Grompe lab discovery offers new clues to diabetes causes and treatment

Diabetes affects nearly 30 million people in the United States. The disease is caused by dysfunction or loss of insulin-producing beta cells that normalize blood sugar levels in the body. Until now, only one type of beta cell was known to exist. But OHSU researchers have developed a method allowing them to identify and isolate four separate subtypes that differ in their susceptibility to metabolic stress and their capacity to proliferate or change from one cell type to another. The results of their research, published July 11 in Nature Communications, may provide new and important avenues for research and treatment of diabetes.

“This study marks the first description of several different kinds of human insulin-producing beta cells,” said Markus Grompe, M.D., principal investigator, director of the Oregon Stem Cell Center at OHSU and the Papé Family Pediatric Research Institute at OHSU Doernbecher Children’s Hospital. “Some of the cells are better at releasing insulin than others, whereas others may regenerate quicker. Therefore, it is possible that people with different percentages of the subtypes are more prone to diabetes. Further understanding of cell characteristics could be the key to uncovering new treatment options, as well as the reason why some people are diabetic and others are not.”

The paper, “Human islets contain four distinct subtypes of cells,” was supported by the National Institutes of Health (Grant #s DK105831 and DK089569) and the Helmsley Trust. Craig Dorrell, Ph.D., and Grompe co-wrote the manuscript. Additional researchers from OHSU, the University of Pennsylvania School of Medicine, and the University of California, San Francisco contributed to this study.

Proposal development webinar for clinical, population, and comparative effectiveness researchers, July 8

Are you an investigator in clinical, population or comparative effectiveness? Do you want to learn more about developing successful proposals to move your research forward? Come hear from experienced scientific investigators who are part of Accelerating Data Value across a National Community Health Center Network, or ADVANCE.

The ADVANCE Clinical Data Research Network is led by Oregon Community Health Information Network, or OCHIN, in partnership with Oregon Clinical & Translational Research Institute, Health Choice Network, and Fenway Health. The goal of the Clinical Data Research Network is to build and maintain a “community laboratory” of Federally Qualified Health Centers serving safety net patients, including the uninsured, the under-insured, undocumented immigrants, and other vulnerable populations. The Research Data Warehouse maintains data on over two million patients and is the nation’s most comprehensive dataset on care and health outcomes in safety net patients. Research conducted in this dataset has the potential to address myriad questions about improving care quality and outcomes among our nation’s most vulnerable patients.

Friday, July 8
Noon to 1 p.m.
Register here.

During this webinar you will:

  • Hear from investigators whose proposals for comparative research funding have been successful
  • Learn more about using the ADVANCE data warehouse
  • Network with other investigators in the ADVANCE network
  • Ask specific questions pertaining to your research and barriers to successful proposal development

New services for OHSU entrepreneurs

Entrepreneurs at OHSU: you now have access to technology development resources via a new agreement with Virogenomics BioDevelopment, a 2015 spin-off of OHSU and Virogenomics, Inc. Working with universities across Oregon, biotech companies, and national institutions, Virogenomics brings together the scientific, regulatory, and funding components necessary to move technology out of the lab and into the marketplace. The idea is to help investigators find solutions to common problems such as applying for and managing STTR/SBIR grants, obtaining independent analyses of technologies and markets, and creating commercialization pipelines. The expectation is that the STTR/SBIR services will be especially helpful for OHSU entrepreneurs because it allows them to apply for funds without the complications and risk of creating a new business with an unproven technology.

Through this collaboration, both OHSU and Virogenomics BioDevelopment are working together to identify technology projects of mutual interest. OHSU researchers who are developing early-stage technologies and want to obtain funding to move forward are the ideal beneficiaries of this partnership.

Virogenomics BioDevelopment’s portfolio includes the spin out of four startup companies. One of these is OHSU spinout Artielle ImmunoTherapeutics, a privately-held, clinical-stage pharmaceutical development company. Under their management, Artielle has raised $19 million in venture financing to complete a Phase 1 clinical trial to treat multiple sclerosis.

