BLRD Research Career Scientist Award Application

申请人的整体研究计划旨在发展新的见解和理解的关键 调节免疫细胞功能和免疫细胞之间相互作用的分子机制， 重点是B和T淋巴细胞以及B细胞衍生的肿瘤。最终目标是将这些知识应用于 发展改进的措施，以预防和治疗涉及淋巴细胞的疾病，以及 通知临床选择的最佳可用治疗特定退伍军人的肿瘤。基本 30年前在申请人的实验室开始的科学研究现在正在导致重要的 与医生科学家合作，将这些研究的结果转化为治疗和临床 审判在本SRCS奖的拟议资助期内将开展的项目及其相关性 退伍军人健康，包括以下内容。 1)定义信号蛋白TNF受体相关蛋白3（TRAF 3）作为肿瘤抑制因子的作用 在B细胞癌中。B细胞淋巴瘤（BCL）和多发性骨髓瘤（MM），是人类最常见的癌症。 淋巴细胞，在退伍军人群体中过度代表。在BCL和MM中，功能丧失 TRAF 3突变是常见的，并且申请人发现TRAF 3蛋白的翻译后丢失可以导致TRAF 3蛋白的缺失。 也会发生。拟议的项目将继续确定TRAF 3如何抑制生存途径， TRAF 3是一种调节异常的蛋白，参与BCL/MM的发病机制，确定TRAF 3如何调节BCL代谢， 衰老过程中B细胞TRAF 3蛋白翻译后缺失的机制及生物学后果 人类，并开发MM起始细胞的新生物标志物。重要的是，所有这些项目都将涉及正在进行的 与临床医生同事合作。2)确定TRAF 3在其他免疫细胞中的临床相关作用 类型申请人的实验室将继续研究揭示TRAF 3如何增强和调节T细胞的功能。 淋巴细胞，对人类对传染病和肿瘤的免疫反应至关重要。一个新项目，在 与两位医生科学家合作，研究了单等位基因TRAF 3破坏的后果， 人类，导致对感染和自身免疫的慢性易感性。我们强烈怀疑这种基因 事实上，缺陷比以前认识到的要普遍得多。3)翻译申请人的知识 CD 40功能进入临床应用。这涉及到寻求优化一种对抗人类的 用于阻断移植排斥的CD 40抗体，这是与退伍军人相关的临床问题， 了解CD 40在抵抗埃博拉病毒感染中发挥的保护作用。4)提供关键的专业知识 在B淋巴细胞生物学资助合作项目在MM和胰腺癌。这两种恶性肿瘤 在退伍军人群体中发生率高于正常水平。除了这4个主要项目领域外， 从主要的研究目标来看，申请人将继续她在指导方面的坚定承诺和活动 教授下一代的生物医学研究人员，包括博士和医学博士，并为科学服务。 社区参与委员会，审查赠款和手稿，并在科学领域发挥领导作用 社会。

The overall research program of the applicant seeks to develop new insights and understanding of the key molecular mechanisms regulating the functions of, and interactions between immune cells, with a particular emphasis on B and T lymphocytes, and B cell-derived tumors. The ultimate goal is to apply this knowledge to development of improved measures to both prevent and treat diseases involving lymphocytes, as well as to inform the clinical selection of the optimal available treatments for a specific Veteran's tumor. The basic science investigations that began in the applicant's laboratory 30 years ago are now leading to important collaborations with physician-scientists to translate the findings of these studies into treatments and clinical trials. The projects to be pursued during the proposed funding period of this SRCS award, and their relevance to Veteran health, include the following. 1) Define the role of the signaling protein TNF Receptor Associated Protein 3 (TRAF3) as a tumor suppressor in B cell cancers. B cell lymphoma (BCL) and multiple myeloma (MM), the most common cancers of lymphocytes in humans, are over-represented in the Veteran population. In both BCL and MM, loss-of-function TRAF3 mutations are common, and the applicant discovered that post-translational loss of TRAF3 protein can also occur. The proposed project will continue to define how TRAF3 restrains survival pathways which, when dysregulated, contribute to BCL/MM pathogenesis, define how TRAF3 regulates BCL metabolism, determine the mechanisms and biological consequences of post-translational loss of TRAF3 protein in the B cells of aging humans, and develop new biomarkers for MM-initiating cells. Importantly, all these projects will involve ongoing collaborations with clinician colleagues. 2) Determine clinically-relevant roles of TRAF3 in other immune cell types. The applicant's lab will continue studies revealing how TRAF3 enhances and regulates the function of T lymphocytes, critical to human immune responses to infectious disease and tumors. A new project, in collaboration with two physician-scientists, investigates the consequences of monoallelic TRAF3 disruption in humans, leading to chronic susceptibility to infections, and autoimmunity. We strongly suspect that this genetic defect is in fact much more widespread than previously appreciated. 3) Translate the applicant's knowledge of CD40 function into clinical application. This involves projects that seek to optimize an antagonistic anti-human CD40 antibody for use in blocking transplant rejection, a clinical problem of relevance to Veterans, and to understand the protective role played by CD40 in resistance to Ebola virus infection. 4) Provide key expertise in B lymphocyte biology to funded collaborative projects in MM and pancreatic cancer. Both these malignancies occur at higher-than-normal rates in the Veteran population. In addition to these 4 major project areas, which form the major research Aims, the applicant will continue her strong commitment and activities in mentoring and teaching the next generation of biomedical researchers, both PhD and MD, and serve the scientific community in committee participation, review of grants and manuscripts, and leadership roles in scientific societies.