Richard K. Assoian, Ph.D.

faculty photo
Professor of Pharmacology
Department: Pharmacology
Graduate Group Affiliations

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
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 (ECM), adhesion receptor signaling, mechanotransduction, microenvironment, integrins, cadherins, actin, cytoskeleton, focal adhesions, matrix remodeling, cell cycle, proliferation, cyclin-dependent kinases, mouse modeling, cardiovascular biology.

Description of laboratory research:

We are a team of cell/molecular biologists and bioengineers interested in the over-arching idea that cells can sense and respond to changes in the mechanical properties of their microenvironment and that this information contributes to cell behavior and function. Within this broad area, we try to understand how physiological and pathological changes in the stiffness of the ECM affects adhesion receptor signaling, the actin cytoskeleton, and proliferation. We perform mechanistic analyses in cell culture, use genome- and proteome-wide approaches, and ultimately test physiological and pathological relevance in mouse models of vascular aging, injury, and atherosclerosis.

We are currently working in the following general areas.

i) Stiffness sensing.
Most mammalian cells live in an elastic microenvironment that is determined by the composition of the ECM. Remodeling of the ECM, which occurs in several diseases, alters the elastic properties as well as the composition of a cell's microenvironment. The effects of matrix elasticity 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), which can mimic the elasticity of tissues that cells inhabit in vivo, to determine how substratum stiffness affects 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, microRNAs controlling the cdk inhibitor, p27kip1, and novel mechanisms of crosstalk between cell-ECM and cell-cell adhesion.

ii) In vivo mechanobiology.
We use a mouse model of vascular injury to study how changes in arterial stiffness affect adhesion receptor signaling and vascular smooth muscle cell (VSMC) proliferation in vivo. We invoke the injury response by gently denuding the endothelium in the femoral artery of mice. By comparing the degree of VSMC proliferation in wild-type mice and mice with knock-outs/knock-ins of integrin regulated signaling and cell cycle genes, we can test the importance of the integrin- and stiffness-regulated signaling 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. 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
Nancy Sehgel, 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)

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.

Castagnino, P.*, Kothapalli, D.*, Hawthorne, E.A., Liu, S-L., Xu, T., Rao, S., Yung, Y., and Assoian, R.K. : miR-221/222 compensates for Skp2-mediated p27 degradation and is a primary target of cell cycle regulation by prostacyclin and cAMP. PLoS One, 8: e56140, 2013.

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: 11/30/2015
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