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7 projects in result set.
Predicting Cell Deformation from Body Level Mechanical Loads
- This project is a NIBIB/NIH funded study (1R01EB009643-01) to establish models and computational platforms to predict cellular deformations from joint level mechanical loading.
Collaborators:
Ahmet Erdemir (PI), Amit Vasanji, Jason Halloran (Cleveland Clinic)
Cees Oomens, Frank Baaijens (Eindhoven University of Technology)
Jeff Weiss (University of Utah)
Farshid Guilak (Duke University)
Summary (from grant proposal):
Cells of the musculoskeletal system are known to have a biological response to deformation. Deformations, when abnormal in magnitude, duration, and/or frequency content, can lead to cell damage and possible disruption in homeostasis of the extracellular matrix. These mechanisms can be studied in an isolated fashion but connecting mechanical cellular response to organ level mechanics and human movement requires a multiscale approach. At the organ level, physicians perform surgical procedures, investigators try to understand risk of injury, and clinicians prescribe preventive and therapeutic interventions. Many of these operations are aimed at management and prevention of cell damage, and to associate joint level mechanical markers of failure to cell level failure mechanisms. Through human movement, one explores neuromuscular control mechanisms and the influence of physical activity on musculoskeletal tissue properties. At a lower level, mechanical sensation of cell deformations regulate movement control. Physical rehabilitation and exercise regimens are prescribed to promote tissue healing and/or strengthening through cellular regeneration. The knowledge of the mechanical pathway, through which the body level loads are distributed between organs, then within the tissues and further along the extracellular matrix and the cells, is critical for the success of various interventions. However, this information is not established. The goal of this research proposal is to portray that prediction of cell deformations from loads acting on the human body, therefore a clear depiction of the mechanical pathway, is possible, if a multiscale simulation approach is used. Multiresolution models of the knee joint, representative of joint, tissue and cell structure and mechanics, will be developed for this purpose. The knee endures high rates of traumatic injury to its soft tissue structures and it is predominantly affected by osteoarthritis, chronically induced by abnormalities in mechanical loading or how it is transferred to the cartilage. Through multiscale mechanical coupling of these models, a map of cellular deformation in cartilage, ligaments and menisci under a variety of tibiofemoral joint loads will be obtained. Comprehensive mechanical testing at joint, tissue and cell levels will be conducted for parameter estimation and validation, including in vitro loading of the knee joint representative of lifelike loading scenarios. In addition, imaging modalities will capture joint and tissue anatomy, and spatial and deformation related information from cell and extracellular matrix. Advanced computational approaches will be used to obtain model properties and to facilitate multiscale simulations. The approach will combine the expertise of many investigators experienced in biomechanical modeling and experimentation at various biological scales, some with clinical expertise. In future, the research team will utilize this platform to establish the relationship between the structural and loading state of the knee and chondrocyte stresses to explore potential mechanisms of cartilage degeneration. Through documented dissemination of data and models, simulations of other pathologies and translation of the methodology to other organs can be carried out by any interested investigator. | |
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Registered: 2009-07-23 17:33 |
BlurLab -- 3D Microscopy Simulation Package
- BlurLab is an easy to use platform for generating simulated fluorescence microscopy data for use in mechanistic modeling visualization, image comparison, and hypothesis testing. The software accepts the 3D positions, intensities and labels of fluorescing objects that are produced by an underlying mechanistic model and transforms them into high quality simulated images. The program includes full 3D convolution with realistic (or even measured) point spread functions; inclusion of thermal, shot and custom noise spectra; simulations of mean and fully stochastic photobleacing; the ability to view scenes in wide-field and TIRF, and perform Z-slicing; and the ability to simulate FRAP experiments.
