Richard K. Assoian

faculty photo
Professor of Pharmacology
Member, Center for Cancer Pharmacology, University of Pennsylvania School of Medicine
Member, Cardiovascular Institute, University of Pennsylvania School of Medicine
Member, Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine
Director, Program in Translational Biomechanics, Institute of Translational Medicine and Therapeutics
Department: Pharmacology

Contact information
Department of Systems Pharmacology and Translational Therapeutics
421 Curie Blvd.
Rm 805(office)/833 (lab)
Philadelphia, PA 19104-6160
Office: (215) 898-7157
Fax: (215) 573-5656
Lab: (215) 898-7265
Graduate Group Affiliations
Education:
B.A. (Natural Science)
Johns Hopkins University, 1975.
Ph.D. (Biochemistry)
University of Chicago, 1981.
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Description of Research Expertise

Key words

Extracellular matrix, microenvironment, adhesion receptor signaling, mechanotransduction, integrins, cadherins, actin, cytoskeleton, focal adhesions, matrix remodeling, deformable substrata, micropatterning, cell cycle, proliferation, cyclin-dependent kinases, mouse modeling, cardiovascular biology.


Overview of laboratory research:

We are interested in understanding how cells sense changes in the physical properties of their microenvironment and how they convert this information into chemical signals, behavior and function. Within this broad area, we try to understand how physiological and pathological changes in the stiffness of the extracellular matrix (ECM) affects adhesion receptor signaling, the actin cytoskeleton, and proliferation. We perform mechanistic analyses in cell culture, use genome- and proteome-wide approaches, assess mechanical properties of tissues and cells, and ultimately test physiological and pathological relevance in mouse models of vascular aging, injury, and atherosclerosis.

We are currently working in the following areas.

i) Stiffness sensing.
The ECM is a dynamic structure that provides both chemical and mechanical cues to cells. Remodeling of the ECM occurs in several diseases and generally tends to increase the stiffness of a cell's microenvironment. The effects of extracellular stiffness on cellular function are difficult to study when cells are cultured on traditional rigid plastic or glass substrata that are irrelevant to in vivo microenvironments. We therefore use deformable substrata (ECM-coated hydrogels) to model the stiffness of tissues that cells inhabit in vivo. With this approach, we can determine how changes in ECM stiffness affect adhesion receptor (integrin and cadherin) expression and signaling as well as downstream gene expression and proliferation. We also use micropatterned substrata to examine the effect of cell-cell adhesion on proliferation. Recent work with these approaches has led to the identification of stiffness-dependent signaling pathways, specific focal adhesion components controlling cyclin D1 expression, and novel mechanisms of crosstalk between cell-ECM and N-cadherin mediated cell-cell adhesion.

ii) In vivo mechanobiology.
We place significant effort on mouse models to document the relevance of adhesion receptor signaling and stiffness-sensing to mammalian biology. For example, we use a mouse model to study how increased arterial stiffness affects adhesion receptor signaling and vascular smooth muscle cell (VSMC) proliferation during the response to vascular injury. By comparing the degree of VSMC proliferation in wild-type mice and mice with knock-outs/knock-ins of integrin regulated signaling, mechanosensing, and cell cycle genes, we can test the importance of the adhesion- and stiffness-regulated events we detect in primary VSMCs cultured on hydrogels as described above. Similar studies are exploring the proliferative effects of N-cadherin and its potential interactions with integrins. This work has strong biomedical relevance since damage to the endothelial lining of blood vessels and smooth muscle cell proliferation play critical roles in cardiovascular disease.

iii) Cardiovascular protection through regulation of arterial stiffness
We are identifying novel regulators of ECM remodeling and arterial stiffness in atherosclerosis. One set of studies has focused on apolipoprotein E (apoE) and apoE-containing HDL. Although best known for their role in reverse cholesterol transport, we find that apoE and apoE-HDL suppress the expression of several ECM genes including those for collagen-I, collagen-VIII, fibronectin and lysyl oxidase. These effects protect against arterial stiffening, reduce monocyte adhesion to subendothelial ECM, and provide cholesterol-independent protection against atherosclerosis in mice. Our newest work has identified a global inducer of arterial stiffening with age, vascular injury and atherosclerosis. Overall, our work in this area is identifying new ways to protect against cardiovascular disease.

Current lab members:

Yong Ho Bae, PhD
Shu-Lin Liu, PhD
Keeley Mui, PhD
Ziba Razinia, PhD
Sue Lee, graduate student
Chris Yu, graduate student (with Rader lab)
Nate Bade, graduate student (with Stebe lab)
Beth Hawthorne, research specialist/lab manager
Tina Xu, research specialist

ITMAT Biomechanics Core:
Paola Castagnino, PhD (Technical Director)

Description of Itmat Expertise

Research in the Assoian lab concentrates on the role of arterial stiffness and smooth muscle cell (SMC) proliferation in vascular injury and atherosclerosis. The lab uses primary cells in culture to identify molecular mechanisms and then tests the relevance of those mechanisms in vivo by comparing the SMC proliferative response after femoral artery injury or in atherosclerosis

Selected Publications

Mui, KM., Bae, YH, Gao, L., Liu, S-L. Xu, T., Radice, GL., Chen, CS, and Assoian, RK: N-cadherin induction by ECM stiffness and FAK overrides the spreading requirement for proliferation of vascular smooth muscle cells. Cell Reports 10: 1477-1486, 2015.

Liu SL, Bae YH, Yu C, Monslow J, Hawthorne EA, Castagnino P, Branchetti E, Ferrari G, Damrauer SM, Puré E, Assoian RK: Matrix metalloproteinase-12 is an essential mediator of acute and chronic arterial stiffening. Scientific Reports 5: 17189, 2015.

Bae YH, Mui KL, Hsu BY, Liu SL, Cretu A, Razinia Z, Xu T, Puré E, Assoian RK. : A FAK-Cas-Rac-Lamellipodin Signaling Module Transduces Extracellular Matrix Stiffness into Mechanosensitive Cell Cycling. Science Signaling 7: ra57, 2014.

Kothapalli, D.*, Liu, S.L.*, Bae, Y.H., Monslow, J., Xu, T., Hawthorne, E.A., Castagnino, P., Byfield, F.J., Rao, S., Rader, D.J., Pure, E., Phillips, M.C., Lund-Katz, S., Janmey, P.A., Assoian, R.K.: Cardiovascular protection by apoE and apoE-HDL linked to suppression of ECM gene expression and arterial stiffening. Cell Reports 2: 1259-1271, 2012.

Klein, E.A., Yin, L., Kothapalli, D., Castagnino, P., Byfield, F.J., Xu, T., Levantal, I., Hawthorne, E., Janmey, P.A., and Assoian, R.K.: Cell cycle control by physiological matrix elasticity and in vivo tissue stiffening. Current Biology 19: 1511-8, 2009.

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Last updated: 01/17/2016
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