Laboratory of Michael Fill, PhD

The research of Michael Fill, PhD, explores the local control of intracellular Ca signals mediated by the ryanodine receptor (RyR) Ca release channel in excitable cells. These control mechanisms are fundamental to many cellular phenomena and, thus, are often sites of pathological failure and potential targets for therapeutic intervention.

Our work

Fill’s lab at Rush is internationally recognized for its world-class RyR experimental expertise. The Ca signals generated by RyRs are known to modulate a myriad of physiological functions. Our lab details clinically significant structure-function attributes of single RyR function in health and disease, including local RyR control by Ca, closely regulatory proteins and post-translational modifications. This provides a strong mechanistic foundation for our group’s ongoing work toward developing new RyR-targeted drugs that will hopefully be applied to limit/treat diseases exacerbated or caused by hyperactive RyR Ca signaling.

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Technology and methods

• Single ion channel recording (patch clamp, planar bilayers)
• Ion channel protein purification and isolation
• Utilization of mutant ion channels and proteins
• Fabrication and use of ion selective electrodes
• Laser flash photolysis of caged compounds
• Confocal intracellular Ca signaling measurements
• Rational design and testing of RyR-targeted drugs

Ryanodine Receptor (RyR) Single Channels Opening and Closing in a Lipid Bilayer

RyR-Mediated Sparks in an Isolated Ventricular Cardiomyocyte

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Publications

High-profile works

Chen … Fill, et al. “RyR store-sensing gate controls C waves and C-triggered arrhythmias.” Nature Medicine. 20(2): 184-92, 2014.

Zhou … Fill, et al. “Carvedilol and its new analogs suppress arrhythmogenic … Ca release.” Nature Medicine. 10;17(8): 1003-9, 2011.

Fill and Copello. “RyR Ca release channels.” Physiological Reviews. 82(4): 893-922, 2002.

Minn … Fill, et al. “Bcl-xL regulates apoptosis by heterodimerization-dependent and -independent mechanisms.” EMBO Journal. 1;18(3): 632-43, 1999.

Minn, et al. and Fill. “Bcl-x(L) forms an ion channel in synthetic lipid membranes.” Nature. 23;385(6614): 353-7, 1997.

Cheng, Fill et al. “Models of Ca release channel adaptation.”Science. 267(5206): 2009-10, 1995.

Györke and Fill. “Ryanodine receptor adaptation: control mechanism of Ca(2+)-induced Ca2+ release in heart.” Science. 7;260(5109): 807-9, 1993. 

Ma, Fill et al. “Ryanodine receptor of skeletal muscle is a gap junction-type channel.” Science. 7;242(4875): 99-102, 1988.

Additional research

A more complete listing of Fill’s published work can be found on PubMed.

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Funding

Current grants

• NIH R01-AR071381-01: “The HH: A Large Cohort of Patients with Congenital Myopathies of Uncertain Etiology.” Multiple principal investigators: Drs. Fill, Riazi and Rios
• NIH R01-AA024769-02: “The Stress Response Kinase JNK and Alcohol Evoked Atrial Fibrillation.” Multiple principal investigators: Drs. Fill, Chen and Ai
• NIH R01-HL057832-19: “Limiting Pathological Calcium Induced Calcium Release in Heart.” Principal investigator: Dr. Fill
• NIH R01-GM11397-03: “Control of IP3R-Mediated Ca Release.” Multiple principal investigators: Drs. Fill, Chen and Ramos-Franco
• NIH R01-AR054098-09: “Sarcoplasmic Reticulum SR K Channel Function.” Principal investigator: Dr. Fill

Past grants

• NIH R01-HL075210: “Molecular Basis and Treatment of Cardiac Arrhythmias.” Co-investigator: Michael Fill
• NIH R01-HL071741: “Local Intracellular Calcium Release in Neonate Heart.” Co-investigator: Michael Fill
• AHA SDG: “RyR Heterogeneity in Striated Muscle.” Co-investigator: Michael Fill
• MDA Grant: “Coordinated Gating of Ryanodine Receptor Channels.” Co-investigator: Michael Fill
• NIH R01-HL64210: “Regulation of Single Ca Release Channels in Heart.” Principal investigator: Michael Fill
• NIH R01-MH53367: “Molecular Analysis of InsP₃R Structure Function.” Co-investigator: Michael Fill
• NIH R01-HL58851: “Isoform Specific Function of InsP₃R Receptor Channels.” Co-investigator: Michael Fill
• AHA Grant: “Development of Cardiac E-C Coupling.” Co-investigator: Michael Fill
• AHA Established Investigatorship: “Regulation of SR Ca Release.” Principal investigator: Michael Fill
• MDA Grant: “Ca Control of SR Ca Release.” Co-investigator: Michael Fill

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Our team

Fill’s lab has trained 15 postdoctoral fellows and 12 PhD students. Join us.

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Contact

Michael Fill, PhD
Professor and Chair
Francis N. and Catherine O. Bard Professor of Physiology

Rush University
Department of Physiology & Biophysics
1750 W. Harrison St.
Chicago, IL 60612
Phone: (312) 942-6434
Fax: (312) 942-8711
Email: michael_fill@rush.edu

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