Opioids remain the major medication for perioperative and chronic pain management, but their side effects, which include respiratory depression, constipation, addiction and others, relate to morbidity and mortality in our patients, as well as presenting a significant economic and political burden. Since both the analgesic and side effects are thought to arise from activation of the mu receptor (MUR), a better understanding of the structural and functional relationships of human MUR might provide clues for addressing this clinical dilemma. My long-term goal is to reveal the molecular recognition mechanism of opiates and opiate receptors by using biochemical, biophysical, protein engineering and the high resolution structural approaches. In this project, 4 specific aims are proposed.
In aim 1, we will establish a novel structural model of the human MUR from a combination of rhodopsin structural data and the newly available experimental structures of human ?2 adrenergic receptor. This will permit opioid and MUR interaction studies at the computational level.
In aim 2, we will engineer a variant of the water soluble, but structurally unaltered water soluble mu receptor (WSMUR) for dynamic opioid and receptor interactions in solution conditions.
In aim 3, we will express the WSMUR for biophysical characterization studies and for various binding studies with opioids in solution conditions.
In aim 4, we will crystallize the WSMUR for structural determinations in the presence or absence of opioids. As an anesthesiologist, formerly trained in academic centers in China, Japan, and United States, Dr. Liu is firmly committed to a career in academic anesthesia. His ultimate career goal is to achieve a better understanding of opioid and opioid receptor interactions, and use these data to develop optimal analgesics to ultimately improve patient care and satisfaction. This proposal will help him to reach his goals by providing further training and resources. His co-mentors have established records of nurturing junior faculty. Together with his current skill set, the advanced training enabled through the K-08 will help transition Dr. Liu towards an independent physician scientist in the area of perioperative medicine.

Public Health Relevance

This project uses alternative structural approaches to investigate the relationship between opioids and human mu receptor. The information derived from this project may help to design novel opioid analgesics with minimal side effects, improve pain control, and solve issues related to opioids administration and abuse. Thus, this project has significant implications for public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08GM093115-04
Application #
8495357
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
2010-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$126,252
Indirect Cost
$9,352
Name
University of Pennsylvania
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Li, Wei; Sun, Huijiao; Chen, Hao et al. (2016) Major Depressive Disorder and Kappa Opioid Receptor Antagonists. Transl Perioper Pain Med 1:4-16
Chen, Chunhua; Xi, Chunhua; Liang, Xuan et al. (2016) The Role of κ Opioid Receptor in Brain Ischemia. Crit Care Med 44:e1219-e1225
Liang, Xuan; Liu, Renyu; Chen, Chunhua et al. (2016) Opioid System Modulates the Immune Function: A Review. Transl Perioper Pain Med 1:5-13
Naylor, Carl H; Kybert, Nicholas J; Schneier, Camilla et al. (2016) Scalable Production of Molybdenum Disulfide Based Biosensors. ACS Nano 10:6173-9
Wu, Fei-Xiang; He, Yan; Di, Hui-Ting et al. (2016) An Engineered Endomorphin-2 Gene for Morphine Withdrawal Syndrome. PLoS One 11:e0149877
Cobb, Benjamin; Liu, Renyu; Valentine, Elizabeth et al. (2015) Breastfeeding after Anesthesia: A Review for Anesthesia Providers Regarding the Transfer of Medications into Breast Milk. Transl Perioper Pain Med 1:1-7
Matsunaga, Felipe; Gao, Lu; Huang, Xi-Ping et al. (2015) Molecular interactions between general anesthetics and the 5HT2B receptor. J Biomol Struct Dyn 33:211-8
Liu, Kun; Liu, Hong; Gao, Wei Dong et al. (2015) Cerebral circulation and ischemia: How to monitor it during surgery? Transl Perioper Pain Med 2:2-8
Meng, Lingzhong; Li, Jian; Lu, Yi et al. (2015) Ketamine - A Multifaceted Drug. Transl Perioper Pain Med 1:20-26
Hu, Lingqun; Zhang, John; Tu, Weifeng et al. (2015) Perspectives of Translational Medicine. Transl Perioper Pain Med 2:12-18

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