BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10337030
• 负责人: GAIL A. BISHOP
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2027-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337030
• 关键词: Abnormal Cell; Adaptor Signaling Protein; Age; Aging; Antibodies; Area; Autoimmunity; Award; B lymphoid malignancy; B-Cell Lymphomas; B-Cell Neoplasm; B-Lymphocytes; Basic Science; Biological; Biological Markers; Blood; Cell Aging; Cell Surface Receptors; Cell Survival; Cells; Characteristics; Chronic; Clinic; Clinical; Clinical Trials; Collaborations; Communicable Diseases; Communities; Community Participation; Development; Disease; Doctor of Philosophy; Ebola virus; Educational process of instructing; Ensure; Event; Funding; Future; General Population; Genes; Genetic Transcription; Glucose; Goals; Graft Rejection; Grant Review; Health; Human; Human Herpesvirus 4; Immune; Immune response; Immunity; Industry; Infection; Inflammatory; Interleukin 6 Receptor; Interleukin-6; International; Intervention; Investigation; Iowa; Knowledge; LMP1; Laboratories; Leadership; Leukocytes; Life; Lymphocyte; Lymphocyte Biology; Lymphocyte Function; Lymphoma; Malignant Neoplasms; Malignant neoplasm of pancreas; Manuscripts; Measures; Mediating; Medical; Mentors; Metabolism; Molecular; Monoclonal Antibodies; Mouse Strains; Multiple Myeloma; Mus; Mutation; Nature; Nuclear Protein; Oncogenic; Oncologist; PTPN22 gene; Pathogenesis; Pathway interactions; Phenotype; Phosphoric Monoester Hydrolases; Physicians; Play; Population; Post-Translational Protein Processing; Predisposition; Preparation; Process; Progress Reports; Proteins; Publications; Regulation; Research; Research Personnel; Resistance; Role; Scientific Societies; Scientist; Services; Signal Transduction; Signaling Protein; Source; Specialist; T-Lymphocyte; TNFRSF1A gene; TNFRSF5 gene; Therapeutic; Toxin; Translating; Translations; Tumor Necrosis Factor Receptor; Tumor Suppressor Proteins; Tumor-Derived; Universities; Veterans; Virus Diseases; Work; c-myc Genes; cancer cell; cancer therapy; career; cell killing; cell type; clinical application; clinically relevant; effective therapy; fighting; genetic regulatory protein; glucose metabolism; glucose uptake; improved; inhibitor; insight; interest; loss of function; military veteran; neoplastic cell; news; next generation; prevent; programs; protein function; receptor; recruit; service organization; small molecule inhibitor; treatment trial; tumor

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.

申请人的整体研究计划旨在发展新的见解和对关键的理解 调节免疫细胞功能和相互作用的分子机制，特定 强调B和T淋巴细胞以及B细胞衍生的肿瘤。最终目标是将此知识应用于 制定改进的措施，以预防和治疗涉及淋巴细胞的疾病，以及 告知特定退伍军人肿瘤的最佳可用治疗方法的临床选择。基本 30年前申请人实验室开始的科学调查现在导致了重要的 与医师科学家的合作，将这些研究的发现转化为治疗和临床 试验。在本SRCS奖的拟议资助期间要进行的项目及其相关性 为了退伍军人健康，包括以下内容。 1）将信号蛋白TNF受体相关蛋白3（TRAF3）作为肿瘤抑制剂的作用 在B细胞癌中。 B细胞淋巴瘤（BCL）和多发性骨髓瘤（MM），最常见的癌症 在人群中，人类的淋巴细胞代表过多。在BCL和MM中，功能丧失 TRAF3突变很常见，申请人发现Traf3蛋白的翻译后损失可以 也发生。拟议的项目将继续定义TRAF3如何限制生存途径，当 失调，有助于BCL/MM发病机理，定义TRAF3如何调节BCL代谢，确定 衰老的B细胞中TRAF3蛋白翻译后丢失的机制和生物学后果 人类，并为MM发射细胞开发新的生物标志物。重要的是，所有这些项目都将涉及 与临床医生的合作。 2）确定TRAF3在其他免疫细胞中与临床上相关的作用 类型。申请人的实验室将继续研究揭示TRAF3如何增强和调节T的功能 淋巴细胞，对人类免疫反应至关重要，对传染病和肿瘤。一个新项目， 与两位医师科学家的合作，研究了Monoallial Traf3中断的后果 人类，导致长期对感染和自身免疫性的敏感性。我们强烈怀疑这个遗传 实际上，缺陷比以前所欣赏的要多得多。 3）翻译申请人的知识 CD40功能到临床应用中。这涉及试图优化对抗反人类的项目 CD40抗体用于阻断移植排斥，与退伍军人相关的临床问题，与 了解CD40在抵抗埃博拉病毒感染中起的保护作用。 4）提供关键的专业知识 在B淋巴细胞生物学中为MM和胰腺癌的合作项目提供了资金。这两种恶性肿瘤 在退伍军人人口中以高于正常的速度发生。除了这四个主要项目领域， 形成主要研究目的，申请人将继续她的坚定承诺和指导活动 并教授下一代生物医学研究人员，包括博士学位和医学博士，并为科学服务 社区参与委员会参与，赠款和手稿的审查以及科学领域的领导角色 社会。