Ellen Kuhl - US grants

PI name: B.L. Pruitt
Institution: Stanford University
Proposal Number: 0735551

EFRI-CBE: Engineering of Cardiovascular Cellular Interfaces and Tissue Constructs


Abstract


Cardiac cells and tissue are ideal targets for regenerative medicine and fundamental studies of the interplay of cellular and biomolecular level signaling and response for several reasons. First, observation of successful stem cell differentiation to cardiac myocytes is facilitated by readily identifiable immunohistochemical markers as well as characteristic electrical action potentials and mechanical contractions. Second, explanted cells in culture lose their morphology and organization in the absence of drugs or electromechanical stimulation, suggesting that cellular organization is dependent on these cues. Last, myocardium damaged during a heart attack does not regenerate and the weakened muscle results in heart failure. Fundamental understanding of how cardiac myocytes and heart tissue can be regenerated is essential to creating successful therapies for patients with heart disease (affecting 71 million Americans). Recently, several studies have shown that stem cells may offer regenerative potential through direct injection of cells into the damaged myocardium or in situ repair using engineered tissue grafts.

The Intellectual Merit of this project lies in the development of basic knowledge and models for cell response to environmental cues. Pluripotent cell responses to changes in environment offer a testbed for characterizing the thresholds and mechanisms of environmental adaptation and remodeling. The outcomes of the baseline and coupled experiments will be made available as a database for other researchers. Models and results will be disseminated by publication and seminars for researchers in the field as well as public seminar forums.

The Broader Impacts of this work lie in the enhanced knowledge of cell signaling and differentiation, the role of culture environmental parameters in tissue engineering, and the enhanced design guidance and technology developed which will ultimately enable regenerative therapies for victims of heart disease. Topics of this research will be incorporated in modules for teaching basic engineering and materials courses and the Principal Investigators (PIs) will recruit undergraduates for research experiences in their labs. The PIs actively participate in outreach, undergraduate research opportunities, and research experience for teacher programs and will expand these efforts related to this project. A workshop on the research topics will be held in the final year of the project.

The research objective of this Faculty Early Career Development (CAREER) award is to create the Virtual Heart, an interactive, hierarchical finite element simulation tool to explore the structure-function relationship in healthy and diseased hearts. The human heart is a fascinating organ that pumps more than 6000 liters of blood through our body every day. Beating more than a billion times during an average lifetime, it provides a steady supply of oxygen and nutrition to all our tissues and organs. Not surprisingly, cardiac dysfunction may have devastating physiological consequences. Our goal is to establish experiments, models, and simulation tools to characterize the electro-active response of cardiac tissue. The Virtual Heart will provide substantial contributions including enhanced insight into excitation-contraction coupling on the cellular level, continuum models for electro-active materials on the organ level, and multi-scale approaches to link both scales. Our project will establish an entirely new way of thinking in cardiovascular medicine, inspired by predictive, patient-specific, simulation-based interventional planning.

Heart disease is the primary cause of death in industrialized nations, claiming more than 16 million lives worldwide each year. Despite tremendous scientific improvements, cardiovascular disease remains one of the most common, costly, disabling, and deadly medical conditions, generating and annual health care cost in excess of $430 billion. Providing new technologies to understand cardiac disease, this project will have direct social, economical, and educational impact. Socially, it will enhance medical care, lower mortality, and improve life and longevity. Economically, it may optimize medical treatment to significantly reduce health care costs. Educationally, through a planned museum exhibit, we will increase public awareness of risk factors that promote cardiac disease.

Stanford University will host the International Workshop on Multiscale and Multiphysics Processes in Geomechanics June 23-25, 2010. The workshop will highlight the diverse and complex processes encountered in geomechanics in terms of scale (from nanometer to kilometer) and scientific scope. Topics of interest include coupled physics phenomena such as thermo-poro-mechanical and electro-poro-mechanical processes, chemical species reactivity and transport, liquefaction and solidification of sediments, strain localization phenomena, double porosity continua, and frictional faulting and fluid flow in porous solids. The workshop will also focus on multiscale numerical techniques, including the lattice Boltzmann, discrete element, finite element and finite volume methods, as well as the laboratory and field investigation methods supporting these numerical techniques. This project provides funds to support younger scientists from U.S. schools (new assistant professors, postdoctoral students, and Ph.D. students in advanced stages of thesis development) so they may be able to travel to Stanford University and participate in the workshop. The Workshop will bring together researchers working on many central challenges facing modern geomechanics. A key strength of the forthcoming workshop is the diversity of research backgrounds, methods, and applications that will be represented. Apart from the area of geomechanics, the broader impact of the workshop spans many other disciplines in science and engineering, including geophysics, geosciences, mechanical engineering, and biomechanics. For example, coupled multiscale and multiphysics phenomena, such as chemo-, poro-, electro-, thermo-, and biomechanics, are characteristic problems in nearly all branches of engineering.

