OHSU researchers identify structure linked to insulin secretion

KATP channel gating model

KATP channel gating model

It was more than 30 years ago that an ATP-sensitive potassium (KATP ) channel was identified as the key molecular link between glucose metabolism and insulin secretion.

The KATP channels sense metabolic changes and translate these energy fluxes into channel gating, which adjusts membrane excitability and regulates insulin secretion. They are the targets of the sulfonylureas, antidiabetic drugs that increase insulin release from beta cells in the pancreas. Genetic mutations of the channel cause several devastating rare diseases characterized by abnormal blood glucose control and neurological symptoms.

It is known that KATP channels are a complex of two proteins, Kir6.2 and SUR1, which are uniquely dependent on each other for expression and function. Still lacking, however, is detailed structural information crucial to understanding how the two proteins assemble and function as a complex in order to regulate insulin secretion.

Now, OHSU scientists have obtained the first subnanometer structure of the channel, which reveals the detailed domain organization of KATP channels and the intricate structural interactions between SUR1 and Kir6.2. The research team, consisting of the lead author Gregory Martin, a student in the Graduate Program in Molecular and Cellular Biosciences, senior authors Show-Ling Shyng, Ph.D., and James Chen, Ph.D., of the Department of Biochemistry and Molecular Biology, as well as Craig Yoshioka, Ph.D. of the Department of Biomedical Engineering and Matt Whorton, Ph.D. of the Vollum Institute published their findings on January 16 in eLife journal.

Single-particle cryo-electron microscopy (cryo-EM) conducted at the OHSU Multiscale Microscopy Core was used to construct a three-dimensional map of the KATP channel assembly and gating. The structure revealed by this map shows how SUR1 and Kir6.2 work together and provides insight into how ATP and glibenclamide interact with the channel to block the channel, hence release of insulin.

The new insight gained from the structure lays the foundation for future structural and functional studies. In particular, structures bound with various stimulatory and inhibitory ligands will further advance understanding of the detailed mechanisms of channel gating. This knowledge will aid in the design of more effective drugs to treat several devastating diseases caused by defective KATP channels.

An interesting observation in this research is that the ATP binding cassette (ABC) core of SUR1 is in a twisted inward-facing conformation, which suggests a possible mechanism by which the antidiabetic drug glibenclamide inhibits KATP channel activity. Because glibenclamide is known to inhibit the activity of other ABC transporter proteins—including cystic fibrosis transmembrane conductance regulator (CFTR) and the multidrug resistance protein MDR—the mechanism proposed by Shyng’s team could have implications much broader than insulin secretion disorders.

The research was supported by National Institutes of Health grants R01DK066485 (to SLS) and F31DK105800 (to GMM) as well as by the OHSU Core Pilot Grant Program, which is funded by the University Shared Resources program and the Office of the Senior Vice President for Research.

Friends of Doernbecher research grant applications deadline extended, Feb. 17

Friends-of-Doernbecher-300x72Friends of Doernbecher, a volunteer organization that raises funds for Doernbecher Children’s Hospital at OHSU, seeks proposals for pediatric-related research projects and programs. The grant program, which provides up to $175,000, is open to any employee of OHSU or Doernbecher proposing research related to children’s health. This includes (but is not limited to) OHSU and Doernbecher faculty, clinical and research staff, graduate students, medical students, fellows, and postdoctoral fellows. The deadline to submit applications have been extended to February 17, 2017.

View program guidelines and application instructions here.

For questions, contact Cassady Kennebeck at at 503-220-8344 or kennebec@ohsu.edu.

OCTRI announces 2017 Biomedical Innovation Program award recipients

The Oregon Clinical & Translational Research Institute has awarded three investigators grants through its Biomedical Innovation Program. The Biomedical Innovation Program aims to cultivate, select and provide strong program management for promising translational projects that develop new biomedical devices, diagnostics, and software. The primary objective of the program is to help bring innovative technologies from academia to the marketplace and thus to make a meaningful impact on human health.

The Biomedical Innovation Program is a collaboration between OCTRI and OHSU Technology Transfer and Business Development (TTBD), with additional funding and support from industry partners, Welch-Allyn and GE Healthcare.

