OHSU researchers reveal atomic structure of a key molecular receptor

The receptor proteins of a cell’s surface are important transmitters of signals between its internal and external environments. The P2X integral membrane proteins, first defined in 1976, modulate processes as diverse as platelet activation, smooth muscle contraction, synaptic transmission, inflammation, hearing and taste, making P2X receptors important pharmacological targets.

P2X receptors are activated by ATP, a major intracellular energy source, resulting in a change in the receptor’s structure and the flow of ions such as sodium and calcium into the cell. The mechanisms of receptor desensitization and the complete structures remain unclear, but OHSU scientists have, for the first time, determined the structure of a P2X receptor in the desensitized state. The team created X-ray crystal structures of the human P2X3 receptor including in open, resting, and desensitized states. Results of their study, “X-ray structures define human P2X3 receptor gating cycle and antagonist action” were published in the journal Nature on Sept. 14, 2016.

“Before our structures, nobody understood the mechanisms by which the receptor opened its pore and then transitioned to a desensitized state,” said lead author Steven Mansoor, M.D., Ph.D., a cardiology fellow in OHSU’s Knight Cardiovascular Institute and Vollum Institute.

“It’s a lot easier to make a new key if you know what the lock looks like,” said corresponding author Eric Gouaux, Ph.D., a senior scientist in the OHSU Vollum Institute and a Howard Hughes Medical Institute investigator. “It’s definitely going to make translational research possible that was not possible before.”

These structures illuminate the conformational rearrangements that underlie P2X receptor gating and provide a foundation for the development of new pharmacological agents for the treatment of conditions including high blood pressure and early formation of blood clots.

Additional authors include Wei Lu, Ph.D., of the Vollum Institute; Wout Oosterheert, now with Utrecht University in The Netherlands; and Mrinal Shekhar and Emad Tajkhorshid, Ph.D., of the Center for Biophysics and Quantitative Biology and Beckman Institute for Advanced Science and Technology, respectively, at the University of Illinois at Urbana-Champaign.

This research was supported by the National Institute of General Medical Sciences (5F32GM108391 to S.E.M and R01GM100400 to E.G.).

OHSU researchers reveal mechanism of neuronal activity that controls fertility

Reproductive function is a highly regulated process that depends on certain hormones interacting in a controlled and rhythmic manner.  The hypothalamus and pituitary together control pubertal development and fertility; the hypothalamus releases a chemical messenger called gonadotropin-releasing hormone, which attaches to specific receptors of the pituitary gland, in turn releasing reproductive hormones that control ovulation in females and sperm production in males.

In females, the hypothalamus releases GnRH in appropriately timed pulses and in one massive release, or “surge”, of GnRH to trigger ovulation. Sets of neurons in the hypothalamus that produce a protein called kisspeptin play an essential role in this process. One population resides in an area called the arcuate nucleus and the other in the preoptic nucleus. Recent studies suggest the arcuate nucleus is responsible for triggering the rhythmic release of GnRH, whereas the preoptic nucleus induces the surge of GnRH. However, the mechanics of how this is achieved in each brain region remained unclear.

Using a technique called optogenetics, researchers from OHSU and the University of Washington explored whether kisspeptin-producing neurons in the arcuate nucleus are able to communicate with each other to drive pulses of GnRH ion mice.  The team genetically modified the mice to express a light-sensitive ion channel protein in their kisspeptin neurons, allowing them to activate these neurons with beams of light. As predicted, this caused kisspeptin neurons throughout the arcuate nucleus to coordinate their activity. Stimulation of the arcuate nucleus also triggered release of excitatory and inhibitory peptides, which synchronized the firing of the neurons. These findings provide a cellular model for previous findings that correlated burst firing activity of arcuate nucleus neurons with serum LH pulses in several species including nonhuman primates.

The light-induced stimulation also triggered the release of the neurotransmitter, glutamate, which caused kisspeptin neurons within the preoptic nucleus to fire in bursts. This in turn excited the GnRH neurons. Together, these findings show that kisspeptin neurons in both areas of the brain coordinate their activity to stimulate the release of GnRH from the hypothalamus, consequently controlling fertility. A future challenge is to investigate in living animals whether the cellular model translates into pulses of GnRH and LH, and that activation of arcuate kisspeptin neurons participate in the generation of the GnRH and LH surge. Therefore, these results set the stage for further exploration of the kisspeptin-GnRH neuronal circuits, and to obtain insights into the role of neuronal peptide signaling in healthy as well as diseased states.

