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Project 2: Physical Mechanisms and Clinical Implications of Mechano-transduction

项目来源

美国卫生和人类服务部基金(HHS)

项目主持人

未公开

项目受资助机构

UNIVERSITY OF PENNSYLVANIA

项目编号

5U54CA193417-05

立项年度

2019

立项时间

未公开

项目级别

国家级

研究期限

未知 / 未知

受资助金额

未知

学科

Bioengineering; Cancer; Digestive Diseases; Liver Cancer; Liver Disease; Rare Diseases;

学科代码

未公开

基金类别

RESEARCH CENTERS

关键词

未公开

参与者

RADHAKRISHNAN, RAVI

参与机构

NATIONAL CANCER INSTITUTE

项目标书摘要： Project 2: Physical Mechanisms and Clinical Implications of Mechano-transduction in Hepatocellular Carcinoma Tumor Microenvironment. In Project 2, a team of investigators from the physical sciences, engineering, and cell biology will interact closely with hepatologists and liver oncologists through the clinical-core, and theorists through the theory-core. We will advance and test a new hypothesis for mechano-transduction in the hepatocellular carcinoma (HCC) microenvironment. We hypothesize that an entire membrane signalosome will translate changes in the physical microenvironment into alterations in membrane-mediated regulatory processes such as receptor trafficking and membrane-cortex interactions. This in turn will alter the specificity of signaling pathways and influence cell fate. Theory/membrane modeling will advance hypotheses on how physical mechanisms govern biological (cellular) behavior, and will direct design of physical parameters tunable in experiments. Super resolution microscopy will be used to track nanoscale assemblies, and force spectroscopy and microrheology will be used to determine static/dynamic responses of the cell membrane and membrane cortex interactions. In parallel, high-dimensional kinome profiling and single-cell gene expression will link these nanoscopic mechanisms with cellular decisions. Outcomes of these experiments will quantitatively and mechanistically relate the physical microenvironment in HCC to dictation of cell fate in cancer progression, as well as providing iterative feedback to the computational models for refinement of mechanisms, formulate new hypotheses. Specifically, the Aims of project 2 will establish quantitative and mechanistic relationships between the physical characteristics of the HCC microenvironment (namely membrane tension, matrix stiffness, substrate stiffness, and uniaxial compressive stress) and membrane-mediated signaling mechanisms, namely how receptor trafficking and membrane cortex interactions alter specificity of downstream of growth factor and G-protein mediated signals to regulate gene expression and cell fate. Our studies in Project 2 will also probe how static and dynamic responses of the cell membrane and membrane-cortex interactions in normal hepatocytes and stromal cells are altered by changes in the physical microenvironment variables relevant for HCC. Our project on mechano-transduction in HCC at the cellular scale is closely aligned with the goals of Project 1, namely HCC disease progression at the tissue scale, and those of Project 3, namely nuclear mechanics and HCC oncogenesis at the subcellular scale. We expect that the new physical-chemical paradigms governing HCC emerging from this project will inform and impact future HCC therapies. In particular, our results provide multidimensional, multiphysics characterization of subcellular (membrane, cortex, signals, gene-expression) alterations in response to changes in the microenvironment variables, some at single-cell resolution. The findings in Project 2 compliment those in Project 1, but extend the analyses and outcomes at the cellular to sub-cellular scale, molecular scale, and help identify physical biomarkers at this finer length-scale. Kinome profiling in Project 2 should also link our physical perspective to possible combinations of therapeutic targets.

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  • 1.Tension in fibrils suppresses their enzymatic degradation - A molecular mechanism for 'use it or lose it'

    • 关键词：
    • Tissue; Extracellular matrix; Collagen; Collagenase; Matrixmetalloproteinases (MMPs); Degradation; Strain;MATRIX-METALLOPROTEINASE EXPRESSION; SKIN FIBROBLAST COLLAGENASE; ICOLLAGEN; PROTEIN-TURNOVER; BINDING DOMAIN; HYPERREACTIVE SITES; DERMALFIBROBLASTS; BASEMENT-MEMBRANE; CONTACT GUIDANCE; CELL-ADHESION

    Tissue homeostasis depends on a balance of synthesis and degradation of constituent proteins, with turnover of a given protein potentially regulated by its use. Extracellular matrix (ECM) is predominantly composed of fibrillar collagens that exhibit tension-sensitive degradation, which we review here at different levels of hierarchy. Past experiments and recent proteomics measurements together suggest that mechanical strain stabilizes collagen against enzymatic degradation at the scale of tissues and fibrils whereas isolated collagen molecules exhibit a biphasic behavior that depends on load magnitude. Within a Michaelis-Menten framework, collagenases at constant concentration effectively exhibit a low activity on substrate fibrils when the fibrils are strained by tension. Mechanisms of such mechanosensitive regulation are surveyed together with relevant interactions of collagen fibrils with cells. (C) 2019 Elsevier B.V. All rights reserved.

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  • 2.Biophysics of membrane curvature remodeling at molecular and mesoscopic lengthscales

    • 关键词：
    • cell membrane curvature; biophysics; cell trafficking; moleculardynamics; Monte Carlo; free energy;N-BAR DOMAINS; CLATHRIN-MEDIATED ENDOCYTOSIS; TERMINAL HOMOLOGY DOMAIN;MONTE-CARLO SIMULATIONS; COARSE-GRAINED MODELS; COUPLING FIELD-THEORY;LIPID-BILAYERS; FLUID MEMBRANES; ALPHA-SYNUCLEIN; BENDING RIGIDITY

    At the micron scale, where cell organelles display an amazing complexity in their shape and organization, the physical properties of a biological membrane can be better-understood using continuum models subject to thermal (stochastic) undulations. Yet, the chief orchestrators of these complex and intriguing shapes are a specialized class of membrane associating often peripheral proteins called curvature remodeling proteins (CRPs) that operate at the molecular level through specific protein-lipid interactions. We review multiscale methodologies to model these systems at the molecular as well as at the mesoscopic and cellular scales, and also present a free energy perspective of membrane remodeling through the organization and assembly of CRPs. We discuss the morphological space of nearly planar to highly curved membranes, methods to include thermal fluctuations, and review studies that model such proteins as curvature fields to describe the emergent curved morphologies. We also discuss several mesoscale models applied to a variety of cellular processes, where the phenomenological parameters (such as curvature field strength) are often mapped to models of real systems based on molecular simulations. Much insight can be gained from the calculation of free energies of membranes states with protein fields, which enable accurate mapping of the state and parameter values at which the membrane undergoes morphological transformations such as vesiculation or tubulation. By tuning the strength, anisotropy, and spatial organization of the curvature-field, one can generate a rich array of membrane morphologies that are highly relevant to shapes of several cellular organelles. We review applications of these models to budding of vesicles commonly seen in cellular signaling and trafficking processes such as clathrin mediated endocytosis, sorting by the ESCRT protein complexes, and cellular exocytosis regulated by the exocyst complex. We discuss future prospects where such models can be combined with other models for cytoskeletal assembly, and discuss their role in understanding the effects of cell membrane tension and the mechanics of the extracellular microenvironment on cellular processes.

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