REGULATION OF DRUG METABOLISM AND INFLAMMATION BY PREGNANE X RECEPTOR

Liver-enriched nuclear receptor (NR) proteins regulate the expression and activity of several pivotal hepatic biochemical pathways including the uptake, metabolism and excretion of cholesterol, bile acids, glucose, and xenobiotic compounds from the body. The pregnane x receptor (PXR, NR1I2) was first identified in 1998 as a member of the NR superfamily. Over the past decade, it has been well established that PXR functions as a master-regulator of xenobiotic- and drug-inducible expression and activity of numerous genes that encode key members of the phase I and phase II metabolic enzymes, as well as several membrane transporter proteins. In this way, activation of PXR serves as the principal defense mechanism defending the body from toxic insult. Similarly, the PXR protein also forms the molecular basis of an important class of drug-drug interactions in the clinical setting. Moreover, ligand-activated PXR negatively regulates inflammatory processes in both liver and intestine. An integrated model is emerging to reveal a key role for the post-translational modification of PXR in the selective suppression of gene expression, and is opening the door to the study of completely new modes of PXR-mediated gene regulation. This dissertation contributes mainly to two key areas of PXR research: (1) Identification a novel PXR target gene- carboxylesterase 6 (Ces6); (2) a study of the SUMOylation and ubiquitination of PXR protein. The results presented in this dissertation were primarily obtained from mouse and cell-culture systems. Data presented here reveal that activation of the inflammatory response modulates the SUMOylation and ubiquitination status of ligand-bound PXR protein. The SUMOylation and ubiquitination of the PXR protein functions to feedback-repress the inflammatory and xenobiotic responses, respectively. Taken together, the data represent a likely mechanism and provides initial molecular details for the connection between the PXR signaling pathway and inflammation. Studies on post-translational modification of PXR indicate how this protein is converted from a positive regulator in drug metabolism into a transcriptional repressor in inflammatory response. Finally, detailed protocols for purification of mammalian proteins necessary to perform in vitro SUMOylation reactions are presented. Taken together, the work presented in this dissertation contributes to understanding the interface between PXR, drug metabolism, and inflammation, which is expected to produce new opportunities for the development of novel therapeutic strategies

Pulse Shape-Aided Multipath Delay Estimation for Fine-Grained WiFi Sensing

Due to the finite bandwidth of practical wireless systems, one multipath component can manifest itself as a discrete pulse consisting of multiple taps in the digital delay domain. This effect is called channel leakage, which complicates the multipath delay estimation problem. In this paper, we develop a new algorithm to estimate multipath delays of leaked channels by leveraging the knowledge of pulse-shaping functions, which can be used to support fine-grained WiFi sensing applications. Specifically, we express the channel impulse response (CIR) as a linear combination of overcomplete basis vectors corresponding to different delays. Considering the limited number of paths in physical environments, we formulate the multipath delay estimation as a sparse recovery problem. We then propose a sparse Bayesian learning (SBL) method to estimate the sparse vector and determine the number of physical paths and their associated delay parameters from the positions of the nonzero entries in the sparse vector. Simulation results show that our algorithm can accurately determine the number of paths, and achieve superior accuracy in path delay estimation and channel reconstruction compared to two benchmarking schemes

Post-translational Modification of Pregnane X Receptor

Pregnane x receptor (PXR, NR1I2) was originally characterized as a broad spectrum entero-hepatic xenobiotic ‘sensor’ and master-regulator of drug inducible gene expression. A compelling description of ligand-mediated gene activation has been unveiled in the last decade that firmly establishes this receptor’s central role in the metabolism and transport of xenobiotics in mammals. Interestingly, pharmacotherapy with potent PXR ligands produces several profound side effects including decreased capacities for gluconeogenesis, lipid metabolism, and inflammation; likely due to PXR-mediated repression of gene expression programs underlying these pivotal physiological functions. An integrated model is emerging that reveals a sophisticated interplay between ligand binding and the ubiquitylation, phosphorylation, SUMOylation, and acetylation status of this important nuclear receptor protein. These discoveries point to a key role for the post-translational modification of PXR in the selective suppression of gene expression, and open the door to the study of completely new modes of regulation of the biological activity of PXR

Mobility increases localizability: A survey on wireless indoor localization using inertial sensors

Wireless indoor positioning has been extensively studied for the past 2 decades and continuously attracted growing research efforts in mobile computing context. As the integration of multiple inertial sensors (e.g., accelerometer, gyroscope, and magnetometer) to nowadays smartphones in recent years, human-centric mobility sensing is emerging and coming into vogue. Mobility information, as a new dimension in addition to wireless signals, can benefit localization in a number of ways, since location and mobility are by nature related in the physical world. In this article, we survey this new trend of mobility enhancing smartphone-based indoor localization. Specifically, we first study how to measure human mobility: what types of sensors we can use and what types of mobility information we can acquire. Next, we discuss how mobility assists localization with respect to enhancing location accuracy, decreasing deployment cost, and enriching location context. Moreover, considering the quality and cost of smartphone built-in sensors, handling measurement errors is essential and accordingly investigated. Combining existing work and our own working experiences, we emphasize the principles and conduct comparative study of the mainstream technologies. Finally, we conclude this survey by addressing future research directions and opportunities in this new and largely open area.</jats:p

Pregnane X Receptor Is SUMOylated to Repress the Inflammatory Response

Long-term treatment of patients with the macrolide antibiotic and prototypical activator of pregnane X receptor (PXR) rifampicin (Rif) inhibits the inflammatory response in liver. We show here that activation of the inflammatory response in hepatocytes strongly modulates SUMOylation of ligand-bound PXR. We provide evidence that the SUMOylated PXR contains SUMO3 chains, and feedback represses the immune response in hepatocytes. This information represents the first step in developing novel pharmaceutical strategies to treat inflammatory liver disease and prevent adverse drug reactions in patients experiencing acute or systemic inflammation. These studies also provide a molecular rationale for constructing a novel paradigm that uniquely defines the molecular basis of the interface between PXR-mediated gene activation, drug metabolism, and inflammation

Regulation of Tissue-Specific Carboxylesterase Expression by Pregnane X Receptor and Constitutive Androstane Receptor

The liver- and intestine-enriched carboxylesterase 2 (CES2) enzyme catalyzes the hydrolysis of several clinically important anticancer agents administered as prodrugs. For example, irinotecan, a carbamate prodrug used in the treatment of colorectal cancer, is biotransformed in vivo by CES2 in intestine and liver, thereby producing a potent topoisomerase I inhibitor. Pregnane X receptor (PXR) and constitutive androstane receptor (CAR), two members of the nuclear receptor superfamily of ligand-activated transcription factors, mediate gene activation in response to xenobiotic stress. Together, these receptors comprise a protective response in mammals that coordinately regulate hepatic transport, metabolism, and elimination of numerous xenobiotic compounds. In the present study, microarray analysis was used to identify PXR target genes in duodenum in mice. Here, we show that a gene encoding a member of the CES2 subtype of liver- and intestine-enriched CES enzymes, called Ces6, is induced after treatment with pregnenolone 16α-carbonitrile in a PXR-dependent manner in duodenum and liver in mice. Treatment of mice with the CAR activator 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene also induced expression of Ces6 in duodenum and liver in a CAR-dependent manner, whereas treatment with phenobarbital produced induction of Ces6 exclusively in liver. These data identify a key role for PXR and CAR in regulating the drug-inducible expression and activity of an important CES enzyme in vivo. Future studies should focus on determining whether these signaling pathways governing drug-inducible CES expression in intestine and liver are conserved in humans