OMB No. 0925-0001 and 0925-0002 (Rev. 10/15 Approved Through 10/31/2018)
BIOGRAPHICAL SKETCH
Provide the following information for the Senior/key personnel and other significant contributors.
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NAME: Ian Parker
eRA COMMONS USER NAME (credential, e.g., agency login): IANPARKER
POSITION TITLE: Professor of Neuroscience, Physiology & Biophysics
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
INSTITUTION AND LOCATION / DEGREE(if applicable) / Completion Date
MM/YYYY / FIELD OF STUDY /
University College, University of London / B.Sc. / 06/1972 / Physiology
University College, University of London / Ph.D. / 01/1984 / Physiology
A. Personal Statement
A major focus of research in my lab over the last three decades has been mechanisms of cellular signaling and communication. In particular, we have elucidated how intracellular calcium waves are generated through a remarkable and complex series of events: they are initiated by stochastic release from clusters of inositol trisphosphate receptor/channels, leading to a hierarchical recruitment of such clusters which culminates in the generation of a cell-wide wave via a self-amplified calcium-induced release. These discoveries were accomplished through novel fluorescence imaging technologies, largely utilizing equipment of my own design and construction. Most recently, we have taken these techniques to the truly single-molecule level, by imaging the functioning and localization of single calcium channels in intact cells with millisecond and nanometer resolution. In addition to studying the fundamental physiological mechanisms of calcium signaling, we have investigated how disruptions in calcium signaling ('calciumopathies') are implicated in neurological disease states including Alzheimer's and, most recently, autism spectrum disorder (ASD) (1).
1. Schmunk, G., Boubion, B.J., Smith, I.F., Parker, I. & Gargus, J.J. Shared functional defect in IP3R-mediated calcium signaling in diverse monogenic autism syndromes. Nature Trans. Psychiatry 5:e643; doi:10.1038/tp.2015.123. 2015.
B. Positions and Honors
Positions
1975-1984 Research Assistant, Department of Biophysics, University College London
1984-1990 Assistant Professor, Department of Psychobiology, University of California Irvine, CA
1990-1994 Associate Professor, Department of Psychobiology, University of California Irvine, CA
1994-present Professor, Department of Neurobiology and Behavior, University of California, Irvine, CA
1996-1997 Acting Chair, Department of Psychobiology, University of California Irvine, CA
2007-present Professor, Department of Physiology & Biophysics, University of California, Irvine, CA
Honors
2008 Elected Fellow of the Royal Society
2009 Elected Fellow of the American Association for Advancement of Science
2010 NIH MERIT Award
2012 Norman Weinberger Award for Lifetime Achievement in Research: Department of Neurobiology & Behavior, UC Irvine
Other experience and professional memberships
1984-present Member, Physiological Society, UK
1998-present Editorial Advisory Board, Journal of General Physiology
2004-2012 Editorial Board, Biophysical Journal
C. Selected Contribution to Science
C1. Elucidation of the hierarchy of cellular calcium signals
Following the development of luminescent and fluorescent calcium indicators during the 1980s it was discovered that cells generated complex patterns of cytosolic calcium transients, which serve to regulate numerous cellular processes. These transients were first identified as periodic ‘spikes’, and then as periodic waves of calcium, sweeping across the cell. In 1991 my lab discovered a fundamentally new and different type of calcium signal that we christened calcium ‘puffs’; brief, local elevations that remained restricted to within just a few micrometers in the cytosol. These are now recognized to be the first example of a large family of ‘elementary’ calcium signals, which serve ubiquitous local signaling functions in numerous cell types. In subsequent studies we showed that calcium puffs arise from the concerted opening of several IP3Rs that are tightly clustered together and interact via calcium-induced calcium release (1); that local puffs act as triggers to initiate cell-wide calcium waves (2); and that interactions between calcium puffs underlie the generation of regularly periodic whole-cell calcium oscillations (3). Taken together, our findings on IP3-mediated calcium signaling have revealed a ubiquitous hierarchy of events, ranging from single-channel openings through concerted openings of clustered channels to global calcium waves that propagate in a saltatory manner from cluster to cluster. The spatiotemporal patterning of these local and global calcium elevations endow calcium signaling with the specificity to regulate processes as diverse as membrane excitability, gene expression and mitochondrial energetics (4).
1. Yao Y, Choi J, and Parker I. Quantal puffs of intracellular Ca2+ evoked by inositol trisphosphate in Xenopus oocytes. J. Physiol. 482: 533-553, 1995.
