Leukemia Stem Cell Antigen Discovery Using Advanced Genomic and Proteomic Methods

描述（由申请人提供）：该指导临床科学家发展奖（K 08）提案的主要目标是发展候选人在白血病生物学和干细胞移植领域的学术生涯。候选人在此申请中提出学习基因组分析和质谱分析的新技能，以完成新的研究调查，发现白血病干细胞相关的次要组织相容性抗原。自从2009年搬到北卡罗来纳州大学以来，该候选人一直受到美国医学部KL 2奖的资助，以开发用于发现次要组织相容性抗原的生物信息学和免疫学方法。在这个K 08提案中，候选人已经确定Chuck Perou博士作为他的主要导师和顾问，应用RNA测序分析，旨在计算预测白血病干细胞相关的次要组织相容性抗原（LSC相关mHA）。Perou博士是癌症基因组学领域的领导者，也是癌症基因组图谱的领导者。他指导了许多研究生和博士后学生，并为候选人制定了全面的培训和指导计划，使他能够发展基因组分析的新技能。该候选人还确定加里Glish博士为共同导师，提供质谱方面的培训和指导。候选人拥有化学博士学位，但没有经过质谱分析方面的正式培训。由于质谱在抗原发现研究中起着至关重要的作用，候选人建议将该领域的培训和研究作为整个K 08项目的一部分。Glish博士是一位教授， 他是麻省理工学院的化学教授，也是美国质谱学会的前任主席。他通过他非常成功的职业生涯指导了许多研究生，并将在生物分子检测中提供质谱理论和实践方面的培训。此外，Glish博士的实验室已经开发并建立了一个原型高场不对称波形离子迁移谱（FAIMS）质谱仪，该质谱仪将首次用于探测生物样品中的特定预测肽。除了Perou博士和Glish博士提供的指导外，候选人还将获得由Jon Serody博士和D.尼尔·海耶斯在人类T细胞免疫学和计算生物学。候选人的研究将密切遵循他的导师计划，因为他将利用他在基因组学和计算生物学方面的培训来预测LSC相关的mHA，然后使用HPLC-FAIMS质谱法确认它们在白血病中的产生。该项目的长期目标是预测和确认常见的免疫原性LSC相关mHA，如本K 08提案中所述，然后将其开发为LSC定向免疫治疗的靶点。从本提案中进行的研究，通过ESTA及其Lineberger综合癌症中心提供的培训，指导和学术研究基础设施，候选人将能够成功过渡到成为独立的NID资助的研究者。

DESCRIPTION (provided by applicant): The major objective of this Mentored Clinical Scientist Development Award (K08) proposal is the development of the candidate's academic career in the field of leukemia biology and stem cell transplantation. The candidate proposes in this application to learn new skills in genome analysis and mass spectrometry in order to complete a novel research investigation to discover leukemia stem cell-associated minor histocompatibility antigens. Since moving to the University of North Carolina in 2009, the candidate has been funded by a UNC Department of Medicine KL2 Award to develop bioinformatic and immunologic methods for minor histocompatibility antigen discovery. In this K08 proposal, the candidate has identified Dr. Chuck Perou, PhD, as his primary mentor and advisor in the application of RNA sequencing analysis aimed at the computational predication of leukemia stem cell associated minor histocompatibility antigens (LSC-associated mHA). Dr. Perou is a leader in the field of cancer genomics, and the leader of the UNC contribution to The Cancer Genome Atlas. He has mentored many graduate and post-doctoral students and has developed a comprehensive training and mentorship plan for the candidate so that he can develop new skills in genome analysis. The candidate has also identified Dr. Gary Glish PhD as a co-mentor to provide training and mentorship in mass spectrometry. The candidate has a PhD in Chemistry, but has no specific formal training in mass spectrometry. Because mass spectrometry plays a crucial role in antigen discovery research the candidate is proposing training and research in this field as part of the overall K08 project. Dr. Glish is a professor of Chemistry at UNC and the Past President of the American Society of Mass Spectrometry. He has mentored numerous graduate students through his very successful career, and will provide training in the theory and practice of mass spectrometry in the detection of biomolecules. Additionally, Dr. Glish's laboratory has developed and built a prototype high-field asymmetric waveform ion mobility spectrometry (FAIMS) mass spectrometer that will be used for the first time to probe for specifically predicted peptides in a biological sample. In addition to the mentorship provided by Dr. Perou and Dr. Glish, the candidate will receive advice and recommendations from an advisory panel consisting of Dr. Jon Serody and Dr. D. Neil Hayes in human T cell immunology and computational biology. The candidate's research will closely follow his mentorship plan as he will use his training in genomics and computational biology to predict LSC-associated mHA, and then confirm their production in leukemia using HPLC-FAIMS mass spectrometry. The long-term goal of this project is to predict and confirm common, immunogenic, LSC-associated mHA, as described in this K08 proposal, and to then develop them as targets for LSC-directed immune therapy. From the research conducted in this proposal, the training, mentorship and academic research infrastructure provided through UNC and its Lineberger Comprehensive Cancer Center the candidate will be able to successfully transition to become in independent NID-funded investigator.