High-frequency stimulation-induced peptide release synchronizes arcuate kisspeptin neurons and excites GnRH neurons,” was published on Aug 23, 2016 in the journal eLIFE. OHSU’s Jian Qiu, Ph.D., research assistant professor in the Department of Physiology & Pharmacology, and Casey C. Nestor, Ph.D., joint postdoctoral researcher in the Kelly/Rønnekleiv Labs, are co-first authors  on the paper. Martin J. Kelly, Ph.D. and Oline K. Rønnekleiv, Ph.D. are joint senior authors. Other contributors are Chunguang Zhang, Ph.D. a senior research associate in the Rønnekleiv/Kelly labs, and Stephanie L. Padilla, Ph.D. and Richard D. Palmiter, Ph.D. from the Department of Biochemistry, Howard Hughes Medical Institute, University of Washington, Seattle.

This research was mainly funded by National Institute of Health (NIH) grants R01-NS38809 (MJK), R01-NS43330 (OKR), R01-DK68098 (MJK and OKR) and F32 DK104366 (CCN).

 

Assessing scientific productivity: A new metric

Publication data – journal impact factors, number of first author publications, prestige of the journal – are commonly used to assess research productivity. But the metrics used to generate these data have substantial limitations. H-index, which looks at the cumulative impact of scientists’ work, disadvantages junior researchers; citation habits and dynamics can be vastly different in different research fields. Alternative methods for quantifying scientific accomplishment are under development, and though many of them have improved our understanding of citation dynamics, none have been widely adopted.

Open Mike blog, Sept. 8, 2016

Open Mike blog, Sept. 8, 2016

A group of NIH researchers is now entering this field. They developed a metric, the Relative Citation Ratio, that normalizes across different fields, institution types, and geographic regions, allowing apples-to-apples comparisons of a paper’s impact. “The goal of the Relative Citation Ratio is to quantify the impact and influence of a research article both in the context of its research field and benchmarked against publications resulting from NIH R01 awards,” according to Michael Lauer, NIH deputy director for extramural research, in his Sept. 8 Open Mike post.

The NIH researchers introduced the algorithm they developed to calculate the RCR in a recent article published in PLOS Biology. To illustrate the algorithm, an “article of interest” is cited by a number of articles. These citations can be counted over time to yield an “actual citation rate.” These citing articles also cite other articles which the authors call the “co-citation network.” This network of papers can be assumed to reflect the citation dynamics of a particular research field (or fields) of the article of interest. From these data, a “field citation rate” can be calculated that can be compared to the actual citation rate, yielding the RCR.

The authors also demonstrate using the RCR to quantify how past influence predicts future performance, but how accurate is this metric in establishing scientific quality? Three separate studies were used to compare expert peer review ratings of papers and the RCR. In all three cases, there was a strong association.

Figure 9 – RCRs correspond with expert reviewer scores. From Hutchins, et. al, (2016) Relative Citation Ratio (RCR): A New Metric That Uses Citation Rates to Measure Influence at the Article Level. PLoS Biol 14(9): e1002541. doi:10.1371/journal.pbio.1002541

RCRs correspond with expert reviewer scores. From Hutchins, et. al, (2016) Relative Citation Ratio (RCR): A New Metric That Uses Citation Rates to Measure Influence at the Article Level. PLoS Biol 14(9): e1002541. doi:10.1371/journal.pbio.1002541

The RCR measure is available here.

New research shows search and destroy function for leukemia cells

kurre-_pape-brochure-pic-2014The rapid growth of leukemia cells that “crowd out” healthy stem cells within the bone marrow has traditionally been considered the root cause for prolonged risk of infections and necessary blood transfusions. A study recently completed by a team of OHSU pediatric cancer biology researchers in the Pape Family Pediatric Research Institute – and published in the journal Science Signaling –  disputes this theory and provides the first description of leukemia cells’ ability to actively target and destroy healthy cells in bone marrow throughout the body. The identification of this process creates an opportunity for the development of new, targeted therapies to protect cells and potentially limit prolonged hospital and clinic admissions for leukemia patients.