2. Marchant J, Callamaras N, and Parker I. Initiation of IP3-mediated Ca2+ waves in Xenopus oocytes. EMBO J. 18: 5285-5299, 1999.
3. Marchant JS and Parker I. Role of elementary Ca2+ puffs in generating repetitive Ca2+ oscillations. EMBO J. 20: 65-76, 2001.
4. Cárdenas C, Miller RA, Smith I, Bui T, Molgo J, Muller M, Vais H, Cheung K-H, Yang J, Parker I, Thompson CB, Birnbaum MJ, Hallows KR and Foskett JK. Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria. Cell 142: 270-283, 2010.
C2. Development of the ‘optical patch-clamp’
The Nobel Prize-winning invention of the patch-clamp recording technique by Neher and Sakmann enabled the first recording of single-channel activity, and remains the ‘gold-standard’ for studying channel kinetics. Nevertheless, patch-clamping has some limitations, including lack of spatial information, restriction to plasma membrane channels with physical access to the recording pipette, and low throughput because only one channel can be recorded at a time. We thus developed an alternative optical approach to resolve the kinetic gating of calcium-permeable channels by imaging the calcium flowing through individual channels. To do this, we employ cytosolic fluorescent calcium indicator dyes together with imaging techniques that restrict fluorescence measurements to very small (sub-femtoliter) volumes adjacent to the channel pore. Our initial approach utilized fast confocal imaging (1), which we then refined to use total internal reflection fluorescence (TIRF) microscopy to further reduce the sampling volume and enable fast camera-based imaging throughout large membrane areas (2,3). Particular advantages of this technique of ‘optical patch-clamp’ recording include the ability to monitor the simultaneous activity of hundreds of channels, to record from channels in intracellular membranes that are inaccessible to a patch-clamp pipette, and to map the locations of individual channels with nanometer precision (4).
1. Demuro A and Parker I. Optical single-channel recording: imaging Ca2+ flux through individual N-type voltage-gated channels expressed in Xenopus oocytes. Cell Calcium 34(6): 499-509, 2003. PMC1304190
2. Demuro A and Parker I. “Optical patch-clamping”: Single-channel recording by imaging Ca2+ flux through individual muscle acetylcholine receptor channels. J. Gen. Physiol. 126(3): 179-92, 2005. PMC2266576
3. Demuro A and Parker I. Imaging single-channel calcium microdomains. Cell Calcium 40: 413-422, 2006. PMC1694561
4. Wiltgen SM, Smith IF and Parker I. Superresolution localization of single functional IP3R channels utilizing Ca2+ flux as a readout. Biophys. J. 99: 437-446, 2010. PMC2905071
C3. Immunoimaging
The functioning of the immune system depends on interactions between diverse cells, including lymphocytes and antigen-presenting cells, which occur deep within lymphoid organs and other tissues. Until recently, these processes could not be directly visualized, and the dynamics of immune cell interactions had to be inferred from static ‘snapshots’ of fixed, sectioned tissues. In a collaborative effort with Mike Cahalan, an immunologist at UCI, I helped pioneer a new field of immunoimaging (1,2) utilizing two-photon microscopy to visualize cellular interactions in real time in explanted tissues and in vivo. Our joint studies continue to illuminate the cellular dynamics and mechanisms of antigen recognition, cellular activation, migration, and immunosuppressive drug action (3,4), and two-photon immunoimaging has been widely adopted by many other labs worldwide.
1. Miller MJ, Wei SH, Parker I, and Cahalan MD. Two-photon imaging of lymphocyte motility and antigen response in intact lymph node. Science. 296: 1869-1873, 2002.
2. Miller MJ, Hejazi AS, Wei SH, Cahalan MD, and Parker I. T cell repertoire scanning is promoted by dynamic dendritic cell behavior and random T cell motility in the lymph node. Proc. Natl. Acad. Sci. 101 (4): 998-1003, 2004. PMC327133
3. Cahalan MD and Parker I. Choreography of cell motility and interaction dynamics imaged by two-photon microscopy in lymphoid organs. Ann. Rev. Immunol. 26: 585-626, 2008.
4. Greenberg ML, Yu Y, Leverrier S, Zhang SL, Parker I and Cahalan MD. Orai1 Function is Essential for T Cell Homing to Lymph Nodes. J. Immunol. doi: 10.4049/jimmunol.1202212 2013.
