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Displaying Available Technologies results for Research Tools & Reagents

TRP-SWITCH: LIGAND ENABLING ON/OFF TRPA1 CONTROL

Technology Summary
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Current optogenetics and chemo-optogenetics suffer from a variety of limitations including low unitary conductance (which requires oversaturation and can result in off-site effects, including cytotoxicity), the need to covalently modify the target channel, and/or the inability to control both on and off switching. These limitations produce uncertainty when trying to dissect complex biological systems.

This work identifies “TRPswitch” as a photoswitchable, nonelectrophilic ligand scaffold for the transient receptor potential ankyrin 1 (TRPA1) channel. TRPswitch A and B are two photoswitchable small molecules that enable optical control of currents in Trpa1b expressing cells in vivo. The TRPswitches specifically enable repeatable optical control of both neuronal and non-neuronal cells. Importantly, the TRPswitches allow for sustained channel activation after only a brief pulse of violet light illumination, but the channel can also be rapidly deactivated with green light illumination. As only short pulses of light are required to control the activity of the TRPA1 channel, cells subjected to the TRPA1/TRPswitch chemo-optogenetic system are less prone to photo-toxicity. Specifically, this new tool will also be beneficial in applications where a large depolarization current is needed, such as in large primary motor neurons, or when sustained channel activation is desirable.


METHOD TO GENERATE HUMAN CORTICAL ORGANOIDS

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Current methods differentiate cerebral cortex organoids from stem cells resulting in a high heterogeneity of cells that yields a high variability in results.

A University of Utah researcher has developed a method for generating three-dimensional cortical organoids from single induced pluripotent stem cell (iPSC)-derived neural rosettes in vitro. Single-rosette-derived cortical organoids grow large in suspension culture, reaching 4-5 mm in diameter by 4 months while maintaining a single internal lumen. They consist of different types of neuronal cells, including cortical neural progenitors, deep and superficial cortical excitatory neurons, inhibitory neurons, and astrocytes, organized around the lumen. Patch-clamp electrophysiology shows that many neurons in slices from single-rosette-derived cortical organoids fire repetitive action potentials, receive excitatory and inhibitory synaptic inputs, exhibit typical pyramidal-like morphologies, and develop dendritic spines. These organoids are useful for defining the organization and functions of human neurons in healthy and diseased developing cortical networks and have potential applications in regenerative medicine and transplantation such as treating certain forms of drug-resistant epilepsy.


QUANTITATIVE MEASUREMENT OF MOUSE STRESS

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Measurement of stress is imperative to psychological and mental disorder mouse model characterization, especially to determine the efficacy of drugs. Yet, conventional behavioral testing relies on indirect measures of stress that are difficult to interpret, time-intensive, and incompatible with concurrent electrophysiology, live imaging, or optogenetics.

University of Utah researchers have developed a protocol, paradigm, and apparatus to measure acute pupil dilation as a quantitative measure of mouse stress. The test is run in a sound and light isolated box, where tones are played to startle the mice. The apparatus is head-fixed, enabling concurrent high-resolution testing of brain activity.


GAS CHROMATOGRAPHY DETECTION SYSTEM

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Gas chromatography (GC) systems detect a wide range of gas species. Yet, current GC systems are limited by short channel lengths that inhibit successful sample separation.

University of Utah researchers have developed a gas chromatography system that increases channel length without any increase in overall system size. In effect, less pressure is required to run samples through the longer channels, enabling micro-scale separation. The system’s small size reduces overall energy consumption, package size, and dead volume while increasing separation capacity.


LIVE-CELL ASSAY FOR NEURONAL ACTIVITY

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Synaptic assays are used to measure neuronal activity in disease and drug research for neurodevelopmental disorders. Existing assays rely on visualization or electrophysiological analyses, but they provide variable results because they fail to track changes in the same population of neurons over time. These methods are also labor intensive, expensive, and unsuitable for large-scale drug screens.

The live-cell assay facilitates quantitative measurement of neuronal activity. The assay involves infecting cultured neurons with an activity-dependent promoter, and then repeatedly measuring the accumulation of photon-yielding enzymatic activity in the medium. This method provides longitudinal tracking of neuronal activity, while identifying small molecules that regulate synapse development and function. The technology will be used as a drug screen in normal synapse development to narrow the field of drug candidates that affect neuronal activation.


GLASS PHASE PLATE FOR HIGH PRECISION WAVELENGTH EXTRACTION

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Traditional localization microscopy uses photo-chemical blinking or switching of fluorescent molecular tags to generate super-resolution (SR) images. Obtaining multi-color images, however, requires filters, which limits the number of colors of fluorescence that can be used at one time.

The etched glass phase plate modifies the point-spread function to have a recognizable shape at each wavelength. Different spectral signals can then be measured without using filters or polarized spatial light modulators. The spectral information may also be rendered in conjunction with an SR image. The phase plate can be tailored to individual imaging needs by adding thin films to affect the slope of the dispersion curve. This may provide increased sensitivity to a desired range of wavelengths. The phase plate can be easily inserted into the Fourier plane of an existing microscope or imaging system.


MULTISEQUENCE CAPTURE BEAD CONSTRUCTION

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Existing high-throughput, fluidics-based RNA sequencing systems are incompatible with short read length platforms and can only capture a single sequence. Additionally, variable regions of T-cell receptor pairs are separated during purification, and existing technology only allows capture of a single sequence making it difficult to accurately determine the existence and relative concentrations of receptor chains.

