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Mitchell Goldfarb Professor of Biology Website:goldfarb.bioweb.hunter.cuny.edu |
Education:
- B. S. 1974, Massachusetts Institute of Technology
- Ph. D. 1979, Massachusetts Institute of Technology
Current Research Projects
- FGF Homologous Factors: Regulators of Sodium Channels Contolling Brain and Cardiac Function
We have discovered and are studying proteins called fibroblast growth factor homologous factors (FHFs). FHF gene mutations engineered in mice or occurring naturally in humans are associated with a range of neurological disorders. FHFs were discovered by virtue of their sequence homology to fibroblast growth factors (FGFs). While FGFs exert pleiotropic biological effects through interactions with their cell surface FGF receptors, we have demonstrated that FHFs are intracellular and bind to specific neuronal protein targets. A principal set of targets are the alpha subunits for voltage-gated sodium channels. Using FHF knockout mice, we have shown that FHFs are required for neurons to fire robustly, and this is accomplished by FHF modulation of sodium channel fast inactivation (Goldfarb et al., 2007). We have also shown that some FHFs induce a rapid onset long-term inactivation of sodium channels, which is mediated by an inactivation particle in the effector N-terminus of these FHF isoforms (Dover et al., 2010). Long-term inactivation progressively slows the firing rate of neurons, a process call accommodation or frequency adaptation (Venkatesan et al., 2014). Ongoing studies are defining the physical mechanisms of FHF actions and the functional significance of neuron-type-specific and neuron-compartment-specific distribution of FHF protein isoforms. Some of these studies entail the use of fast-responsive voltage sensitive dyes to visualize action potentials along axons and dendrites. An example on this technique applied to cultured cerebellar granule cells is shown in Figure 2 and has led to discovery that spike conduction occurs in an FHF-independent manner (Dover et al., 2016) We have also shown mechanistically how FHF dysfunction can lead to severe epilepsies (Siekierska et al., 2016; Fry et al., 2021) and stress-induced cardiac arrhythmias (Park et al., 2016; Park et al., 2020).
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- Fig. 1. A long-term inactivation schematic of voltage-dependent sodium channel transitions. The core domain of FHF (green) is shown tethered to the channel cytoplasmic tail. The channel’s intrinsic inactivation particle in the short cytoplasmic loop (small red oval) and the larger long-term inactivation particle at N-terminus of tethered A-type FHF (larger red oval) compete for access to inactivate the channel at more depolarized voltage-driven transitions near the open state, making long-term inactivation use-dependent. (from Dover et al., 2010) <
- Fig. 2. Visualization of action potential conduction with voltage-sensitive dye. A cultured granule cell was filled with fast-responsive voltage-sensitive dye by break-in with patch pipette, and viewed at either high spatial resolution (upper left panel) or high sensitivity (lower panel). Voltage changes throughout cellular processes were subsequently monitored by fluorescescence imaging during cell stimulation by current injection. The traces shown (upper right panel) correspond to color-highlighted dendrite and axonal regions (lower panel). The action potential emerges from somatic region and propagates through all axonal branches.
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Current Research Funding
Research Foundation of CUNY
Recent Selected Publications
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Goldfarb, M. (2024) Fibroblast growth factor homologous factors: Canonical and noncanonical mechanisms of action. J. Physiol., in press.
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Marra, C., Hartke,T.V., Ringkamp, M., Goldfarb, M. (2023) Enhanced sodium channel inactivation by temperature and FHF2 deficiency blocks heat nociception. Pain 164, 1321-1331.
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Veliskova, J., Marra, C., Liu, Y., Shekhar, A., Park, D.S., Iatckova, V., Xie, Y., Fishman, G.I., Velisek, L., Goldfarb, M. (2021) Early-onset epilepsy and SUDEP with cardiac arrhythmia in mice carrying the EIEE47 gain-of-function Fhf1(Fgf12) missense mutation. Epilepsia 62, 1546-1558.