This grant provides funding for a symposium, from the International Union of Theoretical and Applied Mechanics (IUTAM), that will bring together leading experts in cell biology, physiology, biophysics, applied mathematics, continuum mechanics, computational mechanics, bioengineering, and regenerative medicine to stimulate critical discussions and identify future challenges and opportunities in computational biomechanics. It has the potential to advance the field in the following directions: (i) mathematical modeling and computational simulation on the molecular, cellular, tissue, and organ levels; (ii) characterization of the relevant biological, chemical, electrical, and mechanical fields; (iii) image-based, patient-specific design of computational models; (iv) verification and validation of computational models on the molecular, cellular, tissue, and organ levels. The symposium will be held between August 29 and September 02, 2011 at Stanford University, California. It will feature five keynote speakers, approximately 40 invited speakers, and approximately 60 to 80 participants. This proposal will support undergraduates and young researchers to actively participate in the symposium through podium and poster presentations. Moreover, it will allow dissemination of their research activities in the hardcopy book of conference proceedings.

This IUTAM symposium will have direct academic, scientific, and educational impact. Academically, it will establish and broaden the computational biomechanics community, create synergies, and reach out to scientists who have not traditionally been part of this community. Scientifically, it will identify new research directions and push frontiers in computational biomechanics with results made available to the broad public in the form of a hardcopy book of conference proceedings and a multiple-author expert review paper on challenges and advances in computer models in biomechanics. Educationally, it will encourage the participation of undergraduates and young researchers from underrepresented groups and institutions that are traditionally short of funding which will be crucial to strengthen the computational biomechanics community now and in the future.

This INSPIRE Research Award is co-funded by the Biomechanics and Mechanobiology (BMMB) and the Mechanics of Materials (MoM) Programs in the Division of Civil, Mechanical, and Manufacturing Innovation (CMMI), and the Biophotonics Program in the Division of Chemical, Biological, Environmental, and Transport Systems (CBET), both in the Directorate for Engineering (ENG). In the United States alone, almost half a million people die each year as a result of heart rhythm disorders. Despite its invasive nature, electrical stimulation remains the gold standard treatment for rhythm disturbances in the heart. This project challenges the conventional wisdom of how to manipulate electrical signals in the human heart. The long-term goal is to establish a novel technology to control heart rhythm disorders, safely, precisely, and remotely, simply by means of light using a new concept known as optogenetics. The objective of this research is to create a biological pacemaker of genetically engineered cells that will allow us to decipher the basic mechanisms by which optogenetics can regulate the pump function of the heart. The research approach is a systematic theoretical, experimental, and computational characterization of photostimulation across four biological scales.

This work is highly innovative, since it adopts optogenetics, for the first time, to control human heart cells and tissue. It combines concepts, methods, and recent developments in optics, genetics, stem cell biology, electrophysiology, mechanobiology, biomechanics, mathematical modeling, and computer simulation. Its unusual interdisciplinary nature has the potential to reveal fundamental mechanisms of the photoelectrochemistry and mechanics of living systems. This knowledge gain will stimulate discovery in optogenetics and initiate new technologies to manipulate excitable cells. The transformative potential of the work is that it may open new avenues to support the design of novel therapies for various types of neuronal, musculoskeletal, pancreatic, and cardiac disorders such as depression, schizophrenia, paralysis, diabetes, pain syndromes, and cardiac arrhythmias.

