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Publications in VIVO
 

Assoian, Richard K. Professor

Current Positions

Publications

selected publications

Research

research overview

  • 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)

Contact

name suffix

  • Ph.D.

lab phone

  • (215) 898-7265

fax

  • (215) 573-5656

Other

keywords

  • adhesion-dependent signal transduction, mechanical-based signaling and cell cycle control, cyclin, G1 phase, Rho GTPases, ERK, integrins, growth factors, vascular remodeling, cardiovascular research