Bi-functional mRNA capture beads, synthesized using reversible oligonucleotide chain-blocking, isolate and amplify two different mRNA sequences while maintaining the pairing information for these sequences. The bead has a proprietary base that blocks chain elongation in order to capture and read the complete variable region of each chain. The multiple reads per bead will provide statistical conformation that the sequence is correct. Initial tests have demonstrated that two different capture sequences can be built onto a single bead, enabling specific capture and amplification of multiple different mRNA species.


COLORECTAL-CANCER-PATIENT-DERIVED XENOGRAFTS

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Colorectal cancer (CRC) leads to almost 50,000 deaths in the United States annually. CRC treatment require patients to undergo tumor resection and, in later stages, chemotherapy. Early-stage progression of CRC and risks associated with chemotherapy, however, have caused physicians to question the benefits of chemotherapy in stage II patients. A novel model of CRC tumors allows for testing of drug efficacy prior to treatment. Using a patient-derived CRC tumor, a xenograft is implanted into an immune-deficient mouse in the most physiologically-relevant location. This implantation creates a personalized and high-fidelity model of that person’s tumor. Accurate patient-derived models can be used to determine the most effective treatment method for individual patients. These models are also serially propagatable, creating ample opportunities for research, drug testing, and development of new therapies.


GYNECOLOGICAL-CANCER-PATIENT-DERIVED XENOGRAFTS

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Endometrial cancer (EC) is the most common gynecological malignancy in the United States, with over 49,000 new cases each year. Current animal tumors have insufficient structural architecture and tumor heterogenity and lack of effective drugs hinders treatment of EC. This complicates tests performed to predict patient response to certain treatments.

A novel model for the development of highly personalized gynecological tumors has been created. Orthotopic implantation of tumors derived from patients with gynecological malignancies result in mouse models that simulate human oncogenesis over multiple generations. The model also provides an excellent model for translational studies.


BREAST-CANCER-PATIENT-DERIVED TUMORGRAFTS

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Breast cancer causes over 40,000 deaths in the United States annually. Use of patient-derived tumorgrafts improves treatment efficacy, but availability of such models is limited. Novel models for breast tumor growth and metastasis, derived from patients and engrafted directly into the mammary glands of mice, increase access to patient-derived tumorgrafts. The model promotes angiogenesis, increases tumor growth, and facilitates maintenance of ER protein levels during serial propagation. With twelve developed tumorgraft lines, the model spans all major clinical breast cancer subtypes and several of the known molecular subtypes. The tumorgrafts recapitulate spontaneous metastasis with patterns similar to those observed in the original patients and serve as a critical indicator of patient outcome.


CYCLIC PEPTIDE LIBRARIES

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Cyclic peptide libraries of novel compounds serve as valuable collections for researchers to mine for new therapeutics. The proposed methods for creating cyclic peptide libraries utilize biosynthetic pathways from various organisms. The enzymatic steps are broken into individual components and then reassembled in unique ways to generate large collections of novel chemical entities (NCEs).

One method uses amide-linked peptides created in vivo by expression of constructs in E. coli. Another method centers on prenylated compounds created from marine ascidian enzymes, again expressed in E. coli. The final method utilizes natural pathways from sponges to synthesize compounds for libraries. Methods to increase the yield and potency of peptides, specifically cyanobactin and prenylated peptides, in the libraries have also been developed.


PEPTIDES FOR CLEARING DEGRADED AND UNFOLDED COLLAGEN

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Collagen is a major structure protein found in almost all human tissue. Degraded collagen is present in damaged tissues and is highly associated with many critical human diseases and injuries.

The collagen hybridizing peptide (CHP) can bind to these degraded collagens without affecting intact collagen. The proposed CHP has a high affinity to denatured collagen molecules for use in imaging, diagnosing, and treating diseases and injuries that cause collagen damage. The presence of Aza-Glycine residues from collagen mimetic peptide sequence increases stability of bonding to degraded collagen. The peptide can be paired with existing diagnostics and therapeutic agents to provide highly specific and targeted delivery of therapeutics or imaging markers to damaged collagen. Potential applications range from treating cancer to stabilizing blood clots and treating skin conditions.


POLYMERS FOR EFFICIENT GENE DELIVERY

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Both viral and non-viral delivery systems have been used for gene therapy, but non-viral vectors present a variety of advantages, including scalability, low immune response, flexible loading capacity, and stability. Widespread adoption of non-viral gene vectors, however, has been limited by toxicity and transfection efficiency concerns. Multiple polymers for more efficient delivery of genetic material have been developed. The first is a novel arginine-conjugating bioreducible poly(amido amine) polymer that can degrade into nontoxic molecules in an intracellular environment. Mixing the polymer with PEG inhibits plasmid DNA condensation, improves biocompatibility, and enables in vivo applications. The second polymer is a poly(ethylamine) (PEI)-based gene delivery system, made through polymerization of cysteine and dendrimer branches. The polymer has a smaller molecular weight, which increases the stability of the complex and lowers cytotoxicity. Conjugating PEI to poly(cystaminebis(acrylamide)- diaminohexane) (poly(CBA-DAH)) via a disulfide bond further decreases toxicity and allows genetic material to be released easily.