DESCRIPTION (provided by applicant): Heart failure (HF) is a worldwide epidemic that contributes considerably to the overall cost of health care in developed nations. The number of people afflicted with this complex disease is increasing at an alarming pace-a trend that is likely to continue for many years to come. The overall goals of our proposed research are to identify the mechanical culprits that dictate the bifurcation of the system from the stable healthy state into the instable state of HF and to determine the borderline between physiological/compensatory and pathophysiological/non-compensatory growth and remodeling (G&R). To address these goals, our research approach is to experimentally inform and validate multiscale laws of myocardial growth and remodeling (G&R) using three different clinically relevant large animal HF preparations in order to predict the propensity of patients with a myocardial infarction (MI) developing HF. Our specific Aim 1 is to elucidate a predictive validated multiscale law of myocardial G&R in eccentric hypertrophy associated with cardiac dilation. We hypothesize that a fiber-strain-based growth law can predict cardiac G&R in response to volume-overload, i.e., elevated myofiber strains stimulate concentric growth. Competing hypotheses based on stress-, strain rate-, and strain energy will be tested. Aim 2 is to validate a predictive multi-scale law of myocardial G&R in concentric hypertrophy associated with wall thickening. We hypothesize that a unified cross-fiber strain based growth law can predict cardiac G&R in response to pressure-overload. Similar competing hypotheses as in Aim 1 will be tested. In Aim 3, we will apply these G&R laws to predict the propensity for HF in ischemic heart disease based on specific mechanical indices of myocardial function. We hypothesize that there exists a threshold of a maximal rate of change of strain in reference to sarcomere length, above which compensatory G&R is not possible and the physiological negative feedback loop to maintain homeostasis gives way to a positive feedback loop that leads to progress remodeling and ultimate demise of the myocardium. Successful completion of this work will provide a fundamental understanding of the response of myocardium to mechanical stimuli that has substantial clinical relevance. Scientifically, this approach will provide the first ever validated and calibrated predictive micro-structural model of myocardial growth and remodeling that is fundamental to cardiology, tissue engineering, cardiac rehabilitation, and cardiac surgery. Clinically, we will provide a specific mechanical index to predict the propensity of HF in ischemic heart disease that may have a significant healthcare implication.

With an increasing life expectancy, neurodegeneration has arguably become the most challenging malady of the century. The most common type of neurodegeneration, Alzheimer's disease, causes a devastating and progressive loss of cognition for which there is currently no treatment or cure. Protein tangles, axonal injury, and structural degradation are classic hallmarks of Alzheimer's disease. Growing evidence suggests that these features are shared by a number of other neurodegenerative disorders including traumatic brain injury, chronic traumatic encephalopathy, and Parkinsonism. Yet, the molecular mechanisms of neurodegeneration remain poorly understood. The overall goal of this research program is to establish a mechanistic, bio-chemo-mechanical model of neurodegeneration to simulate and predict normal and abnormal neurophysiology. Towards this goal, the objective of this project is to probe, model, and simulate the tau-microtubule complex to reveal the underlying failure mechanisms of individual axons. This project is truly transformative in that it will open new avenues to understand neurodegeneration from bio-chemo-mechanical principles. This project will feed into a new multidisciplinary undergraduate/graduate course at the interface between mechanics and the neurosciences. Many members of our team are individuals from underrepresented groups who actively serve as role models in various organizations where they will promote this work and recruit underrepresented individuals to join this project. To enhance scientific and technological understanding, we will continue to participate in the National Biomechanics Day, the annual International Brain Bee competition, and Stanford Brain Day.

In an integrative approach that combines theory, experiment, and simulation, this project will characterize tau structure using cryo-electron microscopy, identify the molecular mechanisms by which tau modulates microtubule assembly using molecular dynamics simulation, characterize tau-microtubule function using small angle X-ray scattering, and interpret the molecular failure mechanisms of the tau-microtubule complex using kino-geometric sampling. This knowledge will enter a multiscale computational model to predict the failure mechanisms of the axon from bio-chemo-mechanical principles. This model will provide fundamental links between microtubule polymerization, tau-microtubule binding, and tau-tau cross-linking on the molecular level and stiffness, viscosity, and damage on the cellular level to quantitative failure thresholds for the tau-microtubule and tau-tau interfaces, the microtubule bundle, and the axon as a whole. This project will have broad scientific, social, and economic impact, in that it will stimulate discovery in neurodegeneration and provide enabling, biomechanics-based technologies to characterize damage thresholds, identify potential drug targets, and design inhibitors to slow down, block, or reverse neurodegenerative disorders.