This K22 proposal describes in detail my plan to obtain the necessary biological and educational skills and apply them in a significant health related subject to develop the foundation of my independent research laboratory. I have obtained an extensive computational training during my undergraduate and graduate studies. I have used these computational skills to improve protein secondary structure prediction, to predict enhancer locations, to model enhancer function, and to uncover regulatory grammar. My one-year postdoctoral training so far, has broadened my view of gene regulation, specifically during T cell development. I have studied noncoding RNAs and their role in T helper cell plasticity and differentiation. Using computational techniques, I have identified several lineage-specific noncoding RNAs in T helper cells. I have started to learn how to perform certain biological experiments to experimentally validate my findings and how to follow certain library preparation protocols. During the mentored phase of this award, I intend to expand my biological skills. To this end, I have tailored my career development plan to include several workshops with laboratory trainings. I have asked my biologist lab-mates to let me observe them performing experiments and to teach and supervise me during certain experiments. I have asked my current advisor to provide me with proper material and equipment to perform experiments. The intended skills that I will master during the mentored phase of this award include real-time PCR, flow cytometry, cell culture and transfection, and high-throughput sequencing library preparation. Obtaining these hands-on biological skills will enable me to setup my ideal mixed dry and wet lab and to effectively mentor graduate and postdoctoral students from both computational and biological sciences. My research plan will address several important biological questions regarding a novel class of noncoding RNAs referred to as enhancer RNAs. It will quantify these noncoding RNAs (Aim1) and characterize their role in T helper cell regulation (Aim2). The regulation of T helper cells is associated with our ability to fight against pathogens, and abnormalities may lead to severe immune diseases. Thus, characterizing novel regulators is important and may open new therapeutic avenues. To ensure the successful completion of this proposal, I have assembled a committee of experts and collaborators that will help me on various aspects of this proposal. Dr. Leonard, an expert in T cell development, will provide me the necessary advice on biological findings. As my primary mentor, he will also provide me the space, equipment, and material needed for the mentored phase of this award. Dr. Jun Zhu, an expert in sequencing technologies, will help me on method development. Dr. Stubbs, an expert in mechanisms of transcriptional regulation, will advice me on the role of enhancer RNAs. Dr. Geller, the director of education at NHLBI, will provide me advice on job search, interview, and transition to the independent phase. Dr. Spolski and Dr. Liao will help me to learn how to perform experiments.
Dysregulation of T helper cell responses typically leads to various immune-mediated diseases such as allergy and asthma. There is growing evidence that noncoding RNAs play a significant role in regulation and plasticity of T helper cells. In this proposal, we identify enhancer RNAs, a recently discovered class of noncoding RNAs, and characterize their role in several T helper cell populations. Identification of enhancer RNAs in T helper cells may lead to the discovery of novel therapeutics for T helper cell related disorders.
|Afzali, Behdad; Grönholm, Juha; Vandrovcova, Jana et al. (2017) BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency. Nat Immunol 18:813-823|
|Lin, Jian-Xin; Du, Ning; Li, Peng et al. (2017) Critical functions for STAT5 tetramers in the maturation and survival of natural killer cells. Nat Commun 8:1320|
|Kazemian, Majid; Ren, Min; Lin, Jian-Xin et al. (2015) Possible Human Papillomavirus 38 Contamination of Endometrial Cancer RNA Sequencing Samples in The Cancer Genome Atlas Database. J Virol 89:8967-73|
|Kazemian, Majid; Ren, Min; Lin, Jian-Xin et al. (2015) Comprehensive assembly of novel transcripts from unmapped human RNA-Seq data and their association with cancer. Mol Syst Biol 11:826|