Li Li, MD, PhD - US grants

Overall Summary/Abstract The Case Cancer Disparities P20 proposal provides for planning and development of a Specialized Program of Research Excellence (SPORE) in cancer health disparities. This proposal places an emphasis on colon adenoma, precursor lesion of colorectal cancer (CRC), and on breast cancer, which are the two leading causes of cancer death in the United States, and of which, racial disparities persist and are widening. This proposed P20 program builds on the resources of the Case Comprehensive Cancer Center to propose two cutting edge translational Research Projects that use multi-level risk assessment approaches for examining racial difference and epigenetic aging in the development of early colon neoplasia (Project 1) and use systems biology approaches for interrogating molecular mechanisms underlying racial disparities in triple negative breast cancer (TNBC) response to treatment and survival (Project 2). These two Research Projects each are built upon substantial preliminary data, cutting edge technology and methodology, and enabling patient cohorts and tissues to test novel hypotheses with high translational significance. This P20 program will further develop a comprehensive infrastructure for catalyzing a robust Developmental Research Program (DRP) that extend our efforts to other cancers and socioeconomic, demographic and behavioral factors contributing to cancer disparities. A series of 2 core resources support these projects and also establish a strong programmatic infrastructure for transdisciplinary translational research in cancer health disparities. The proposal brings together a highly transdisciplinary team of investigators that work collaboratively through every stages and aims of the proposed research studies to accomplish the translational goal of this P20 application.

PROJECT SUMMARY The main goals of this training proposal is 1) to provide Li Li, MD, PhD, a practicing anesthesiologist at the University of Washington, with additional scientific and professional skills to facilitate his transition to become an independent investigator, and 2) to better understand how the locus coeruleus (LC), at the cellular and circuit levels, contributes to opioid-induced sleep disturbances. Studying sleep disturbances caused by opioids is important because opioids have enormous societal impact, causing over 46,000 overdose deaths in 2018 and almost $80 billion in economic cost annually in the United States; and because recent studies have implicated several aspects of sleep disturbances caused by opioids, including poorer cognition, decreased pain tolerance, and increased negative affect, in contributing to chronic opioid use and relapse. Interestingly, the LC and paraventricular thalamus (PVT) are two brain regions that modulate sleep-wake balance and mediate withdrawal behaviors from opioids, but their roles in opioid-induced sleep disturbances are relatively unknown. Thus, during his K99 phase, Dr. Li aims to 1) examine LC neuronal activity in relation to sleep patterns in a mouse model of acute and chronic opioid administration and 2) determine the role of local opioid receptors in the LC in opioid- induced sleep disturbances. Furthermore, he plans to receive training in 1-photon microendoscopic imaging, optogenetic manipulation of opioid receptors, and cell-specific drug targeting using drug acutely restricted by tethering (DART); and will be mentored by Prof. Michael Bruchas, a world-renowned expert in opioid neurobiology, and a committee of experts in neural circuitry analysis, sleep, and substance abuse disorders. Together, his training will help transition to his independent R00 phase, where he plans to use his trained skills 1) to examine PVT neuronal activity in relation to sleep patterns in acute and chronic opioid administration, and to determine role of local opioid receptors in PVT in opioid-induced sleep disturbances. Studies in the independent phase will prepare him for a future R01 submission to further examine arousal neural circuitry response to sedative and anesthetic drugs. Thus, this proposal aims to characterize the LC-PVT circuit in a mouse model of acute and chronic opioid administration using cutting-edge tools in neural circuit analysis and cell-specific pharmacology in order to better understand the cellular and circuit mechanism underlying opioid- induced sleep disturbances, and provides the essential training and mentorship for Dr. Li to help him achieve his career goal of starting his own lab and becoming an independent investigator.