OHSU researchers find cognitive dysfunction resulting from obesity, diabetes can be treated

Brief Reduction in Dietary Fat Improves Cognitive Dysfunction in Mice with Obesity and Type II Diabetes

OHSU researchers, led by Jacob Raber, Ph.D., have discovered that the cognitive dysfunction that that often results from obesity and type II diabetes can be treated.  The study reveals that even a brief reduction in dietary fat content in mice that are fed a high-fat diet for a substantial period of time led to a complete rescue of cognitive function.

Their findings, based on a mouse model, were published in the journal EBioMedicine.

After five months of subsisting on a high-fat diet, mice in this study developed multiple cognitive impairments, including deficits in novel object recognition, in cued fear memory and in spatial learning and memory. However, after giving the obese mice a low fat diet for an additional month, the researchers saw improvements in metabolism, and notably a full reversal in some of the cognitive problems and insulin signaling that they had developed.

Additionally, for the first time, researchers infused obese mice that had type II diabetes and cognitive impairments with “healthy” plasma from age-matched, low fat diet-fed mice to determine whether it would improve their cognitive abilities. Remarkably, infusions of “healthy” plasma were found to improve memory in obese mice that were fed a high fat diet, in spite of their continued consumption of high fat food.

With society facing twin tidal waves of an aging population at risk of developing Alzheimer’s disease and rising obesity rates – both of which are also risk factors for cognitive impairment and Alzheimer’s disease, this research casts new light on how certain cognitive impairments can be reversed.

To build on this foundation, researchers will next look at mice with genetic risk factors to develop age-related cognitive decline and Alzheimer’s disease.

Hope for MS patients through understanding roots of the disease in monkeys

New research led by Scott W. Wong, Ph.D., senior scientist, Vaccine and Gene Therapy Institute; interim division chief, Division of Pathobiology and Immunology at the Oregon National Primate Research Center; and professor, OHSU’s Department of Molecular Microbiology and Immunology, describes the similarities between multiple sclerosis and a unique, spontaneous paralytic disease that occurs in nonhuman primates. This model opens the door to discovering the mechanisms driving MS in humans.

The model, called Japanese macaque encephalomyelitis, or JME, is an inflammatory demyelinating disease that occurs in a colony of Japanese macaques at OHSU’s Oregon National Primate Research Center and causes the clinical symptoms of MS: decreased mobility due to leg weakness or paralysis, and vision problems. JME is the only spontaneously occurring MS-like disease in nonhuman primates in the world. Other nonhuman models of MS are artificially induced by immunizing animals with myelin or myelin proteins.

The study, “Immunopathology of Japanese macaque encephalomyelitis is similar to multiple sclerosis,” is published in the Journal of Neuroimmunology.

Researchers found that JME encompasses several key signatures that are associated with MS. These findings cast new light on the cause and progression of MS in humans, and will enable researchers to identify and target pathways to treat people with MS. These types of studies are not otherwise feasible in patients with MS.

The researchers sought to determine if JME possesses features of an autoimmune-like disease in the central nervous system. They found that the central nervous system of animals with JME contain active lesions that harbor many of the important immunological signatures observed in MS that hints to MS being an autoimmune-like disease.

The JME model also holds great potential for verifying imaging techniques being developed by researchers to visualize and measure remyelination in humans. This paper demonstrates that researchers will be able to image the brains of the Japanese macaques using MRI, study the pathology of the JME lesions and verify the usefulness of new MRI techniques for studying MS in humans. Many MRI techniques being developed for MS cannot be verified using rodents, but can be verified in monkeys.

The cause of MS remains unknown. Importantly, this study paves the way for future studies aimed at determining whether the causes of JME and MS are similar or even identical.

OHSU startup receives $11.45 million to help treat neurologic disorders

Thomas Scanlan, Ph.D.

Thomas Scanlan, Ph.D.

