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Poulos J.L.,Librede Inc. | Portonovo S.A.,University of California at Los Angeles | Bang H.,Seoul National University | Schmidt J.J.,University of California at Los Angeles
Journal of Physics Condensed Matter | Year: 2010

Artificial lipid bilayer membranes have been used to reconstitute ion channels for scientific and technological applications. Membrane formation has traditionally involved slow, labor intensive processes best suited to small scale laboratory experimentation. We have recently demonstrated a high throughput method of membrane formation using automated liquid-handling robotics. We describe here the integration of membrane formation and measurement with two methods compatible with automation and high throughput liquid-handling robotics. Both of these methods create artificial lipid bilayers by joining lipid monolayers self-assembled at the interface of aqueous and organic phases using sessile aqueous droplets in contact with a measurement electrode; one using a pin tool, commonly employed in high throughput fluid handling assays, and the other using a positive displacement pipette. Membranes formed with both methods were high quality and supported measurement of ion channels at the single molecule level. Full automation of bilayer production and measurement with the positive displacement pipette was demonstrated by integrating it with a motion control platform. © 2010 IOP Publishing Ltd. Source


Neronov A.,Data Center for Astrophysics | Semikoz D.V.,Paris West University Nanterre La Defense | Semikoz D.V.,RAS Institute for Nuclear Research | Tinyakov P.G.,Librede Inc. | Tkachev I.I.,RAS Institute for Nuclear Research
Astronomy and Astrophysics | Year: 2011

We analyze the gamma-ray halo around stacked AGNs reported by Ando & Kusenko (2010, ApJ, 722, L39). First, we show that the angular distribution of γ-rays around the stacked AGNs is consistent with the angular distribution of the γ-rays around the Crab pulsar, which is a point source for Fermi/LAT. This makes it unlikely that the halo is caused by an electromagnetic cascade of TeV photons in the intergalactic space. We then compare the angular distribution of γ-rays around the stacked AGNs with the point-spread function (PSF) of Fermi/LAT and confirm the existence of an excess above the PSF. However, we demonstrate that the magnitude and the angular size of this effect is different for photons converted in the front and back parts of the Fermi/LAT instrument, and thus is an instrumental effect. © 2011 ESO. Source


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 163.75K | Year: 2011

DESCRIPTION (provided by applicant): Ion channels pharmaceutical discovery and safety screening is slow and expensive and as a result, there are currently no high quality, high throughput assays for ion channel screening. Librede Inc. is developing alternative cell-free technologies for ion channel measurement which have the potential for higher throughput and lower cost. In preliminary work, we have demonstrated a platform for formation and measurement of artificial cell membranes that is compatible withautomated motion control hardware. Measurements of these membranes show that they are able to house ion channels with properties matching the scientific literature. The initial work with this platform utilized manual positioning and assembly of the components under constant monitoring and feedback. Although this was sufficient to demonstrate the technology, it is not sufficient to demonstrate its suitability for high throughput and automation processes. Here we propose to construct a mechanical jig which will allow assembly of the membrane components blind , simulating automated processes. With this jig, we will cycle the membrane formation apparatus, measuring the properties of the resultant artificial membranes to determine the degree of reproducibility and therefore the suitability of this process for automation and high throughput. We have designed a plate which is compatible with industry standard 384 well fluid handling systems and contains a modification of our initial membrane formation apparatus which tolerates minor mechanical positioning errors. In the proposed work, we will use the plate and ascertain whether these modifications are sufficient or require further improvement. We will cycle the apparatus over 500 times, measuring the yield of the resulting membranes and their ability to reconstitute ion channels. The processes developed will be scalable an entire 384 well plate and the mechanical jig easily adapted for use with motion control robotics, positioning our platform for Phase II adapting it for high throughput automation. PUBLIC HEALTH RELEVANCE: Measurement of ion channel interactions with drugs is a key process in drug screening, but current technologies are slow and expensive. Our team has recently developed a method for formation of an artificial cell membrane that is compatible with robotic automation. We propose here to develop tools and processes that enable the scaling and cycling of this technology resulting in high throughput ion channel measurement.