For more information about this collaboration, please contact Andrew Watson, Ph.D., director of technology transfer, at watsonan@ohsu.edu or 503-494-8309.

Cyagen Biosciences to present on new rapid generation technology, July 12

Marvin Yingbin Ouyang, Ph.D., vice president of technology at Cyagen Biosciences, Inc., will present “CRISPR/Cas9 and TurboKnockout: Technologies for rapid generation of knockout/knockin mouse models,” sponsored by Cyagen Biosciences.

Tuesday, July 12
noon to 1 p.m.
OHSU Auditorium
Marquam Hill

Dr. Ouyang will review the traditional model of pronuclear injection based transgenics and ES cell homologous recombination based gene targeting, and go over the recently developed CRISPR-mediated genome editing technology, with an emphasis on the pros and cons of each technology and their applications. He will introduce TurboKnockout, the newest ES-cell based gene targeting technology which allows the generation of conditional knockout/knockin mouse models in as fast as six months. This presentation will also highlight VectorBuilder, a novel online tool which promises to revolutionize the way DNA vector cloning is done.

OHSU researchers visualize architecture of the TARP complex

Glutamate receptors are the most prevalent molecular “switches” mediating communication between nerve cells in the brain. They play keys roles in nearly all human behaviors, from learning to memory and movement, as simply a few examples.  Glutamate receptors are also the targets of a broad range of therapeutic agents, from anti-seizure medications to antidepressants.

Glutamate receptors do not function alone, however: they form complexes with other proteins called transmembrane AMPA-receptor regulatory proteins, or TARPs. These accessory proteins modulate the properties of the receptor and are made in different regions of the brain, thus giving rise to brain-region-specific receptor function. How glutamate receptors interact with TARPs has been a long-standing question.

In a Nature paper, published online on July 1, 2016, OHSU researchers from the Vollum Institute and the Department of Biomedical Engineering in the School of Medicine, describe the long sought after structure of a glutamate receptor – TARP complex, thus showing how the proteins interact with each other. The team led by Eric Gouaux, Ph.D., Yan Zhao, Ph.D., and Shanshuang Chen, Ph.D., used x-ray crystallography and single particle cryo-electron microscopy (cryo-EM) to capture images of the TARP structure. Their findings offer clues into how TARPs modulate receptor function and provide a template for receptor – TARP specific design of novel small molecules, entities that might prove useful as therapeutic agents.

Drs. Zhao and Chen, both postdoctoral researchers in the Gouaux Lab, contributed equally to the research reported in “Architecture of fully occupied GluA2 AMPA receptor–TARP complex elucidated by cryo-EM.” In addition to Eric Gouaux, Craig Yoshioka, Ph.D., from the Department of Biomedical Engineering and Isabelle Baconguis, Ph.D. from the Vollum Institute, contributed to this paper.

Shanshuang Chen is supported by an American Heart Association postdoctoral fellowship (16POST27790099).This work was supported by the NIH (Eric Gouaux, NS038631). Eric Gouaux is an investigator with the Howard Hughes Medical Institute.

2016 BIP Drug Discovery awardees announced

The Oregon Clinical & Translational Research Institute and OHSU Technology Transfer & Business Development are pleased to announce the funding of two Biomedical Innovation Program  drug discovery awards. A new track supports drug discovery platforms and early stage therapeutic technology projects, including validation of drug targets and the development of small molecules, antibodies, vaccines, or biologics. The BIP provides funds, project management, and mentorship to facilitate the development of innovative technologies at OHSU, and accelerate their translation from academia to the marketplace.

Congratulations to the 2016 BIP Drug Discovery awardees:

penny

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Penny Hogarth, M.D. –Associate Professor, Molecular & Medical Genetics: Fast-track CoACT

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Xiao2_2
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Xiangshu Xiao, Ph.D. – Associate Professor, Physiology & Pharmacology, Knight Cancer Institute:
Novel lamin-binding ligands for the treatment of triple negative breast cancer

 

“I am thrilled to see the BIP expand and meet the need of support for early-stage drug discovery research at OHSU,” says OCTRI Director David Ellison, M.D. “By prioritizing commercialization outcomes, the BIP helps position technologies such that they have the best possible chance of making it to market and improving human health.”