The software provides a platform for adjusting and saving these simulated images, as well as a number of helpful, semi-automated features to make image simulation easy and less error prone. | |
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Activity Percentile: 79.01 Registered: 2011-08-05 01:17 |
T cell calcium dynamics regulated by age-induced oxidation
- T cells reach a state of replicative senescence characterized by a decreased ability to proliferate and respond to foreign antigens. Calcium release associated with TCR engagement is widely used as a surrogate measure of T cell response. Using an ex vivo culture model that partially replicates features of organismal aging, we observe that while the amplitude of Ca2+ signaling does not change with time in culture, older T cells exhibit faster Ca2+ rise and a faster decay. Gene expression analysis of Ca2+ channels and pumps expressed in T cells by RT-qPCR identified overexpression of the plasma membrane CRAC channel subunit ORAI1 and PMCA in older T cells. To test whether overexpression of the plasma membrane Ca2+ channel is sufficient to explain the kinetic information, we adapted a previously published computational model by Maurya and Subramaniam to include additional details on the store-operated calcium entry (SOCE) process to recapitulate Ca2+ dynamics after T cell receptor stimulation. Simulations demonstrated that upregulation of ORAI1 and PMCA channels is not sufficient to explain the observed alterations in Ca2+ signaling. Instead, modeling analysis identified kinetic parameters associated with the IP3R and STIM1 channels as potential causes for alterations in Ca2+ dynamics associated with the long term ex vivo culturing protocol. Due to these proteins having known cysteine residues susceptible to oxidation, we subsequently investigated and observed transcriptional remodeling of metabolic enzymes, a shift to more oxidized redox couples, and post-translational thiol oxidation of STIM1. The model-directed findings from this study highlight changes in the cellular redox environment that may ultimately lead to altered T cell calcium dynamics during immunosenescence or organismal aging. | |
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Registered: 2016-07-01 17:00 |
Acetaminophen Induced Liver Injury
- The AILI project is a type of In-Silico Liver (ISL) project, which consists of a body of Java code used and reused for exploring hypothetical liver mechanisms. For AILI, the liver mechanisms are those that cause cellular damage, specifically necrosis, because of exposure to acetaminophen. Moreover, the model, a mouse analog, is used for virtual experimentation to explore and explain AILI phenomena, analogous to wet-lab experimentation. A recent addition to this project is studying the disconnect between in vitro and in vivo wet-lab experiments by comparing and contrasting virtual Mouse and Culture Analogs. | |
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Activity Percentile: 0.00 Registered: 2015-05-07 23:25 |
Neurogene: Elucidating apoptotic pathways in brain tumor models
- Genomics has brought many important discoveries and changes into science and medicine. The central dogma of molecular biology where "DNA makes RNA and RNA makes protein" is well established (yet controversial). Watson and Crick had originally proposed a double stranded model of DNA. This served as a useful foundation for further understanding and research. Throughout the years more investigations demonstrated that human evolution was far more complex than originally believed. There was originally a great deal of migration around the world causing some hereditary lineages to become isolated and others to become more robust.
The life cycle of a cell usually begins with division and continues with replication. However, errors in mitosis can cause a cell to undergo apoptosis or form into a tumor. Differentiating between the two final pathways may be critical in helping to guide cells towards a less destructive pathway for the host organism. The critical component has to do with the environment the cell is in. The cell receives information from the outside environment and adapts according to received stimuli.
This project has been conceived to leverage a team based approach for elucidating the underlying apoptotic pathways responsible for tumor lysis and cell death. Combining the current understanding of molecular dynamics, genomics, and contrast imaging agents to discover novel therapeutic targets and further the current understanding of tumor biology within the genomic era. | |
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Registered: 2010-03-17 09:26 |
Structural Dynamics of Kinesin Motor protein during ATP hydrolysis
- TO see if there is a conformational change in Kinesin motor protein during the process of ATP hydrolysis . | |
Activity Percentile: 0.00 Registered: 2014-06-16 16:20 |
NetworkPainter: Biological pathway animation
- NetworkPainter is a web-based program for drawing and painting signaling network diagrams with high-dimensional cytometry data. Two versions of NetworkPainter are available. The <a href="http://covert.stanford.edu/networkpainter">NetworkPainter stand-alone version</a> is capable of visualizing any uploaded cytometry data. NetworkPainter is also available through the <a href="http://www.cytobank.org/networkpainter.html">Cytobank</a> flow cytometry repository. This version is capable of analyzing flow and mass cytometry data stored in Cytobank. | |
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Registered: 2014-01-10 00:11 |