C4. Imaging IP3 receptors at the single-molecule level in intact cells
Calcium puffs are the basic building block of cellular calcium signaling, and we have thus sought to understand how the puffs themselves are constituted: How many IP3Rs are present in a cluster and how many open to generate a puff? How is the gating of these receptor/channels coordinated? Are clusters pre-formed, stable entities, or do IP3Rs cluster in response to stimulation? By utilizing the optical patch-clamp technique we have been able to address these questions by dissecting calcium puffs into their quantal units. Most recently, we have applied super-resolution imaging techniques to visualize and track individual IP3Rs, tagged with a photoactivatable fluorescent protein, in live cells.
1. Smith IF and Parker I. Imaging the quantal substructure of single IP3R channel activity during Ca2+ puffs in intact mammalian cells. Proc. Natl. Acad. Sci. USA 106: 6404-6409, 2009. PMC2669345
2. Smith IF, Wiltgen SW, Shuai J and Parker I. Ca2+ puffs originate from preestablished clusters of inositol trisphosphate receptors. Science Signaling 2: Issue 98: ra77, 2009. PMC2897231
3. Dickinson GD and Parker I. Factors determining the recruitment of inositol trisphosphate receptor channels during calcium puffs. Biophys. J. 105: 2474-2484, 2013. PMC3853323
4. Smith IF, Swaminathan D, Dickinson GD and Parker I. Single-molecule tracking of inositol trisphosphate receptors reveals differing motilities and distributions. Biophys. J. 107: 834-845, 2014. PMC4142249
C5. Alzheimer’s disease as a calciumopathy
Complementing our studies of fundamental, physiological mechanisms of cellular calcium signaling, I have long been interested in how disruptions of calcium signaling (’calciumopathies’) may be implicated in disease pathogenesis. We have identified distinct, but interacting calciumopathies in Alzheimer’s disease (AD). We initially showed that mutations in Presenilin genes associated with early-onset AD result in exaggerated calcium release evoked in neurons by IP3R (1), and subsequently discovered that this effect involves not only IP3Rs but is further amplified by enhanced calcium-induced calcium release through ryanodine receptors (2). Separately, we examined the actions of the beta amyloid (Ab) oligomers that are overproduced in AD. We showed that Aboligomers forming calcium-permeable pores in the membrane (3), and further induce cytotoxic elevations of cytosolic calcium by promoting excess production of IP3 and consequent liberation of calcium from the ER (4).
1. Stutzmann GE, Caccamo A, LaFerla FM, and Parker I. Dysregulated IP3 signaling in cortical neurons of knock-in mice expressing an Alzheimer’s-Linked mutation in Presenilin1 results in exaggerated Ca2+ signals and altered membrane excitability. J. Neurosci. 24(2): 508-513, 2004.
2. Stutzmann GE, Smith I, Caccamo A, Oddo S, LaFerla FM and Parker I. Enhanced ryanodine receptor recruitment contributes to Ca2+ disruptions in young, adult and aged Alzheimer's disease mice. J. Neurosci. 26: 5180-5189, 2006.
3. Demuro A, Smith M and Parker I. Single-channel Ca2+ imaging implicates Ab 1-42 amyloid pores in Alzheimer's disease pathology. J. Cell Biol. 195: 515-524, 2011.
4. Demuro A and Parker I.Cytotoxicity of intracellular Ab42 amyloid oligomers involves Ca2+ release from the endoplasmic reticulum by stimulated production of inositol trisphosphate. J. Neurosci. 33: 3824-3833, 2013. PMC3708452
D. Research Support
NIH R37 GM-048071. MERIT Award; PI – I. Parker. 08/01/2011-07/30/2021.
Elementary Events of Calcium Signaling
This project aims to understand the mechanistic basis underlying the generation and functions of local and global Ca2+ signals, and combines confocal and TIRFM and other biophotonic approaches.
NIH R01 GM-065830. Multi-investigator award; PIs – I. Parker, J.E. Pearson, D. Mak. 01/15/2014-11/30/2017.
Multi-scale observation and modeling of IP3/Ca signaling
This project combines experimental studies with multi-scale mathematical simulation to develop a comprehensive model of intracellular IP3-mediated Ca2+ signaling. My role is to provide experimental data and biological input on elementary Ca2+ events and waves, and to work in collaboration with mathematicians and physicists to develop mathematical models of these processes.
NIH AI 121945 PI – M.D. Cahalan, I. Parker co-investigator. 06/20/2016-05/31/2021
Cellular and Molecular Mechanisms of Regulatory T Cells in EAE
This project investigates the role of regulatory T cells in mediating the pathophysiology of a murine model of multiple sclerosis. My role is to oversee experiments utilizing two-photon microscopy to visualize the motility and cellular interactions of regulatory T cells in lymph node and spinal cord.