Detailed information on both awards, including project abstracts, can be found on the OCTRI website. For more information on other OCTRI’s other research support services, please visit: www.octri.org.

OCTRI is supported by (UL1TR000128) from the National Center for Advancing Translational Science (NCATS) at the National Institutes of Health (NIH).

Learn about new technologies and sequencing services in the Integrated Genomics Lab Cores

Join Bob Searles, Massively Parallel Sequencing Shared Resource, and Chris Harrington, Gene Profiling/RNA and DNA Services Shared Resources, who will discuss new genomics technologies available in the cores. Among the new services to be discussed: RNA-seq from FFPE tissue, miRNA sequencing, high throughput DNA and RNA extraction, cell-line authentication, and single cell RNA-seq. All members of the OHSU community are invited to attend.  The Integrated Genomics Lab cores are members of the OHSU University Shared Resources Program.

Thursday, July 7
10 to 11:30 a.m.
Rirchard Jones Hall, room 4320

The presentation will last an hour followed by 30 minutes of Q & A.

Who’s new at OHSU? Sudarshan Anand

Sudarshan Anand, Ph.D., is an assistant professor in the School of Medicine’s Departments of Cell, Developmental & Cancer Biology and Radiation Medicine. He arrived at OHSU in March 2014 and is one of a team of researchers at OHSU examining factors that shape the tumor microenvironment.Anand, Sudarshan

Where are you from originally and what shaped your early career?
I was born and raised in India and came to the U.S. in 2001 for graduate school. I started out the University of Maryland in cell biology but quickly realized I wanted to work in immunology, so I moved to the Mayo graduate school and worked with Dr. Lieping Chen. When I joined his lab, he had just discovered PDL1, which is involved in the immune response to tumors. When Dr. Chen moved to Johns Hopkins, I went with him. I joke that my Ph.D. degree comes with standard error bars because I did it three times! After graduate school, my mentor told me that if I wanted to do cancer research, I needed to expand beyond immunology, and I took that to heart so I completed my postdoc working with David Cheresh at UCSD who is an expert on tumor blood vessels (angiogenesis). This experience shaped my future research.

What brought you to OHSU?
When I was looking for a faculty position, I knew OHSU would be the right place to start the research program I wanted to build. My decision was based on a combination of faculty expertise and the institutional culture here. I love the vision of my chair Dr. Lisa Coussens in building a unique research hub centered on the tumor microenvironment. I also greatly appreciate the collaborative nature of OHSU. I’ve had help from a number of people in starting my lab, recruiting staff, getting clinical samples. It’s particularly unique to have access to this expertise and the amazing resources here as a junior faculty member. Also, this is a rather special moment for the Knight Cancer Center. It’s great to be participating in the process of rapid growth of an institution.

What is the current focus of your research?
The major focus of our lab is in understanding small RNAs or microRNAs in blood vessels and how they respond to DNA damaging agents such as radiation. Primarily we’re looking at blood vessel cells in cancer; they’re a unique species. In adults, blood vessel cells rarely divide because we don’t have the need to build new ones unless an area is affected by injury. But blood vessel cells in cancer, by nature of what they’re supplying, constantly divide and don’t have enough time to form properly. So these vessels are irregular and often not good at delivering blood. This creates a problem for a couple of reasons – one, you decrease the oxygen being delivered to the tumor. Under these conditions, any normal cell would starve and die but cancer cells have special adaptations that make them more aggressive in that situation. Cancer cells starved of metabolic pathways, tend to be the ones that metastasize and travel to distant targets. Two, once you have lower perfusion in the tumor, chemotherapy drugs don’t get to all the cancer cells and radiation therapy doesn’t work as effectively.

