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Publications in VIVO
 

Assoian, Richard K. Professor

Current Positions

Publications

selected publications

Research

research overview

  • Key words

    Adhesion-dependent signal transduction, mechanotransduction, mechanochemical signaling, microenvironment, extracellular matrix, ECM, integrin, cadherin, actin, cytoskeleton, focal adhesions, matrix remodeling, cell cycle, proliferation, cyclin-dependent kinases, mouse modeling, cardiovascular biology.


    Description of research:

    We are cell and molecular biologists interested in understanding how physiological and pathological changes in cell adhesion affect tissue stiffness, the actin cytoskeleton, the composition of adhesion receptor signaling complexes, intracellular forces, and proliferation. Our goal is to combine mechanistic analysis in cell culture, bioinformatics, and functional testing in mouse models of vascular aging, injury, and atherosclerosis.

    We are currently working in the following general areas.

    i) Effects of extracellular stiffness and intracellular tension on the cell cycle.
    Most mammalian cells live in an elastic microenvironment; stiffening of the microenvironment occurs in several diseases and perturbs normal cellular function. 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 are using bioengineered substrata (ECM-coated hydrogels), which can mimic the elasticity of tissues that cells inhabit in vivo, to determine how substratum stiffness affects signaling pathways regulating the cell cycle. With this approach, we study the effect of changes in matrix stiffness on the spatial distribution of intracellular forces, focal adhesion composition, and adhesion receptor (integrin and cadherin) expression/signaling. We also use micropatterned substrata to examine effect of cell-cell adhesion on proliferation. Recent work with these approaches have led to the identification of stiffness-dependent signaling pathways, specific focal adhesion components controlling cyclin D1 expression, and microRNAs controlling the cdk inhibitor, p27kip1.

    ii) In vivo mechanobiology.
    Ultimately, the importance of biomechanics to cellular function must be documented in vivo. We are approaching this issue by examining adhesion receptors and signaling pathways that regulate matrix remodeling, tissue stiffness, and vascular smooth muscle cell (VSMC) proliferation during the response to injury. 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, in vivo, the importance of the integrin- and stiffness-regulated signaling events we detect in primary VSMCs cultured on hydrogels. 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, biomechanically-inspired ways to protect against cardiovascular disease.

    Current lab members:

    Yongho Bae, PhD
    Paola Castagnino, PhD
    Shulin Liu, PhD
    Ziba Razinia, PhD
    Philip Haines, MD
    Keeley Mui, graduate student
    Sue Lee, graduate student
    Beth Hawthorne, research specialist/lab manager
    Tina Xu, research specialist

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