Grant
Agency: NSF | Branch: Standard Grant | Program: | Phase: | Award Amount: 150.00K | Year: 2012

This Small Business Innovation Research Phase I project is aimed at developing improved technology for drug discovery and safety screening of ion channels. Ion channels are present in every cell and play key roles in a wide range of physiological processes including the cardiac cycle and neural activity. Librede Inc. is developing an ion channel screening platform based on artificial cell membrane technology that has the potential for decreased instrumentation and running costs with higher throughput and minimal training. In the work proposed here, Librede will design and fabricate a consumable prototype ion channel array plate with 32 measurement sites and measure an ion channel across the whole plate simultaneously. At the completion of this Phase I work we will have an SBS standard consumable array plate ready for integration into an automated platform with solution perfusion to be developed in Phase II.

The broader/commercial impacts of this research are to decrease the cost and increase the throughput of ion channel screening. These are well-recognized pain points felt by pharmaceutical and academic researchers. This problem is shared for screening of all drug candidates, since all drugs must be screened against cardiac ion channels for issues of safety. Librede?s fundamentally different approach to ion channel screening will streamline the screening process, reducing its cost and time, resulting in better/safer drugs reaching the market sooner. Our platform gives us a competitive advantage in cost, throughput, and ease of use when compared to the state of the art.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 128.33K | Year: 2010

DESCRIPTION (provided by applicant): Electrophysiological assays of ion channels for pharmaceutical discovery and safety screening are problematic to perform in high throughput because the ion channels must be incorporated into a lipid bilayer membrane to enable measurement of their ionic conductance. As a result, there are currently no high quality, high throughput assays for ion channel screening. Recent developments of automated patch clamp instrumentation are still over two orders of magnitude lower throughput than conventional drug screening for soluble proteins and also require expensive instrumentation, specialized cell lines, and consumables. For existing methods of ion channel screening, there is a large gap in information quality, throughput, and cost. Librede Inc. is developing an alternative technology for ion channel measurement in which the ion channels are reconstituted in artificial lipid bilayer membranes. Librede's patent pending formulation of cell-free artificial bilayers has the potential for significantly higher throughput and lower consumable costs, while requiring less expensive equipment and trained personnel. Librede was founded by the UCLA inventors of this technology; we are now working to transfer this technology from the academic laboratory and develop it commercially. In preliminary work, we have developed inexpensive, disposable, shippable bilayer array chips capable of supporting ion channel measurement in 48 sites simultaneously. We have measured bilayers and ion channels in these chips previously using a multiplexed single channel amplifier; in the work proposed here, we aim to demonstrate higher throughput by measuring all sites in the chip simultaneously using a 48 channel patch clamp amplifier. Simultaneous measurement will be a key test of our technology; we will explore the effects of noise, crosstalk, and bilayer size on our ability to measure bilayers and incorporated ion channels over the entire chip at once. The noise and bandwidth achieved with our system using this instrument will determine our signal detection and temporal resolution and determine the feasibility of this platform for high throughput measurement of ion channels as well as paths to improvements in performance. The ability to measure ion channels in bilayer arrays in parallel will be a major milestone in the development of this technology toward commercialization, and is a preliminary step of the full demonstration of our final product. We will use the materials and experience gained in our Phase I research for Phase II development in which we will integrate low cost mass-producible injection molded shippable bilayer chips with automatable instrumentation for fluid handling and parallel ion channel measurement. This will bring us closer to our goal of reducing the cost and expertise required for ion channel screening by eliminating cell culture and cellular manipulation in pharmaceutical screening, thus significantly increasing throughput and decreasing costs, enabling more effective searches for ion channel drugs. PUBLIC HEALTH RELEVANCE: Measurement of ion channel interactions with drugs is a key process in drug discovery and drug safety screening, but due to the difficulty in working with ion channels the existing processes used are slow, laborious, and expensive. Librede has recently developed a platform for ion channel measurement which is much less expensive and much easier to use, based on lipid membranes that can be shipped-a world first. We propose here to develop instrumentation for simultaneously measuring arrays of ion channels contained in these membranes.

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