CD4+ T cells in Invasive Aspergillosis

描述(由申请者提供)：Amariliz Rivera博士是新泽西医学和牙科大学医学院(UMDNJ-NJMS)的一名新任命的终身教职助理教授。里维拉博士是一名波多黎各裔女性，她致力于作为一名成功的独立科学家的职业生涯。她的科学兴趣在于进行研究，有可能改善患有机会性真菌感染的癌症患者的治疗选择。里维拉博士的长期职业目标是：成为公认的真菌免疫学专家，建立一个成功的、资金充足的研究项目，并成为一名有影响力的终身教授，为缩小我国的健康差距做出贡献。在短期内，她渴望获得资金来支持她的新实验室及其未来的成员，并成功地完成这项申请中提出的科学目标。为了实现这些目标，里维拉博士将参加旨在促进她的职业发展的各种项目，包括以下方面的研讨会：赠款写作、演示技能、实验室管理和领导力。此外，高斯博士和萨尔加梅博士将成为Amariliz的职业发展导师。这两位科学家都有资金充足的实验室，而且都是终身教授--他们成功地培训了其他初级教员。他们将为她的职业发展提供个性化的建议，审查她的补助金和论文，并指导她完成终身教职过程。UMDNJ-NJMS致力于Rivera博士作为一名科学家的成功。她被提供了一个设备齐全的实验室和毗邻的办公室，以及在隔壁有足够的空间来放置她的老鼠品系。更重要的是，她将获得受保护的时间，专注于进行研究和建立她的实验室。里维拉博士将可以使用各种核心设施来帮助她的研究，她将被一个拥有不同专业知识并愿意帮助她的职业发展的科学家同行社区包围。Rivera博士的职业生涯还将受益于成为西班牙裔卓越中心(HCOE)的成员，在那里她将参加专门为提高来自贫困背景的个人的学术表现而设计的活动。此外，通过HCOE，里维拉博士将获得具有共同个人背景的科学家同行的专业支持。在这项K22应用中提出的研究的科学目标集中在了解和利用CD4T淋巴细胞对真菌疾病的防御。接受血液系统恶性肿瘤或骨髓移植治疗的癌症患者患侵袭性曲霉病(IA)的风险增加。IA是一种难以治疗的机会性感染，据报道死亡率超过50%。IA最常见的病原体是烟曲霉，这是一种经常存在于环境中的霉菌。有可能使IA受益的基于免疫的疗法包括疫苗接种和过继T细胞转移。由于缺乏对什么构成保护性烟曲霉菌特异性记忆CD4T细胞反应以及它们是如何诱导和调节的了解，这种基于免疫的治疗方法的进步一直受到阻碍。在以前的研究中，Rivera博士培育了一只针对烟曲霉的T细胞受体转基因小鼠(Af3.16-TCR-TG)，以跟踪真菌特异性CD4T细胞在体内的激活、运输和分化。她之前的研究剖析了先天细胞和先天受体在形成真菌特异性CD4T细胞分化方面的特殊作用，以应对原发的肺部感染烟曲霉菌孢子。在拟议的研究中，她将进一步利用Af3.16-TCR-TG小鼠来评估记忆CD4T细胞对烟曲霉菌反应的形成。这些研究的具体目的是：1)确定免疫调节机制在控制真菌特异性CD4T细胞记忆形成中的影响；2)研究天然细胞亚群和天然受体在调节真菌特异性CD4T细胞记忆反应的扩展和分化中的作用；3)建立针对不同侵袭性真菌病模型的最佳过继T细胞疗法。总之，拟议的研究将大大加深我们对烟曲霉菌特异性CD4T细胞记忆的形成、调节和潜在治疗益处的理解。此外，拟议研究的成功完成可能有助于开发新的治疗干预措施，以对抗侵袭性真菌疾病。

DESCRIPTION (provided by applicant): Dr. Amariliz Rivera is a newly appointed, tenure-track, assistant professor at the University of Medicine and Dentistry of New Jersey-New Jersey Medical School (UMDNJ-NJMS). Dr. Rivera is a woman of Puerto Rican descent who is committed to a career as a successful, independent scientist. Her scientific interest lies in performing research with the potential to better the therapeutic options of cancer patients afflicted with opportunistic fungal infections. Dr. Rivera's long-term career goals are: to become a recognized expert in fungal immunology, to establish a successful, well-funded research program and to be a tenured professor with the influence to contribute to diminishing the health disparities in our country. In the short term, she aspires to secure funding to support her new laboratory and its future members and to successfully complete the scientific aims proposed in this application. To attain these goals Dr. Rivera will participate in a variety of programs aimed at promoting her career development including workshops for: grant writing, presentation skills, lab management and leadership. Moreover, Drs. Gause and Salgame will be Amariliz's career development mentors. Both scientists have well-funded laboratories and are tenured-professors who have successfully trained other junior faculty. They will provide personalized advise on her career progression, will review her grants and papers and will guide her through the tenure process. UMDNJ-NJMS is committed to Dr. Rivera's success as a scientist. She has been provided with a fully equipped laboratory and adjacent office as well as with ample space in the vivarium for her mouse strains. More importantly, she will be given protected time to focus on performing research and establishing her laboratory. Dr. Rivera will have access to a diversity of core facilities to aid in her studies and she will be surrounded by a community of fellow scientists with diverse expertise and willingness to help in her career progression. Dr. Rivera's career will also benefit from being a member of the Hispanic Center for Excellence (HCOE) where she will participate in activities specifically designed to enhance the academic performance of individuals from underserved backgrounds. Moreover, through HCOE Dr. Rivera will have the professional support of fellow scientists with common personal backgrounds. The scientific goals of the studies proposed in this K22 application are centered in understanding and exploiting CD4 T lymphocytes in defense against fungal disease. Cancer patients that receive treatment for hematologic malignancies or bone marrow transplantation are at increased risk for developing invasive aspergillosis (IA). IA is a difficult to treat, opportunistic infection with reported mortality rates in excess of 50%. The most common causative agent of IA is Aspergillus fumigatus, a mold frequently present in the environment. Immune based therapies with the potential to benefit IA include vaccination and adoptive T cell transfers. The advancement of such immune-based therapies has been hampered by a lack of understanding of what constitutes protective A.fumigatus-specific, memory CD4 T cell responses and how are they elicited and regulated. In previous studies Dr. Rivera generated a T cell receptor transgenic mouse specific for A. fumigatus (Af3.16-TCR-tg) to track the in vivo activation, trafficking and differentiation of fungus-specific CD4 T cells. Her previous studies dissected the specific contributions of innate cells and innate receptors in shaping fungus-specific CD4 T cell differentiation in response to a primary, pulmonary infection with A.fumigatus spores. In the proposed studies she would further exploit Af3.16-TCR-tg mice to assess the formation of memory CD4 T cell responses to A.fumigatus. The specific aims of the proposed studies are: 1) Determine the impact of immune regulatory mechanisms in controlling fungus-specific CD4 T cell memory formation, 2) To examine the role of innate cell subsets and innate receptors in regulating the expansion and differentiation of fungus- specific CD4 T cell memory responses, 3) To establish optimal adoptive T cell therapies for diverse models of invasive fungal disease. Altogether, the proposed studies would significantly further our understanding of A.fumigatus-specific CD4 T cell memory formation, regulation and potential therapeutic benefit. Moreover, the successful completion of the proposed studies is likely to contribute to the development of novel therapeutic interventions to combat invasive fungal diseases.