Research and Professional Interests:

Biomechanics of cardiac and skeletal muscle; BioNanotechnology

General research areas: Biophysics of muscle tissue, molecular motor proteins, and calcium regulation of contraction; cellular and molecular biomechanics of cardiac and skeletal muscle; BioNanotechnology.

Research tools: Cellular and molecular biomechanical assays of permeabilized cardiac and skeletal muscle; in vitro motility assays; molecular biology; bioinformatics; biochemical and biomechanical modeling.

Major ongoing projects: Functional consequences of mutations in troponin I that cause hypertrophic cardiomyopathy; molecular and cellular biochemical/biomechanical model of striated muscle—a component of NASA/NSBRI’s "digital human." Inquire about additional projects.

The central theme of my research program is to understand the biophysical basis of biological motility, its regulation, and its modulation by cellular metabolism. Much remains to be learned about actomyosin interactions and their regulation, especially in cardiovascular function and diseases, cancer (metastasis), human performance, and bionanotechnology (biological nanomotors and protein mechanics). My experimental work has most often been directed toward answering molecular and cellular questions related to these topics; future experimental directions are, at one end of the spectrum, integrative studies using intact animals and, at the other, investigations at the single molecule level.

Troponin I and cardiac hypertrophy: In terms of clinical significance, the most important application—and currently my main focus—is understanding specific forms of cardiovascular disease, particularly the inherited (familial) forms of hypertrophic cardiomyopathy (FHC) and idiopathic dilated cardiomyopathy (IDC). In the first stage of the project, mutant forms of cardiac troponin I or troponin T are expressed in E. coli for incorporation into molecular and cellular assays that will test for changes in biomechanical function relative to wild type proteins. In its simplest terms, the hypothesis we are testing is whether the mutations cause hypertrophy by inhibiting function (causing compensatory hypertrophy) or by enhancing function (causing exercise-like hypertrophy). In later stages of the project, we will test whether mutants affect cardiac-specific modulations: sarcomere length (Starling’s law) and protein phosphorylation associated with adrenergic stimulation. See Chase et al. (2001) Biophys. J. 80:342a. These studies complement our previous work on troponin C, the calmodulin-like, Ca²⁺-binding subunit of troponin.

Metabolites, fatigue, and ischemia (intracellular environment): A long-standing problem I have worked on is the cellular basis for contractile deficit in fatigue or ischemia. We use permeabilized cellular preparations—in which we directly control metabolite concentrations (e.g., of ATP, ADP, Pi, [H⁺], and others)—to study the effects of altered metabolite levels on contractility. Related investigations use structural analogs of inorganic phosphate, aluminum fluoride, and beryllium fluoride. These analogs are interesting for biomechanical studies not only because they permit investigation of Pi in force generation but also for evaluation the physiological relevance of crystallographic structures of myosin motor domain complexes containing these analogs—structures considered central to our understanding of how molecular motors work. Other recent studies involve deoxy-ATP as a substrate for actomyosin. The biomechanical response to changes in metabolite concentration depends on the protein isoform(s) being studied (different proteins from different genes or from alternative splicing of mRNA) and could be altered by FHC-related mutations in cTnI (see above).

Modeling: A third research area is molecular and cellular biochemical and biomechanical modeling. Our Monte-Carlo modeling suggests that biomechanical "tuning" arises from finite stiffness of the proteins, and that this property contributes to apparent cooperativity of force generation in the steady-state, isometric situation. This tuning, observed under load-bearing conditions, will probably be an important design consideration for nanomechanical systems. Future directions for this project include expanding the model to handle larger ensembles of molecules and developing the tools necessary to test the model predictions.

Chase lab (Summer '09)

Left to right: John Williams, Maggie Shoemaker, Nancy Meyer, Campion Loong, Alex Pérez, Aya Kataoka Takeda, Linda Stroud, Dr. Chase, Carl Whittington (Ellington / Moerland lab), Myriam Badr, Katie Tieman, Faizal Asumda, Vinnie LaBarbera, Paul Gignac (Erickson lab), Joelle Kane. Missing: Allana O'Brien, Brian Storz (Chase / Moerland lab. (Photographer: Ken Womble)

See more pictures from the Chase Lab 

Selected Publications (since 2000):

Chase, P. B., Y. Chen, K. Kulin, and T. L. Daniel. 2000. Viscosity and solute dependence of F-actin translocation by rabbit skeletal heavy meromyosin. American Journal of Physiology, Cell Physiology. 278:C1088-C1098.

Regnier, M., A. J. Rivera, Y. Chen, and P. B. Chase. 2000. 2-deoxy ATP enhances contractility of rat cardiac muscle. Circulation Research 86:1211-1217.

Mariano, A. C., G. M. C. Alexandre, L. C. Silva, A. Romeiro, L. C. Cameron, Y. Chen, P. B. Chase, and M. Sorenson. 2001. Dimethyl sulphoxide enhances the effects of Pi in myofibrils and inhibits the activity of rabbit skeletal muscle contractile proteins. Biochemical Journal 358:627-636.

LaMadrid, M. A., P. B. Chase, and A. M. Gordon. 2002. Motility assays of calcium regulation of actin filaments. In: Molecular Interactions of Actin: Myosin Interactions, Motility Assays and Ca²⁺- Regulatory Proteins. C. Dos Remedios and D. D. Thomas, eds. Springer-Verlag, NY. Volume also published as Results and Problems in Cell Differentiation 36:133-148.

Regnier, M., A. J. Rivera, C.-K. Wang, M. A. Bates, P. B. Chase, and A. M.Gordon. 2002. Thin filament near-neighbour regulatory unit interactions affect rabbit skeletal muscle steady-state force­Ca²⁺ relations. Journal of Physiology 540:485-497

Martyn, D. A., P. B. Chase, M. Regnier, and A. M. Gordon. 2002. A simple model with myofilament compliance predicts activation dependent crossbridge kinetics in skinned skeletal fibers. Biophysical Journal 83:3425-3434.

