Investigating the role of the microbiota in enhancing memory T cell function during caloric restriction to promote melanoma control

研究热量限制期间微生物群在增强记忆 T 细胞功能以促进黑色素瘤控制中的作用

• 批准号: 10599286
• 负责人: Nicholas Collins
• 金额: $ 24.9万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-06 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599286
• 关键词: Acetates; Address; Adoptive Transfer; Antitumor Response; Area; Autoimmunity; Bacterial Infections; Bifidobacterium; Bioinformatics; CD8-Positive T-Lymphocytes; CRISPR/Cas technology; Caloric Restriction; Cardiovascular Diseases; Cell physiology; Cells; Chromatin; Collaborations; Communication; Confocal Microscopy; Data; Development; Development Plans; Diet; Diet Modification; Dietary Intervention; Dietary intake; Digestion; Disease; Educational process of instructing; Enrollment; Environment; Epigenetic Process; Fasting; Feedback; Flow Cytometry; Fostering; Gene Deletion; Gene Expression; Genes; Germ-Free; Gnotobiotic; Goals; Health; Health Benefit; Histone Acetylation; Human; Immune response; Immune system; Immunologic Memory; Immunologics; In Vitro; Incidence; Infection; Institution; Intestines; Laboratories; Lysine; Malignant Neoplasms; Maps; Mediating; Memory; Mentors; Mentorship; Microbiology; Molecular; Molecular Biology; Monitor; Mus; Mutagenesis; Nerve Degeneration; Phase; Play; Process; Publications; Publishing; RNA; Research; Research Personnel; Resources; Retroviral Vector; Role; Scientist; Signal Pathway; Site; Sorting; Specialist; T cell response; T memory cell; Techniques; Therapeutic; Therapeutic Uses; United States National Institutes of Health; Vaccination; Volatile Fatty Acids; Work; Writing; XCL1 gene; animal facility; cancer immunotherapy; cancer therapy; career; career development; dietary; experimental study; genome-wide; germ free condition; gut microbiota; high standard; immune checkpoint blockade; immune system function; immunoregulation; improved; insight; instrument; melanoma; member; metabolic profile; microbial community; microbiota; novel; novel therapeutics; overexpression; prevent; rational design; single-cell RNA sequencing; skills; synergism; teacher; transcriptomics; tumor; tumor growth; vaccine development; vaccine immunotherapy

Project summary/Abstract Research: To discover novel factors and mechanisms that enhance the quality of memory T cells has the potential to impact the development of cancer immunotherapies. My recent publication demonstrated that caloric restriction (CR) enhanced the function of memory T cells to control melanoma and significantly extend host survival. As such, CR could represent an accessible nutritional intervention to modulate the function of the immune system for the treatment of cancer. However, the molecular determinants and signalling pathways involved remain unclear, which are critical to uncover in order to rationally design and implement diet-based therapeutic approaches. Based on preliminary data and the published work of others, this proposal will investigate the role of microbiota-derived acetate in enhancing memory T cell function during CR to promote melanoma control. Such information has the potential to benefit human health by improving strategies aimed at treating cancer. Career Goals: My overarching career goal is to become an independent investigator at an academic institution where I study the mechanisms by which CR can be utilized as a nutritional intervention to modulate the immune system for the treatment cancer. Furthermore, I believe that teaching and mentoring are essential aspects of being an independent investigator and therefore aspire to become an inspirational teacher and an outstanding mentor. Career Development Plan: To become a successful independent investigator I will need to develop various research, professional and personal skills. These will include acquiring expertise in molecular biology and microbiology techniques, as well as fostering collaborations and developing skills in writing, mentoring, teaching, communicating and laboratory management. The NIH provides an outstanding academic environment in which trainees can fulfil these criteria by regularly presenting data, receiving feedback from prominent scientists, fostering collaborations and enrolling in courses to develop skills in specialist scientific areas, personal development and laboratory management. Furthermore, in addition to my mentor and co-mentor, I have support from several independent investigators with extensive expertise in areas that will greatly facilitate the completion of experiments proposed here. As such, the NIH is an ideal environment to develop during the K99 phase as I progress to become a successful independent investigator. Career Development Environment: I will perform the K99 phase in the laboratory of Dr. Yasmine Belkaid at the NIH, which provides an unprecedented environment in terms of the resources and facilities available. The laboratory has access to all of the instruments and facilities necessary to complete the experiments proposed in this application. These include a gnotobiotic animal facility and a sequencing facility that also provides bioinformatics analysis. The mentorship I will receive will be of the highest standard and there will be numerous opportunities to collaborate.

项目概要/摘要 研究：发现增强记忆T细胞质量的新因素和机制， 影响癌症免疫疗法的发展。我最近的出版物表明，热量限制（CR） 增强记忆T细胞控制黑色素瘤的功能，并显著延长宿主存活时间。因此，CR可以 代表了一种可获得的营养干预，以调节免疫系统的功能，用于治疗 癌然而，所涉及的分子决定因素和信号传导途径仍不清楚，这对 为了合理地设计和实施基于饮食的治疗方法。根据初步数据 和其他人发表的工作，这项建议将调查微生物来源的乙酸盐在增强 记忆T细胞在CR期间发挥功能，以促进黑素瘤控制。这些信息有可能造福人类。 通过改善旨在治疗癌症的策略来改善健康。 职业目标：我的首要职业目标是成为一个学术机构的独立调查员， 我研究的机制，CR可以作为一种营养干预，以调节免疫系统， 治疗癌症。此外，我相信教学和指导是成为一个 我希望成为一名独立的调查员，因此渴望成为一名鼓舞人心的教师和杰出的导师。 职业发展计划：要成为一名成功的独立调查员，我需要开展各种研究， 专业和个人技能。这些将包括获得分子生物学和微生物学方面的专业知识 技术，以及促进合作和发展写作，指导，教学，沟通技能 实验室管理。美国国立卫生研究院提供了一个优秀的学术环境，学员可以履行这些 通过定期提交数据，接受杰出科学家的反馈，促进合作， 参加课程，以发展专业科学领域，个人发展和实验室管理方面的技能。 此外，除了我的导师和共同导师，我还得到了几位独立调查员的支持， 在将大大有助于完成此处提议的实验的领域拥有广泛的专门知识。因此，NIH 是一个理想的环境，发展在K99阶段，因为我的进展，成为一个成功的独立 调查员 职业发展环境：我将在NIH的Yasmine Belkaid博士的实验室进行K99阶段， 就现有的资源和设施而言，这提供了一个前所未有的环境。实验室已 使用完成本申请中提出的实验所需的所有仪器和设施。 其中包括一个非生物动物设施和一个也提供生物信息学分析的测序设施。的 我将得到的指导将是最高标准的，并将有许多合作机会。