已经选择了一位在这两项研究中都有良好记录的导师和共同导师 导师和科学成就，因此能够很好地提供专家 指导。此外，申请人还建立了一个职业指导委员会，具有发展的专门知识。 小分子蛋白质-蛋白质相互作用抑制剂，在淋巴细胞生物学和动物模型分析中 炎症性疾病。申请人还确定了在免疫方面具有所需专业知识的主要合作者 牛皮癣和生物统计学中的功能障碍。匹兹堡大学提供了一个极好的环境 作为一名多产的生物医学科学家，开始独立的职业生涯。主要导师和共同导师 致力于引导申请者通过正式的 科学和专业里程碑评估计划。关键里程碑强调掌握具体的 科学技术，研究指导技能的发展，向高级/相应的过渡 科学手稿的作者和申请人准备独立发起自己的申请 实验室计划。申请人的职业发展计划是精心设计的，以充分利用 匹兹堡大学出色的环境，包括研究生水平的免疫学和 生物化学，生物信息学的研讨会和正式课程，小鼠疾病模型的教育学，Face- 通过学术职业发展办公室提供的面对面职业发展讲习班，以及 负责任的研究行为研讨会。申请人已经找到了展示她的作品的机会 在地方和国家会议上也是如此。在她的导师和共同导师的全力支持下，申请人很高兴 继续这种培训，以便开始她的职业生涯，作为一名独立科学家，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。