Köhler J, Chen Y, Brenner B, Gordon AM, Kraft Th, Martyn DA, Regnier M, Rivera AJ, Wang C-K and PB Chase. 2003. Familial hypertrophic cardiomyopathy mutations in troponin I (K183Δ, G203S and K206Q) enhance filament sliding. Physiol Genomics 14:117-128.

Schlenoff JB, Salloum DS, Jaber JA and PB Chase. 2003. Biofunctional Polyelectrolyte Multilayers. ACS Proc. PMSE 89:76-77.

Liang B, Chen Y, Wang C-K, Luo Z, Regnier M, Gordon AM and PB Chase. 2003. Ca²⁺ regulation of rabbit skeletal muscle thin filament sliding: role of cross-bridge number. Biophys J. 85:1775-1786.

Jaber J, Chase PB and JB Schlenoff. 2003. Actomyosin driven motility on patterned polyelectrolyte mono- and multilayers. Nano Letters. 3:1505-1509

Mihajlović G, Brunet NM, Trbović J, Xiong P, von Molnár S and PB Chase . 2004. An all-electrical switching and control mechanism for actomyosin-powered nanoactuators. Appl Phys Lett. 85:1060-1062 (This article was featured in Physics Today, and was also published in the Virtual Journal of Nanoscale Science & Technology )

Chase PB, Macpherson M and TL Daniel. 2004. A spatially explicit nano-mechanical model of the half-sarcomere: myofilament compliance affects Ca²⁺-activation. Ann Biomed Eng. 32:1559-1568.

Gafurov B, Fredricksen S, Cai A, Brenner B, Chase PB and JM Chalovich. 2004. The Δ14 mutant of troponin T enhances ATPase activity and alters the cooperative binding of S1-ADP to regulated actin. Biochemistry 43:15276-15285

Scholstoff B, Kataoka A, Clark A and PB Chase. 2005. Effects of rapamycin on cardiac and skeletal muscle contraction and crossbridge cycling. J Pharmacol Exp Ther. 312:12-18

Manandhar P, Huang L, Grubich JR, Hutchinson JW, Chase PB and S Hong. 2005. Highly selective directed assembly of functional actomyosin on Au surfaces. Langmuir 21:3213-3216

Grove TJ, Puckett KA, Brunet NM, Mihajloviæ G, McFadden LA, Xiong P, von Molnár S, Moerland TS and PB Chase. 2005. Packaging actomyosin-based biomolecular motor-driven devices for nanoactuator applications. IEEE Trans Adv Pack. 28:556-563

Grove TJ, McFadden LA, Chase PB and TS Moerland. 2005. Effects of temperature, ionic strength and pH on myosin function from skeletal muscle of the mummichog, Fundulus heteroclitus. J Muscle Res Cell Motil., 26:191-197

Schoffstall B, Clark A and PB Chase. 2006. Positive inotropic effects of low dATP/ATP ratios on mechanics and kinetics of porcine cardiac muscle. Biophys J. 91:2216­2226.

Huang L, Manandhar P, Byun K-E, Chase PB and S Hong. 2006. Selective assembly and alignment of actin filaments with desired polarity on solid substrates. Langmuir 22:8635-8638.

Schoffstall B, Brunet NM, Wang F, Williams S, Barnes AT, Miller VF, Compton LA, McFadden LA, Taylor DW, Dhanarajan R, Seavy M and PB Chase. 2006. Ca²⁺-sensitivity of regulated cardiac thin filament sliding does not depend on myosin isoform. J Physiol. 577:935-944.

Kataoka A, Tanner BCW, Macpherson JM, Xu X, Wang Q, Regnier M, Daniel TL and Chase PB. 2007. Spatially explicit, nano-mechanical models of the muscle half-sarcomere: Implications for biomechanical tuning in atrophy and fatigue. Acta Astronautica 60:111-118.

Moreno-Gonzalez A, Gilles TE, Rivera AJ, Chase PB, Martyn DA and M Regnier. 2007. Thin filament regulation of force redevelopment kinetics in rabbit skeletal muscle fibres. J Physiol. 579:313-326.

Kataoka A, Hemmer C and PB Chase. 2007. Computational simulation of hypertrophic cardiomyopathy mutations in troponin I: influence of increased myocyte calcium sensitivity on isometric force, ATPase and [Ca²⁺]. J Biomech 40:2044-2052.

Chase PB. 2007. Tropomyosin in the groove? Molecular insights into an inherited myopathy. J Physiol. 581:889.

Byun K-E, Kim M-G, Chase PB, and S Hong. 2007. Selective assembly and guiding of actomyosin using carbon nanotube network monolayer patterns. Langmuir 23:9535-9539.

Schoffstall B, and Chase PB. 2008. Increased intracellular [dATP] enhances cardiac contraction in embryonic chick cardiomyocytes. J Cell Biochem 104, 2217-2227.

Chase PB, Brunet NM, Mihaljlović G, Xiong P and von Molnár S (2008). Molecular motor-based assays for altered nanomechanical function of Ca²⁺-regulatory proteins in cardiomyopathies. In Molecular Motors, Nanomachines and Active Nanostructures, ed. Hess H, Flood A, Linke H & Turberfield AJ, pp. 1096-FF1002-1002. Mater. Res. Soc. Symp. Proc., San Francisco, CA.

Postdoctoral Associates:

Takeda, Aya Kataoka

Graduate Students:

Badr, Myriam
Loong, Campion
Meyer, Nancy
Williams, John

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