Congratulations to our 2017 Biomedical Innovation Program Pilot Award Winners:

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David Huang, M.D., Ph.D., Peterson Professor of Ophthalmology, Professor of Biomedical Engineering 

Dry Eye Treatment Device (abstract pending)

 

 

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David Sheridan, M.D., Department of Emergency Medicine

Wearable Monitoring for Mental Health Patients

 

 

 

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David Simons, M.D., Ph.D., Glaucoma Fellow, Casey Eye Institute

Glaucoma Tube Implant with Modulated Flow

 

 

 

 

“The Biomedical Innovation Program meets a critical need at OHSU by funding promising early stage and potentially marketable technologies,” said OCTRI Director David Ellison, MD. “This funding, along with project management and mentorship, helps move the needle substantially, to put these technologies in the best possible position for commercialization where they can ultimately improve patient outcomes. We are very excited to fund these new technologies for 2017, and look forward to working closely with the investigators.”

Detailed information on all three awards, including project abstracts, is on the OCTRI website.

 

 

Vaccine technology developed by OHSU researchers acquired by industry

Louis Picker, M.D., of the OSHU Vaccine and Gene Therapy Institute. (OHSU/Boone Speed Photography)

Louis Picker, M.D., of the OSHU Vaccine and Gene Therapy Institute. (OHSU/Boone Speed Photography)

OHSU researchers made international headlines in 2013 when they published findings that their HIV vaccine not only controlled SIV, the nonhuman primate form of HIV, but cleared it in nearly 60 percent of the monkeys in the trial.

The HIV vaccine—developed by of a team of scientists at the OHSU Vaccine and Gene Therapy Institute that includes Jay Nelson, Ph.D.; Klaus Frueh, Ph.D.; Scott Hansen, Ph.D.; and Louis J. Picker, M.D.—has shown such promise in pre-clinical trials that it is headed to phase 1 human clinical trials next year.

The vaccine platform is based on a unique model that uses the common herpes virus cytomegalovirus, or CMV, as the viral vaccine vector to deliver a knock-out blow to the various pathogens. Importantly, this platform is not limited to fighting HIV. It has the real potential to fight the world’s deadliest diseases, from tuberculosis and hepatitis B to malaria and papillomavirus.

The technology has now been acquired by Vir Biotechnology, a San Francisco-based biotech startup backed by the Bill & Melinda Gates Foundation and ARCH Venture Partners. The deal involves Vir buying TomegaVax Inc., an OHSU spinoff that holds the rights to the vaccine technology. This is a taken a critical step in translating a basic science concept pioneered at OHSU into a portfolio of commercial vaccines.

Research at VGTI was first made possible through a state-funded Oregon Opportunity Grant. The research has since been funded primarily through grants from the National Institutes of Health’s National Institute of Allergy and Infectious Disease, and the Bill & Melinda Gates Foundation, which has committed $46 million in grants to support Picker’s work at VGTI.

People Management for Principal Investigators, Mar. 10-11

Every principal investigator wants to build and maintain a lab that attracts and retains outstanding trainees and staff members. Juggling this endeavor with everything else the PI must do – writing papers, teaching, mentoring, gaining and maintaining funding, creating collaborative and productive relationships with other PIs – can be challenging at best. This 1.5-day course, led by Melanie Erskine and Rachel Dresbeck from the Office of the Senior Vice President for Research, will help you learn to manage people with a focus on the particular needs of running a lab or research group.

When: Friday, Mar.10, 9 a.m. to 5 p.m. and Saturday, Mar. 11, 9 a.m. to 12 p.m.
Location: School of Nursing, room 116
Register on Compass

In this course you will learn:

  • Strategies for approaching the role of “coach” in the lab – developing your leadership style
  • Recruitment and retention strategies – building (and maintaining) the best team for your lab
  • Steps to take when coaching doesn’t work – performance management in the lab
  • Resources that are available to you to support you and your lab staff

Enrollment is limited; there is no cost to participants.

NRSA application workshop: Technical components, Feb. 21

If you’re planning to apply for a pre- or post-doctoral NRSA fellowship from the NIH in the near future, we encourage you to attend this workshop to learn about essential, non-research elements of your fellowship application. Topics covered include elements needed for an InfoEd proposal, how to develop a budget, how to manage reference letters, biosketches and PMCID numbers, and elements of a great training plan.

This upcoming workshop is led by Johanna Colgrove, coordinator of the MD/PhD program, Gavin Hamilton, grants and contracts administrator with the Office of Proposal and Award Management, and Rachel Dresbeck, Ph.D., director of Research Development and Academic Communications.

NRSA Application Workshop
Tuesday, Feb. 21
10:30 a.m. to 12 p.m.
Biomedical Information Communication Center (BICC), room 124

Open to researchers and administrators. Registration now available on Compass.

