LABORATORY

Rosania Laboratory

Gus Rosania

Gus Rosania, PhD

The Rosania lab studies the microscopic transport properties of small drug-like molecules inside cells. Our overarching hypothesis is that a drug’s microscopic distribution within organelles is as important as its macroscopic distribution in organs in determining efficacy and toxicity. We use microscopic imaging instruments to capture the local distribution and dynamics of small molecules inside cells and analyze image data with innovative computational tools and statistical strategies, combining cheminformatics and machine vision to relate the chemical structure of small molecules to their subcellular distribution. We also develop biochemical analysis methods to study the microdistribution and cellular pharmacokinetics of small drug-like molecules. Lastly, we build mathematical models to simulate drug transport and distribution in single cells and higher order cellular organizations, based on biophysical principles governing molecular transport phenomena at the cellular level.

We envision a day when drugs are designed, optimized, and approved based on their site of action, much as drugs today are designed, optimized, and approved based on their molecular mechanism of action.

734/763-1032

[email protected]

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Lab and Research Overview

Macrophage-targeted Drug Development Team

Our goal is to probe the subcellular transport properties of small molecule chemical agents to develop and study therapeutic agents that bioaccumulate in macrophages and that exert their pharmacological or toxicological effects in macrophages and surrounding microenvironment.

Pharmacy Collaborators

Non-Pharmacy Collaborators

Projects

Molecular Engineering of Self-Organizing & Site-Directed Intracellular Crystals in Living Organisms

Objective: To study the structure, function and biogenesis of intracellular clofazimine crystals and study redox changes upon accumulation of clofazimine in macrophages.

Related Publications:
Macrophages sequester clofazimine in an intracellular liquid crystal-like supramolecular organization. (2012) Baik, J and Rosania GR PlosONE Doi 10.1371/journal.pone.0047494

Multiscale Distribution and Bioaccumulation Analysis of Clofazimine Reveals a Massive Immune System-mediated Xenobiotic Sequestration Response (2012) Baik J, Stringer KA, Mane G, and Rosania GR. Antimicrob. Agents Chemother., doi10.1128/AAC.01731-12

Molecular imaging of intracellular drug-membrane aggregate formation. (2011) Baik J; Rosania GR. Mol PharmaceuticsOct 3;8(5):1742-9.PMCID: PMC3185106

Macrophage-targeted Immunomodulatory Therapies for Lung Diseases

Objective: To study the microdistribution and bioaccumulation of clofazimine in the lungs, in relation to its pro-/anti-inflammatory effects on the airways and alveoli and related changes in lung physiology.

Related Publications:
Multiscale Distribution and Bioaccumulation Analysis of Clofazimine Reveals a Massive Immune System-mediated Xenobiotic Sequestration Response (2012) Baik J, Stringer KA, Mane G, and Rosania GR. Antimicrob. Agents Chemother., doi10.1128/AAC.01731-12

Yu J-Y, Zheng N, Mane G, Min KA, Hinestroza JP, Zhu H, Stringer KA, and Rosania, GR (2012) A cell-based computational modeling approach for developing site-directed molecular probes. PloS Computational Biology. 8(2): e1002378. doi:10.1371/journal.pcbi.1002378. PMC number in progress.

Madathilparambil VS. Wagner MC, Rosania GR, Stringer KA, Min KA, Risler L, Shen DD, Georges GE, Reddy AT, Parkkinen J, and Reddy RC (2012) Pulmonary Administration of Water-soluble Curcumin Complex Reduces ALI Severity.American Journal of Respiratory Cell and Molecular Biology. doi:10.1165/rcmb.2011-0175OC PMC number in progress.

Lab Members

Rahul Keswani

Research Fellow

W.G. Rajeswaran

Chemist Lead

Sudha Sud

Research Lab Specialist

Gi Sang Yoon

Research Fellow

Mason Chiang

Laboratory Assistant

Victor Vitvitski

Department of Biological Chemistry

Teaching & Resources

Careers

Would you be interested in driving a macrophage-targeted, collaborative drug development effort between the Medical School and the College of Pharmacy? We are looking for people who are interested in subcellular drug transport and targeting; drug delivery; drug discovery and development; as well as the following: macrophage biology, innate immunity, redox signaling, inflammation, microbial infection, microscopic imaging, pharmacokinetics, etc.

Why Macrophages?:

  • Clofazimine is an anti-inflammatory, immunomodulatory and redox active antibiotic.
  • Clofazimine is the most potent, cell type-specific, subcellular-targeting compound known.
  • Clofazimine massively bioaccumulates in macrophages to form intracellular crystal-like drug inclusions upon long term (8 week) oral administration.

Why Clofazimine?:

  • Discovered in 1957 by Dr. Vincent Barry (Ireland) as active against leprosy (originally considered ineffective against TB).
  • Marketed as Lamprene by Novartis. In clinical use since 1960s.
  • Recommended by WHO in combination chemotherapy against leprosy in 1980s.
  • FDA approved in the US 1986 (used with special permission from CDC; IRB approval is needed for treatment of MDR-TB and other mycobacterial infections.)
  • Currently entering 3 phaseII clinical trials and beginning a phase III clinical trial against multidrug resistant tuberculosis (http://www.tballiance.org/downloads/Pipeline/TBA-Pipeline-November-2012.pdf)

Publications 

Our project team has access to all the Resources and Core Facilities at the University of Michigan:

Resources:

Core Facilities: