Mike A. Geeves

Department of Biosciences, University of Kent, Canterbury, Kent, UK

Professor Mike Geeves joined the School of Biosciences in April 1999. He studied biochemistry as an undergraduate at the University of Birmingham then went on to the University of Bristol to work on a PhD with David Trentham. It was here that he first came to work on the myosin motor which has been the focus of his work ever since. In those early days it was muscle myosin - the only known form of myosin. After completing his PhD he spent 2 years at the University of California, Santa Cruz studying enzymology at sub-zero temperatures with Anthony Fink. He then return to spend 14 years at the University of Bristol working alongside Freddie Gutfreund, first as an SERC Junior Fellow then as a Royal Society University Fellow. At the end of the fellowship he moved to become a Group Leader in the new Max Planck Institute of Molecular Physiology that was being established in Dortmund by Roger Goody. He left there to take up the current position as Professor of Physical Biochemistry.

Mike is a member of the Mechanobiology group also known as MaDCaP.

Michael Regnier

Department of Bioengineering, College of Engineering & UW Medicine, University of Washington The HAAM Laboratory

Our group is interested in the sarcomere protein interactions involved in the activation and regulation of cardiac and skeletal muscle. Our studies, at both the isolated protein and cellular levels, use a wide variety of biophysical, mathematical, molecular biology and engineering approaches. Information from these studies is used to decide therapeutic themes to treat cardiac and skeletal muscle disease.

Thomas C. Irving

Department of Biology, Illinois Institute of Technology

Operate a NIH funded Biotechnology Research Center at the Advanced Photon Source, Argonne National Laboratory for non-crystalline diffraction and scattering from biological molecules and tissues.

Richard L. Moss

Department of Physiology, University of Wisconsin, Madison, Wisconsin

My laboratory studies contractile processes in heart and skeletal muscles and alterations in contraction in diseases such as heart failure. A primary focus of our research is the set of mechanisms by which calcium, various physical factors and signal transduction pathways regulate myocardial contraction.

We use a range of investigative approaches including biophysics, biochemistry and molecular biology in our studies of these mechanisms. Most of our experiments involve measurements of contractile properties of single muscle cells in response to alteration in contractile protein composition, which is done by biochemical exchange, gene knock-outs, and expression of proteins on a null background. In this way, we are able to assess the roles of specific proteins in regulation and determine the roles of specific domains in protein function.

Another focus of our research is the molecular mechanisms that determine the work capabilities of myosin molecules, which is essentially a study of the kinetics of nucleotide turnover by myosin. Our interest in this problem is stimulated by the observation that different myosin isoforms have widely varying work rates, which gives rise to variable work rates among the muscles of the body. Even the same myosin isoform expressed in different species can have dramatically different turnover kinetics, and work rates can be dramatically slowed in disease states such as heart failure and ischemic heart disease.

Our investigations of this mechanism feature systematic mutation of myosin molecules, expression in a baculovirus/insect cell system, and measurement of function using an in vitro motility assay system. Studies such as these are probing the most fundamental processes of the actomyosin ATPase, and results will presumably also have implications for our understanding of altered contraction in diseased heart muscle.

In this regard, the laboratory is presently engaged in extensive studies of the basis for contractile dysfunction in animal models of heart failure (CREB-A133 dominant-negative mouse) and myocardial stunning.

Jeffrey J. Fredberg

Department of Environmental Health, Harvard T.H. Chan School of Public Health

Our laboratory seeks to discover physical laws governing the abilities of the cytoskeleton to deform, contract, and remodel. These basic mechanical processes underlie a range of higher level phenomena in health and disease including many aspects of cancer, cardiovascular disease, malaria, and morphogenesis, but our major research emphasis is the role of these processes in airway narrowing in asthma. Trainees with backgrounds in engineering sciences, cell biology, or physics of soft condensed matter learn how to work side-by-side to pose new questions, invent new nanotechnologies, apply these technologies in novel experimental investigations, and analyze resulting data in terms of evolving mechanistic understanding of the physical properties of the living cell.

Martin Karplus

Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts

The research of Professor Martin Karplus and his group is directed toward understanding the electronic structure, geometry, and dynamics of molecules of chemical and biological interest. In each study a problem that needs to be solved is isolated and the methods required are developed and applied. In recent years, techniques of ab initio and semi-empirical quantum mechanics, theoretical and computational statistical mechanics, classical and quantum dynamics as well as other approaches, including experimental NMR, have been used.

Wayne Mitzner

Division of Physiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland

My research interests are focused on the structural basis of physiologic lung function and how this normal structure manifests itself in pathologic situations and environmental exposures.   Current work is concerned with understanding the mechanisms that underlie the chronic lung tissue destruction that occurs in emphysema.  These functional and immunological studies in the mouse are directed toward investigating mechanisms of alveolar destruction with age or with emphysematous lesions.  How this tissue destruction impacts the interaction between the lung parenchyma and airways plays a key role in the ability to breath in this pathology, and ongoing work is involved in studying this interaction.  Additional funded work involves evaluating methods of impairing the ability of airway smooth muscle to shorten, as a possible treatment of asthma.  The approach, termed bronchial thermoplasty, has direct clinical implications for the most severe asthmatic subjects.   I also have a keen interest in understanding and developing methods to properly phenotype pulmonary function in the mouse, which is the most common experimental animal model of most human diseases.  I’ve chaired several minisymposia and postgraduate courses in this area of mouse phenotyping.   

Daniel Tschumperin

Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts

The research of Daniel J. Tschumperlin, Ph.D., focuses on the respiratory system and how the structure, function and mechanics of the lung are regulated in health and disease.

Lung function is inherently mechanical in nature, and changes to the structure and mechanical properties of the lung are central in a number of respiratory conditions. Moreover, changes in respiratory mechanics can alter cellular function, resulting in feedback loops that drive disease progression. Researching the interplay between mechanics, structure and cellular function within normal and diseased lungs will ultimately lead to better treatments for respiratory diseases such as pulmonary fibrosis, pulmonary hypertension and asthma.

Focus areas

  • Dr. Tschumperlin has pioneered use of atomic force microscopy to characterize the mechanical properties of normal and diseased lung tissue at the molecular and cellular scale. This gives insight into the spatial and temporal alterations in mechanics that accompany disease.

  • New cell and tissue culture model systems are actively being developed and used to mimic specific aspects of the cellular and extracellular environment such as matrix stiffness, as well as studying their effects on cellular function.

  • Cellular and molecular studies focus on how cells probe and remodel their mechanical environment, and how cells transduce changes in their mechanical environment into biochemical signals that alter cell function.

  • The myofibroblast, a cell capable of both matrix synthesis and contraction, is essential in lung development yet also contributes to fibrosis in the lung and other soft tissues. Ongoing studies are aimed at identifying novel regulators of myofibroblast activation and function.

Thomas J. Eddinger

Department of Biological Sciences, Marquette University, Milwaukee, Wisconsin

Muscle cells are unique in their ability to generate large amounts of force in a short period of time. In skeletal, cardiac and smooth muscle cells the method by which force is generated, the time scale required, and the mechanism for regulation are similar but yet unique. The differences within and between these tissues allow them to maximally perform their required functions.

 

One of the many differences between the muscle types are the contractile proteins themselves--the proteins directly involved in force generation. The major contractile proteins, actin and myosin, show tissue-specific types. These isoforms allow optimization of each muscle type for its specific function, including variation in speed of shortening, amount of force generated, and energy consumption. Differences in numerous other proteins within these cells, as well as their anatomical organization, regulatory mechanisms, innervation, etc., all contribute to the diversity between these tissues.

Research work in this lab involves the study of contractile, regulatory and cytoskeletal proteins in muscle including their  expression, regulation and function in SM contraction. Molecular, mechanical, biochemical, histochemical, and immunological approaches are used to further our understanding of the function and regulation of these proteins and their isoforms.

 

 

In addition to this work I collaborate with Dr. John LaDisa in the Biomedical Engineering Department on Coarctation of the aorta (CoA). CoA is a constriction of the proximal descending thoracic aorta and is one of the most common congenital cardiovascular defects. Treatments for CoA have improved life expectancy. However, these individuals still suffer a reduced average lifespan and morbidity resulting from cardiovascular disease, mostly due to hypertension. Identifying the mechanisms of morbidity is problematic in humans due to confounding variables such as differences in age at repair, time between correction and follow-up, severity of CoA before correction, and concurrent anomalies (e.g. bicuspid aortic valves or septal defects). To address this question, we developed a novel animal model that allows us to study CoA independent of these factors. This model replicates aortic changes in humans, and mimics correction at various durations using dissolvable suture. Our results to date using a putative clinical treatment guideline (20 mmHg pressure gradient) have revealed increased medial wall thickness and stiffening, a phenotypic shift in smooth muscle cells to the de-differentiated state, and endothelial dysfunction (decreased nitric oxide relaxation) all of which persist after correction. Microarray analysis of the aorta exposed to hypertension during the coarctation period revealed differentially expressed genes (DEG) in pathways unique to CoA and Corrected groups. These DEG include those associated with excitation contraction coupling that explain our findings, as well as unanticipated metabolic pathway genes, and have elucidated therapeutic options not previously considered for CoA patients.

 

Based on these findings, we hypothesize that the extent of vascular remodeling and endothelial dysfunction after Correction of CoA results from the severity of adverse hemodynamics caused by the coarctation, and can be mitigated by more discerning treatment guidelines or pharmacologically targeting DEG.

David A. Smith

Department of Physiology, Monash University, Victoria, Australia

John Sleep

Randall Division of Cell and Molecular Biophysics, King's College London, London, UK

Actomyosin crossbridge cycle. Elastic properties of red blood cell

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