Targeting Chaperones

We study protein quality control across translational models of cancer, cardiovascular disease and neurodegeneration with the goal of defining mechanisms of protein homeostasis and identifying therapeutic targets. Our unified approach is based on the realization that a single cellular machinery, the Hsp90/Hsp70 based chaperone machinery, controls the activity, turnover and trafficking of hundreds of client proteins, and as such plays a critical role in the pathogenesis of these varied disorders. Our goal is to define the mechanism by which this machinery triages unfolded or damaged proteins for degradation in order to develop strategies to achieve therapeutic benefits in disease.

Meeting Schedule

(all meetings are from 1:30 pm until 3:00 pm in 6340 MSRB 3)

March 13, 2017 – Yoichi Osawa’s Lab
April 10 – Sharlene Day’s Lab
May 8 – Andy Lieberman’s Lab
June 12 – Mukesh Nyati’s Lab

Co Directors

Andrew Lieberman

Andrew Lieberman

Andrew Lieberman is the Gerald Abrams Collegiate Professor of Pathology and Director of Neuropathology. His laboratory uses cellular and mouse models to study inherited forms of neurodegeneration in hopes of identifying targets for therapeutic intervention.

Yoichi Osawa

Yoichi Osawa

Yoichi Osawa is the Warner-Lambert/Parke-Davis Professor in Medicine and Professor of Pharmacology.  His laboratory studies the Hsp90 and Hsp70 chaperone machinery in protein quality control with a focus on the ubiquitination and regulation of NO synthases and P450 cytochromes.

Members

Mark S. Cohen

Mark S. Cohen

Mark S. Cohen is Associate Chair in Surgery and Associate Professor of Surgery and Pharmacology, Director of the Medical School Pathway of Excellence in Innovation/Entrepreneurship, Innovation Chief for the U of M Cancer Center, and a Principal Investigator in the Translational Oncology Program. His translational/basic laboratory is focused on the development of novel cancer therapeutics as well as improved drug delivery strategies to enhance local/regional drug effect and lower toxicity. This work has focused on novel withanolides, novel selective HSP90 inhibitors, and innovative drug delivery strategies with hyaluronic acid and mimetic HDL nanoparticles for all types of solid tumor malignancies.
Sharlene Day

Sharlene Day

Sharlene Day is an Associate Professor in Cardiovascular Medicine and Molecular and Integrative Physiology. Her research spans basic biology, translational and clinical studies in genetic cardiomyopathies. Her laboratory is focused on pathways by which genetic mutations that lead to protein misfolding cause hypertrophic cardiomyopathy.
Daniel Southworth

Daniel Southworth

Daniel Southworth’s lab is focused on elucidating the structure and function of dynamic molecular chaperone complexes that maintain the integrity of the cellular proteome. Our aim is to understand how malfunction of the chaperone network leads to toxic protein aggregation, abnormal cell growth and the progression of many diseases including cardiovascular disease, Alzheimer’s disease, and cancer. We employ state-of-the-art techniques in single particle cryo-electron microscopy to determine high resolution structural snapshots of these molecular machines in distinct states of action. By uncovering new and fundamental mechanisms of proteostasis our approaches identify new areas to target therapeutically to prevent protein misfolding diseases.
Mukesh Nyati

Mukesh Nyati

Mukesh Nyati’s lab conducts research around understanding EGF-Receptor mediated signaling in tumors. We now know that the clinical effectiveness of kinase-targeted agents has been inconsistent, mainly because of the acquired resistance. It has been shown that EGFR has scaffold/allosteric functions in addition to tyrosine kinase activity. Therapies that induce protein degradation of EGFR remains effective in tumors that acquire resistance to tyrosine kinase inhibitors. Based on our current understanding of TKI resistance and EGFR dimerization we are developing new therapeutic strategies targeting the intracellular dimerization interface of EGFR to induce protein degradation as a potential therapy option for EGFR-driven cancers.
Erik Zuiderweg

Erik Zuiderweg

Erik Zuiderweg is Professor of Biological Chemistry. His laboratory uses multidimensional NMR to study the structures, interactions and dynamics of the Hsp70 chaperone family as an aid to the design of therapeutics for cancer and neurodegeneration.
Theodore Lawrence

Theodore Lawrence

Theodore Lawrence is the Isadore Lampe Professor and Chair of the Department of Radiation Oncology. His interests in the laboratory are focused on chemotherapeutic and molecularly targeted radiation sensitizers. His clinical research combines these laboratory studies with advanced radiation therapy techniques guided by sophisticated imaging and blood biomarkers for the treatment of patients with gastrointestinal and central nervous system malignancies.
Kristen Verhey

Kristen Verhey

Kristen Verhey is a Professor of Cell and Developmental Biology. Her laboratory uses biochemical and cell biological approaches to understand the mechanisms of microtubule-based transport by kinesin motors and their role in trafficking to the primary cilium in normal and diseased states.