Led by principal investigator Peter Kurre, M.D., the team discovered this process by identifying small vesicles, or exosomes, released from acute myeloid leukemia cells and their systematic study in mouse models. The leukemia vesicles circulate in the bloodstream and serve as messengers of small regulatory molecules, or microRNA. The research team showed that these vesicles act by degrading the machinery central to the function of healthy bone marrow stem cells and are unaffected by traditional cancer therapies.

Along with other studies in the field, this discovery suggests the effect of cancer may not be locally limited, but instead has the capacity to compromise healthy tissue function even before the spread of cancer cells.

 The paper, “AML suppresses hematopoiesis by releasing exosomes that contain microRNAs targeting c-MYB,” was supported in part by a grant from Hyundai Hope on Wheels. The research team included Kurre and members of his lab–Noah I. Hornick (co-first author), Ben Doron (co-first author), Sherif Abdelhamed, Kianya Huan, and Santhosh Chakkaramakkil Verghese–as well as OHSU faculty members  Christina A. Harrington and  Xiaolu A. Cambronne; and Rongkun Shen, from the College at Brockport, State University of New York.

NIH wants to hear from you

nhlbi-logo-septHelp shape the agenda of a planned future conference on coronary heart disease

In 1978, the Bethesda Conference on the Declining Mortality from Coronary Heart Disease brought together international experts from a wide range of disciplines and expertise to call attention to and illuminate the previously unappreciated and unexplained abatement of the epidemic of heart disease. Since then cardiovascular death rates have continued to decline sharply, and despite the huge growth in knowledge and advances in treatment, there remain many unresolved issues about this decline. The National Heart, Lung, and Blood Institute proposes to call another meeting to answer the big questions about the drivers of past changes and the likely trajectories in the future. To help plan this conference, the NHLBI is asking for comments and suggestions related to current and projected trends in cardiovascular disease within and between populations, modelling strategies to monitor disease burden and to examine various factors influencing disease prevalence such as socioeconomics.
Submit your comments by Dec. 31, 2016 here

niehs-logoContribute to the development of a translational research framework

The Division of Extramural Research and Training at the National Institute of Environmental Health Sciences drafted a translational research framework for environmental health sciences and is seeking input on the draft. The aim is to provide a framework that 1) represents the full spectrum of the research NIEHS grantees conduct, 2) captures all the nuances of environmental health research, especially at the more “basic” end of the research spectrum, 3) provides a common language for describing translational research in the environmental health sciences, and 4) promotes the telling of translational research stories in progress reports and other research documents. NIEHS is seeking comments on the applicability of the proposed translational research framework map to your translational research; benefits and challenges of the proposed framework, elements that are missing, other suggestions.
Submit your responses by Oct. 30, 2016 here.

NIH director to give annual Mark O. Hatfield Lecture, Oct. 24

The Director of the National Institutes of Health, Francis S. Collins, M.D., Ph.D, will be giving this year’s Mark O. Hatfield Lecture. The talk will examine recent advances in fundamental knowledge about biology—and highlight the ways in which that knowledge is serving to improve human health. Topics may include research developments at the NIH at the Mark O. Hatfield Clinical Research Center, the Precision Medicine Initiative, the Cancer Moonshot, and updates on Zika and other global health issues.
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Mark O. Hatfield Lecture

Monday, Oct. 24, 2016
7 to 8 p.m.
Collaborative Life Sciences Building
1st floor lecture hall, 1A001

Add to your calendar

Collins is a physician and geneticist known for spearheading the Human Genome Project and for his landmark discoveries of disease genes. He has also written a number of books on science, medicine, and religion.

The Mark O. Hatfield Lecture is a special presentation of the Marquam Hill Lecture Series, which features a variety of experts providing free lectures on topics that greatly impact the health of Oregonians.