Why study microRNAs?
Generally microRNAs are small RNAs encoded in our genomes that function to decrease gene expression and protein output in cells. But many of the targets of these microRNAs are in a related pathway, so if you take away 25% of protein A, B and C, but A, B and C function in the same pathway, you have a geometric progression of effects, and the whole pathway is significantly impacted. So we have done a number of microRNA profiles of blood vessel cells (endothelial cells) and have developed 1-2 microRNA candidates that appear to have significant biological effects in mouse tumor models.

Now our goal is to a) understand these microRNAs – to find out if they play a role in response to certain therapies and b) identify if we can use some of them for diagnostic purposes. The hope is that we will be able to develop predictors, for example, in blood to know which patients will and will not respond to specific therapies. And if they’re not going to respond, we can put them on an alternative therapy and save them from side-effects of radiation exposure or specific chemotherapies. This is the focus of a project we’re doing in collaboration with Dr. V Liana Tsikitis, an associate professor of surgery here at OHSU. She has a cohort of patients with rectal and colorectal cancer. Many patients with this type of cancer receive radiation to shrink the tumor and then surgery to remove it. But roughly 30% of patients don’t respond to the radiation. If we can predict which patients will not respond from a biopsy, we may be able to avoid radiation toxicities or have them on other therapies to shrink the tumor before surgery. So we’ve done microRNA profiles on biopsies of patients who have and have not responded to chemoradiation and generated some preliminary data that suggest we’ll be able to identify meaningful signatures. We hope to eventually move this to a Phase I trial.

View SnapshotTherapeutic application is a few years away but we’re moving in the direction of manipulating the microRNAs in blood vessel cells to potentially shift the balance by either inducing more cell death or preventing blood vessel cells from dying. If we found 3 or 4 microRNAs were lower in patients who responded better to a specific treatment, can we knock it down in a cell culture in tumors where there is poor response and convert these tumor cells into better responders? There is a lot of excitement in the field right now because the first phase I trial to test the premise that you can inject microRNA agents into patients, get them into cells, and have them well tolerated and safe is already underway.

One of the more advanced projects we’re working on is examining a microRNA that targets a protein implicated in lupus, a disease characterized by a particularly strong autoimmune response against the body’s own cells. What we’re trying to do is essentially create lupus in the blood vessel cells of a tumor. This is a high-risk strategy because you want the delivery specific to the blood vessels in the cancer, not throughout the body. So, we’re working with a collaborator at MIT who has created a nanoparticle that delivers only to blood vessel cells, and this particular microRNA only works in dividing blood vessel cells. Again, since most normal blood vessel cells are not dividing at any given moment, this mitigates some toxicity concerns. But we are always on the look out to deliver RNAs precisely to different cells that are within a tumor.

lab-lunch-2016

Anand lab members enjoying time away from the bench.

If you had no constraints on resources, what research problem would you try to solve?
Without a limit on resources and technology, I believe we would tackle cancer in a different way. We would engineer cells or even nanoparticles to spy on tumors, report what’s going on at all times, and equip them with the ability to take action and kill cancer cells. It’s like designing the “James Bond” of cells. As an example of what I mean by reporting: cells could be programmed to produce a synthetic molecule when triggered by enzymes shed by cancer cells. Imagine if this molecule would show up in, say, urine or blood long before a metastasis shows up on a scan. Patients with a high risk of recurrence or relapse could have simple, at-home diagnostic tests they can use once a week, and if they see a signal, schedule a visit for follow-up. This could become a reality in a decade or so.

Tell us something about yourself that’s not on your resume
One thing that really influenced my decision to pursue a career in science was the opportunity I had to do research in a lab early on, even as a high school student. So I’m very committed to outreach and communicating the excitement of science. I have two summer interns and a high school student in the lab. In addition to teaching them to do the science, we also try to teach them how to communicate science and work in teams, understand career paths in science etc. It’s never too early to be introduced to these concepts.

Outcomes for second-time R01 resubmissions

It’s been over two years since the NIH revised their grant resubmission policy. This revision allows applicants whose R01 application (called an A0) and subsequent resubmission (an A1) are unsuccessful to submit a new application without having to demonstrate significant changes in scientific direction from the previously reviewed applications. When the policy went into effect in April of 2014, there was a sigh of relief but also uncertainty about how these “new” applications, now referred to as “virtual A2s,” would fare.

