Core B: Computational Systems Pharmacology Project Summary The Computational Systems Pharmacology Core (Core B) will provide computational biology and quantitative systems pharmacology (QSP) support to Projects 1-3. The Core will contribute to the research goals of the P01 in three major ways: identification of targets (proteins, pathways or networks) implicated in ATZ accumulation (Specific Aim 1); quantitative modeling and analysis of the cellular networks identified to be associated with ATZ elimination, and systematic interrogation of these networks to generate plausible hypotheses for (poly)pharmacological strategies (Specific Aim 2); and refinement of drug candidates discovered in the first term (e.g. glibenclamide and its analog G2, cyclodextrin family members, and selected agonists of mucolipins) and identification of new testable candidates (both repurposable drugs and new compounds) to assist in the design and development of mechanism-based ATD therapeutics (Specific Aim 3). In line with the progress and contributions made in the first term, the Core will analyze high-throughput/content (RNAi, EMS chemical mutagenesis, and small-molecule library screening) data collected by Project 2 and gene expression profile data of ATZ-expressing iPS cells (Project 3). Quantitative model construction and analyses will support Project 1 team to assess (i) the cell signaling and regulation mechanisms that predominantly determine the cell fate in response to the proteotoxic effect of ATZ accumulation, with focus on autophagic, proteostasis and calcium signaling pathways; (ii) the pathophysiological effects of sequence variants detected in cohort exome sequencing studies (in coordination with Project 3); (iii) optimal modifications of drug candidates to increase their potency, and particular combination therapies (e.g. prochlorperazine and amlodipine) that may act synergistically. The Core will use a broad range of machine learning algorithms, and bioinformatics, cheminformatics, QSP and molecular modeling methods, tools and software developed by the Core members as well as relevant databases and software publicly available.

Public Health Relevance

Core B: Computational Systems Pharmacology Narrative The Computational Systems Pharmacology Core (Core B) will provide computational biology and quantitative systems pharmacology (QSP) support for accelerating Projects 1-3. Core activities include quantitative analysis of high-content screening data to extract information on targets and pathways implicated in ATD, construction and analysis of mathematical models for assessing therapeutic strategies, and identification and refinement of drug candidates for possible prevention of ATD liver disease or alleviation of ATZ accumulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
2P01DK096990-06A1
Application #
9700926
Study Section
Special Emphasis Panel (ZDK1)
Project Start
Project End
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Yokota, Shinichiro; Ono, Yoshihiro; Nakao, Toshimasa et al. (2018) Partial Bile Duct Ligation in the Mouse: A Controlled Model of Localized Obstructive Cholestasis. J Vis Exp :
Khan, Zahida; Orr, Anne; Michalopoulos, George K et al. (2017) Immunohistochemical Analysis of the Stem Cell Marker LGR5 in Pediatric Liver Disease. Pediatr Dev Pathol 20:16-27
Liu, Bing; Oltvai, Zoltán N; Bay?r, Hülya et al. (2017) Quantitative assessment of cell fate decision between autophagy and apoptosis. Sci Rep 7:17605
Khan, Zahida; Yokota, Shinichiro; Ono, Yoshihiro et al. (2017) Bile Duct Ligation Induces ATZ Globule Clearance in a Mouse Model of ?-1 Antitrypsin Deficiency. Gene Expr 17:115-127
Li, Hongchun; Chang, Yuan-Yu; Lee, Ji Young et al. (2017) DynOmics: dynamics of structural proteome and beyond. Nucleic Acids Res 45:W374-W380
Khan, Zahida; Venkat, Veena L; Soltys, Kyle A et al. (2017) A Challenging Case of Severe Infantile Cholestasis in Alpha-1 Antitrypsin Deficiency. Pediatr Dev Pathol 20:176-181
Polgar, Zsuzsanna; Li, Yanfeng; Li Wang, Xia et al. (2017) Gunn Rats as a Surrogate Model for Evaluation of Hepatocyte Transplantation-Based Therapies of Crigler-Najjar Syndrome Type 1. Methods Mol Biol 1506:131-147
Paranjpe, Shirish; Bowen, William C; Mars, Wendy M et al. (2016) Combined systemic elimination of MET and epidermal growth factor receptor signaling completely abolishes liver regeneration and leads to liver decompensation. Hepatology 64:1711-1724
Stern, Andrew M; Schurdak, Mark E; Bahar, Ivet et al. (2016) A Perspective on Implementing a Quantitative Systems Pharmacology Platform for Drug Discovery and the Advancement of Personalized Medicine. J Biomol Screen 21:521-34
Khan, Zahida; Yokota, Shinichiro; Ono, Yoshihiro et al. (2016) BILE DUCT LIGATION INDUCES ATZ GLOBULE CLEARANCE IN A MOUSE MODEL OF ALPHA-1 ANTITRYPSIN DEFICIENCY. Gene Expr :

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