 

Grand opening of Center for Radiochemistry Research, Sept. 20

The OHSU Knight Cardiovascular Institute cordially invites you to attend the ribbon cutting of the Center for Radiochemistry Research, the newest research building on Marquam Hill since the Biomedical Research Building opened in 2005. The center will provide OHSU scientists with a new suite of powerful imaging tools and expertise, including new labs, a cyclotron for isotope generation, and advanced imaging technology for preclinical and clinical research. The the facility and its resources will give OHSU the new capacity to develop radioactive isotopes to address specific research questions using real-time imaging.

Tuesday, Sept. 20, 2016
12:30 to 1:30 p.m.
Research Courtyard
Marquam Hill

Featured speakers include:

Joe Robertson, M.D., OHSU president
Sanjiv Kaul, M.D., chief executive officer, OHSU Knight Cardiovascular Institute
Jeanne Link, Ph.D., director, Center for Radiochemistry Research

Tours of the facility will be provided immediately following the program. Refreshments will be served.

Webinar on The National Microbiome Initiative, Sept. 16

nmiIn May of this year the White House announced a collaboration with various Federal agencies and private-sector stakeholders to foster the study of microbiomes, communities of microorganisms, across different systems. The National Microbiome Initiative supports interdisciplinary research, development of platform technologies, and expansion of the microbiome workforce with the aim of protecting and restoring healthy microbiome function.

sbertuzzi

Stefano Bertuzzi

Microbiomes live on or in people, plants, soil, oceans, and the atmosphere, but how do they impact human health? Join Research!America for a webinar led by Stefano Bertruzzi, Ph.D., M.P.H., executive director and CEO of the American Society for Microbiology, who will provide an overview of the NMI, and insight about the implications and opportunities that will arise from this massive undertaking.

“The Microbiome Initiative: A closer look”

Friday, Sept. 16, 2016
10:00 – 10:30 a.m. PDT

Register today.

 

NRSA application workshop: Technical components, Oct. 11

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, Oct. 11
11 a.m. to 1 p.m.

Mackenzie Hall 2136

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

TTBD expands entrepreneur-in-residence program

After a one-year launch, Technology Transfer and Business Development is expanding its entrepreneur-in-residence program. The program has recruited two additional entrepreneurs-in-residence to provide support to inventor teams and new companies that form when they license technology intellectual property from OHSU. The current entrepreneurs-in-residence, Richard Rylander and Robert Masterson, have helped inventors by saving them time and resources, performing faculty education and outreach, providing grant support, and executing management oversight and commercialization guidance. The new entrepreneurs-in-residence will join the program to continue identifying technologies with commercial promise and provide OHSU researchers with real-world insights about the commercialization process. The new entrepreneurs-in-residence begin their residency at OHSU on Sept. 14.

Rob-Arnold+Color

Rob Arnold, new OHSU entrepreneur-in-residence

Rob Arnold is a healthcare innovation advisor at the University of Washington and partner at Quad+Aim Partners, advising emerging-growth companies on business strategy, planning, and investment. Prior to UW, Arnold was CEO of Geospiza, Inc., a leader in cloud computing solutions for genetic analysis, which was sold to Perkin Elmer in May of 2011. Before that, he was CEO of Crossport Systems, a leader in internet security solutions, which was sold to Lineo/Metrowerks, a division of Motorola. Arnold also co-founded and was CEO of ST Labs, Inc., an international leader in software quality assurance and testing, which was sold to Lionbridge.

 

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Steve Runnels, new OHSU entrepreneur-in-residence

Steve Runnels has more than twenty-eight years of management experience in the healthcare industry. He has held the position of president and CEO of several startup biopharmaceutical companies in the US and Internationally. He was executive vice president and board member of publicly traded NeoTherapeutics, Inc. and vice president of marketing and business development at Sigma-Aldrich, a Fortune 500 company. Mr. Runnels is also an entrepreneur-in-residence at the University of Washington. Mr. Runnels holds a B.S. in cell biology and certification from the American Society of Clinical Pathology as a specialist in immunohematology. He is an M.B.A. and Ph.D. candidate in management.

To see a video of TTBD’s Lunch & Learn presentation on “How to start a company,” presented by entrepreneurs-in-residence, please click here.

For more information on the entrepreneur-in-residence program or to inquire about startup companies at OHSU, please contact Daphne Emerson at emersond@ohsu.edu.

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