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Fry, A.E., Marra, C., 18 others, Goldfarb, M., Chung, S.-K. (2021) Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked infantile onset developmental and epileptic encephalopathy. Am. J. Hum. Genet. 108, 176-185.
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Park, D.S., Shekhar, A., Santucci, J., Redel-Traub, G., Solinas, S.M.G., Mintz, S., Lin, X., Chang, E.W., Narke, D., Xia, Y., Goldfarb, M., Fishman, G.I. (2020) Ionic mechanisms of impulse propagation failure in the FHF2-deficient heart. Circ. Res. 127, 1536-1548.
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Dover, K., Marra, C., Solinas, S., Popovic, M., Subramaniyam, S., Zecevic, D., D'Angelo, E., Goldfarb, M. (2016) FHF-independent conduction of action potentials along the leak-resistant cerebellar granule cell axon. Nature Commun. 7, 12895.
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Park, D.S., Shekhar, A., Marra, C., Lin X., Vasquez, C., Solinas, S., Kelley, K., Morley, G., Goldfarb, M., Fishman, G.I. (2016) Fhf2 gene deletion causes temperature-sensitive cardiac conduction failure. Nature Commun. 7, 12966.
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Siekierska, A., Isrie, M., Liu, Y., Scheldeman, C., Vanthillo, N., Lagae, L., de Witte, P.A.M., Van Esch, H., Goldfarb, M., Buyse, G. (2016) Gain-of-function FHF1 missense mutation causes early-onset epileptic encephalopathy with cerebellar atrophy. Neurology 86, 2162-2170.
- Venkatesan, K., Liu, Y., Goldfarb M. (2014) Fast-onset long-term open-state block of sodium channels by A-type FHFs mediates classical spike accommodation in hippocampal pyramidal neurons. J. Neurosci. 34, 16126-16139.
- Goldfarb, M. (2012) Voltage gated sodium channel associated proteins and alternative mechanisms of inactivation and block. Cell. Mol. Life Sci. 69, 1067-1076.
- Dover, K., Solinas, S., D’Angelo, E., and Goldfarb, M. (2010) Long-term inactivation particle for voltage-gated sodium channels. J. Physiology (London) 588, 2695-2711.
- Goldfarb, M., Schoorlemmer, J., Williams, A., Diwakar, S., Wang, Q., Huang, X., Giza, J., Tchetchik, D., Kelley, K., Vega, A., Matthews, G., Rossi, P., Ornitz, D. M., and D'Angelo, E. (2007). Fibroblast growth factor homologous factors control neuronal excitability through modulation of voltage-gated sodium channels. Neuron 55, 449-463.
- CLICK HERE FOR FULL PUBLICATION LIST (h-index = 63)
- CLICK HERE FOR PROFILE ON RESEARCHGATE
Lab Members
Click Here for people in the Goldfarb lab
Prior Collaborations
Our laboratory has had prior collaborations with the following principal investigators:
Egidio D'Angelo, University of Pavia, Pavia, Italy
Sergio Solinas, University of Sassari, Sardinia, Italy
Gunnar Buyse, University of Leuven, Leuven, Belgium
Dejan Zecevic, Yale University School of Medicine, New Haven, CT
Glenn Fishman, NYU Langone Medical Center, New York, NY
Libor Velisek, NY Medical College, Westchester, NY
Matthias Ringkamp, Johns Hopkins Medical Institute, Baltimore, MD
Andrew Fry, Cardiff University, Cardiff, Wales
Courses Taught
BIOL370: Physiology of Nervous System (undergraduate at Hunter College)
BIOL471.45: Molecular Basis of Brain & Heart Disorders (undergraduate at Hunter College)
BIOL710: Molecular Biology (graduate at Hunter College)
BIO 72301: Neuroscience Core I (graduate at CUNY Graduate Ctr)