Upcoming deadlines for Collins Medical Trust

The Collins Medical Trust is a local foundation that provides up to $30,000 three times a year to faculty and postdoctoral fellows. The purpose of these awards is to aid, further, promote and develop research related to the cause, cure, and treatment of human diseases. The Trust typically provides seed funding for projects that will be eligible for NIH or other substantial funding. Successful proposals will impact the heath of Oregonians, but also have the potential impact the research nationally. Young investigators applying should describe their relationship with a mentor to demonstrate they have guidance in their work.

OHSU can submit up to 15 applications for each deadline. Instead of accepting applications on a first-come, first-served basis, interested applicants will have a one-week window to submit a Notice of Intent Form to the OHSU Foundation. If multiple submissions are received from one department, the department  may be asked to determine which application will move forward. Preference will be given to applicants that have not recently received Collins Medical Trust funding. Resubmissions are not encouraged.

Upcoming deadlines:

The Notice of Intent window is February 3-10. Please note that NoIs will only be accepted during this window. If you have already submitted an NoI, you will need to resubmit during the submission window. Full applications are due to OPAM by April 10 and must be sent to the OHSUF by April 21. The Collins Medical Trust deadline is May 1.

If you are interested in submitting an application for an upcoming deadline, the first step in the process is to fill out the OHSU Foundation Notice of Intent Form, which can be found on the Collins Medical Trust O2 page along with policies and procedures and frequently asked questions.

 

Save the date: Research Week 2017

FPP 21469239 Research Week 2017 ART RGBMark your calendars for the event of the year: OHSU Research Week. Our annual celebration of research performed by faculty, students, research staff, postdocs, and others across all schools, centers, institutes, and education programs will take place May 1 through 3, 2017.

A call for abstract submissions is coming soon. More details about keynote speakers, presentations, and opportunities to connect with colleagues, students, and people from other areas of the institution are being solidified now. Questions or ideas? Contact the planning committee at researchweek@ohsu.edu.

Participate in FASEB survey on shared research resources

FASEBYou’re invited to participate in a national survey on research cores. Much of the life-changing research conducted at OHSU is made possible by the university’s more than 20 research cores. Crucial research activities are supported by state-of-the-art equipment, advanced techniques, and specialized expertise in cores ranging from the Cytogenetics Core Laboratory and Biostatistics & Design Program to Proteomics and Massively Parallel Sequencing.

The shared research resources model facilitates research activities at institutions around the world. Providers and users of shared research resources in the United States have been invited by the Federation of American Societies for Experimental Biology participate in a survey of their experiences with shared resources. FASEB is a significant policy voice of biological and biomedical researchers and the survey will inform the organization’s policy discussions and future activities related to shared research resources.

FASEB encourages researchers to share the survey link with their colleagues and collaborators.

The survey is open to providers and users of shared research resources in the United States and takes 10 to 15 minutes. Topics in the survey range from resource utilization and unmet needs to careers in resource provision and development as well as training on best practices.

Responses should be submitted by March 2.

 

Shared instrumentation funding, internal applications due Mar. 17

Last week, NIH released three RFAs related to shared instrumentation. The Shared Instrument Grant Program (S10) provides groups of NIH-supported investigators funds to purchase or upgrade shared equipment costing up to $600,000. The High-End Instrumentation Grant Program is specifically designed to fund instrumentation that costs at least $600,000 with a maximum award of $2 million. Types of instruments supported include, but are not limited to, X-ray diffraction systems, nuclear magnetic resonance (NMR) and mass spectrometers, DNA sequencers, biosensors, electron and confocal microscopes, cell-sorters, and biomedical imagers.

New this year: The Shared Instrumentation for Animal Research (SIFAR) Grant Program provides $20,000 to $750,000 to purchase or upgrade scientific instruments necessary to carry out animal experiments.

OHSU is not limited in the number of applications we may submit, provided the applications are for different types of equipment; however, internal review is required. A minimum of three major users who are PIs on active NIH research grants must be identified.

Internal coordination: To apply, you must submit a brief 1-3 page preliminary proposal to Sue Aicher, Ph.D., who is coordinating the review process, by Friday, March 17, 2017. External applications are due May 31, 2017. Your email should include the following:

1. What instrument will be requested, and why it is needed
2. Cost of the instrument, including vendor quote
3. Cost of maintenance contract
4. Where the instrument will be located
5. Major user group info (group of at least 3 scientists with qualifying federal funding at time of the award)
6. Institutional support

Proposals will be evaluated based on whether the instrument will enhance the proposal research, whether there is a good match between the proposal science and the requested instrument, the justification of need, the organization of the project, continuing commitment to the instrument, and the benefit to the overall research community.

Contact Sue Aicher for more information.

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