In a June 24 Open Mike blog post, NIH’s Deputy Director for Extramural Research, Michael Lauer, analyzes the data, showing the changed policy has slightly increased the success of second-time revisions.

Events-after-Unfunded-A1-Virtual-A2-analyses-for-final-blog

Events following unfunded A1 applications. Baseline: unfunded R01 applications in FY2014; subsequent application: at least one R01 or R21 application submitted by a PI in the baseline group; “virtual A2”: at least one subsequent application/award with text that significantly matched with the baseline group; “nonmatching”: at least one subsequent application/award without a significant text match in the “baseline” group. June 24, 2016 Open Mike.

Lauer and his team used text-mining software to identify these virtual A2s and to describe their review outcomes compared to other submissions from the same investigators. Following is a summary of their findings:

  • Investigators are taking advantage of the new policy. For about 22% of unsuccessful A1 applications, NIH receives a materially similar subsequent submission, a virtual A2;
  • PIs were more likely to submit a virtual A2 if their unfunded A1 had been discussed and received relatively favorable scores;
  • Investigators who fail to obtain funding on an A1 remain active. 80% of the PIs with unsuccessful A1 applications submitted at least one application within the following fiscal year;
  • New investigators are less likely to submit virtual A2s; and
  • Of the cases in which at least one virtual A2 application was submitted, 20% had at least one application funded.

 

Limited submission funding process refresher

Faculty and departments have recently been asking “What should I do when I’m applying for a grant and I notice that only one application is accepted per institution?” To clarify what’s involved in identifying and applying for limited submission funding opportunities, the following information should help those of you who are new to the process and anyone else who may need a refresher.

What is a limited submission?
Limited submission funding opportunities are programs in which the sponsor sets a limit for the number of applications or proposals an institution can submit (typically 1 to 2). Institutional coordination is required to ensure fairness, transparency, and adherence to the sponsor’s requirements.

How are applications or proposals selected by the institution?
OHSU’s Limited Submission Program is a service of the Office of the Senior Vice President for Research to help faculty identify limited submission opportunities and to coordinate internal reviews. The review process is conducted by OHSU’s Limited Submissions Committee, composed of 10 senior faculty members, which makes recommendations to the SVPR regarding which applications should move forward as proposals to external sponsors. Internal applications are ranked according to criteria established by the sponsor as well as on the merit of the proposal and principal investigator.

How do I know if a funding opportunity is a limited submission?
All limited submission opportunities are posted on the OHSU Internal Funding Database. You can identify these opportunities in the “Internal Coordination” column when you search the database:

internalfundingdatabase-screenshot

As a general rule, it’s advised to check the eligibility criteria provided by the sponsor in the Request for Proposals or Applications (RFP or RFA) before working on a submission. This is where you’ll find the most complete information on PI requirements and whether the sponsor is limiting the number of applications OHSU may submit.

How do I submit a limited submission application for consideration?
Refer to the OHSU Internal Funding Database to determine the deadline for submitting your internal proposal. This deadline is set roughly four to eight weeks before the sponsor’s external deadline to allow time for review and for the nominated PI(s) to prepare a full proposal. Interested candidates must complete an application via the Competitive Application Portal (CAP). This online application provides basic information for the review and selection process. You will attach the following materials to your application:

  • Curriculum vitae (CV) or Biosketch
  • 1- to 5-page summary of candidate’s research proposal– This document can be written in NIH style but should be written in a manner readable by a group of educated interdisciplinary scientists. Avoid using jargon, and assume that no reviewers are specialists in your field.
  • Letter of support/recommendation from a department head, chair, mentor, or other appropriate person. In many cases, this letter is optional, but the review committee finds letters helpful. The letter should detail your strengths and can be used in your full application, if selected to submit.

If you have any questions on the limited submission process, please email funding@ohsu.edu or call 503 494-0107.

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