DESCRIPTION (provided by applicant): Candidate: Dr. Han is a postdoctoral fellow at the University of Texas, MD Anderson Cancer Center who has developed a unique set of expertise in microRNA biogenesis, DNA damage response, ncRNA and in the identification and characterization of Drosha-associated DDX1. Through her graduate and postdoctoral studies Dr. Han has established a productive track record, with 18 research and review papers published, seven of which as first/joint-first author. Her work has been published in high impact peer-reviewed journals including Nature, Cell Reports, EMBO Journal, Cellular and molecular life sciences, Antioxidants & redox signaling, Biology of Reproduction, Fertility and Sterility. Dr.Han's research has in part been funded by three-year Odyssey fellowship award and Cockrell Foundation at MD Anderson cancer center. Career Development/Training: Dr.Han's long-term goal is to establish an independent research program, where she will elucidate molecular mechanisms by which deregulated RNA-binding proteins plays a role in cancer by altering the expression of various types of RNA and tumor-suppressor RNA. Importantly, these findings will translate into the development of novel therapeutic strategies. The K99/R00 career award will help in achieving this goal by advancing her training in technologies of microRNA biogenesis; DEAD-box RNA helicases; microRNA biogenesis, RNA-protein interaction analysis, RNA-sequencing data analysis in genome wide, DNA damage response, in vitro cancer research, in vivo ovarian tumor xenograft. During the mentored phase Dr. Han will work closely with her mentorship team to learn techniques and hands-on experience in microRNA study and DNA damage response (from Dr. Xiongbin Lu), ncRNA discovery and analysis (from Dr. Chang- Gong Liu), Cancer biology (from Mien-Chie Hung) and ovarian cancer in vivo mouse study and clinical translation (from Dr. Anil K Sood). Strong consultant team (Dr. Xinna Zhang, microRNA analysis; Dr. Cristina Ivan, in silico data analysis) also supports Dr. Han to achieve her research and training plan. The very inspiring scientific environment at the university of Texas, MD Anderson Cancer Center, also part of the world-largest Texas Medical Center, will not only provide her with the expertise and facilities necessary for the completion of the mentored phase of this project, but will also prepare her to transition smoothly into an independent faculty position and lead the research team for basic and clinical understanding of microRNA regulation in cancer progression. Research: Cancer often displays aberrant profiles of microRNA, leading to the global alteration of target proteins that can increase cell proliferation, cellular migratio, and apoptotic resistance. Due to their central role in controlling gene expression at the post-transcriptional level, RNA-binding proteins are emerging as fundamental players in tumor development. Dr. Han's previous studies demonstrated that DDX1 interacts with Drosha microprocessor and regulates posttranscriptional processing of a subset of miRNAs including miR- 200 family which are well known tumor suppressive miRNAs in ovarian cancer. Based on her strong preliminary data, she hypothesize that DDX1 1) specifically binds and promotes a subset of miRNA processing, (2) transmits DNA damage stress signals to miRNA biogenesis to maintain cellular homeostasis, and (3) dysregulation of DDX1 leads to cancer through altering tumor suppressive miRNAs. During the K99 mentored phase, under the guidance of primary mentor Dr. Xiongbin Lu and co-mentorship of Dr. Anil K Sood, Dr. Han will define the activity and role of DEAD-box RNA helicase 1 (DDX1) in the microRNA biogenesis with complement of her strong preliminary studies. In the subsequent R00 independent phase, she will identify function of DDX1 and its regulatory mechanism on tumor suppressive miR-200 family in ovarian cancer that could constitute therapeutic targets to pursue during my future independent research. During the K99 phase, Dr. Han will complete to learn all techniques that are necessary to conduct proposed studies for R00 phases. In Aim 1, Dr. Han will determine how Drosha-associated DDXs binds and promotes processing a subset of miRNAs in miRNA biogenesis. In Aim 2, Dr. Han will further dissect how DDX1 activity or function is regulated in response to DNA damage stresses. In Aim 3, Dr. Han will explore the role of DDX1 as a posttranscriptional regulator to determine the level of tumor suppressive miR-200s and metastasis in ovarian cancer. The information we gain from these studies will provide vital knowledge about RNA-binding proteins, DDX1- mediated regulation of miRNA processing and will help us discover novel regulators of miRNA activity that can serve as druggable targets, potentially offering more specificity and ease of targeting than miRNAs themselves.

PUBLIC HEALTH RELEVANCE Aberrant microRNA expression and activity are associated with many human diseases, particularly cancer. Currently little is known about molecular mechanism by which how miRNA processing is dynamically and specifically regulated in response to several cellular signals. The proposed research will help improve our understanding on RNA-binding proteins, DEAD box RNA helicases as key modulators of microRNA processing and tumorigenesis, which will offer valuable insights for RNA-binding proteins as effective diagnostic markers and targeted therapy.