NeuroVia, Inc., an OHSU startup company, recently closed Series A equity financing, raising $11.45 million to support the company’s mission and commitment to developing therapeutics for the treatment of neurological disorders. Thomas Scanlan, Ph.D., professor of physiology and pharmacology and director of the OHSU program in chemical biology, is the founder of NeuroVia. Novartis Venture Fund, Sanofi-Genzyme Bioventures, and BioMed Realty Ventures participated in the Series A financing.

NeuroVia is committed to addressing unmet medical needs in neurological diseases. The company worked to develop a selective thyromimetic agent for the treatment of X-linked adrenoleukodystrophy (X-ALD), a genetic disease that primarily affects adolescent boys and young men with a spectrum of debilitating neurological symptoms and deficits. Thyromimetics are synthetic small molecule drugs that selectively activate thyroid hormone receptors and their signaling pathways in a subset of organs and tissues of the body. Scanlan is a leading expert in the design, synthesis, and biological actions of thyromimetic agents. NeuroVia’s drug development program is based on the hypothesis that activation of thyroid hormone signaling in cells that reside in or access the central nervous system will provide therapeutic benefit for X-ALD patients.

NeuroVia will use the Series A funding to support the initial stages of pre-clinical and clinical development for this program.

Training Opportunity for Responsible Conduct of Research

Are you participating in an NIH training grant award or fellowship? Do you need RCR training? The Oregon Clinical and Translational Research Institute (OCTRI) is offering an 8-hour seminar that meets RCR requirements for Ks, Ts, and other career development or individual fellowship grants. This seminar is an interactive and practical experience  focused on addressing real issues that have arisen in the course of your research. These may be related to ethics, integrity, or regulatory matters, including anything from how to recruit and consent patients to how to keep laboratory notebooks to determining authorship.

This seminar is also open to training grant faculty who have an RCR requirement—faculty members are needed to serve as small group facilitators. Priority is given to scholars and trainees funded by an NIH K-award or clinical or translational, postdoctoral T-award or any federal or non-federal career development grant.

Schedule – must attend all 4 sessions:

Session 1: February 5, 2 to 4 p.m.
Session 2: February 19, 2 to 4 p.m.
Session 3: March 4, 2 to 4 p.m.
Session 4: March 18, 2 to 4 p.m.

Please contact Karen McCracken for questions and to register.

View this on the OCTRI web site >>

Clarifications on new NIH requirement to consider sex as a biological variable

This past summer, we reported on a new NIH policy that goes into effect Jan. 25, 2016, requiring a deliberate approach to the consideration of sex as a biological variable (SAVB) in pre-clinical research.

In a Dec. 11 Open Mike blog post, Deputy Director for Extramural Research Michael Lauer, Ph.D., clarified the application and review process and provided additional information on the origins of the policy. A current high-priority focus at NIH is improved rigor and transparency in federally funded biomedical research–and accurate, detailed reporting of experimental conditions, including  consideration of sex, is a key component of responsible practices to that end. By including sex in experimental design, researchers enhance the scientific knowledge base for future studies and help prevent unnecessary and costly duplication of experiments.

NIH has heard many concerns about this policy, including the perception that researchers now need to double the number of animals used or reduce project aims to adjust for additional costs. Some are wondering if all experiments now must be powered for both sexes. Not so, according to Lauer. Considering SABV is not the same as looking for sex differences.

He cites a recent article by Dr. Janine Clayton, Director of the NIH Office of Research on Women’s Health, that dispels some of the misconceptions surrounding the policy and lays out exactly what it is not. Clayton makes it clear that NIH will not require any specific research design or method in its efforts to enhance reproducibility and transparency. Rather, each project and the state of knowledge in a particular research area will determine how the investigator considers SABV. The overarching goal is to add to this knowledge base in order to learn even more about how sex affects human biology beyond reproduction. This concept applies to detecting differences across a wide range of biological variables including age, environmental conditions, and genetics.

Clayton’s article provides a contextual summary of studying both sexes and outlines specific strategies and experimental design approaches to help investigators address this new policy without slowing ongoing research. A graphic included in her article summarizes consideration of SABV at each stage of investigation:

 

From Studying both sexes: a guiding principle for biomedicine by Janine Clayton, The FASEB Journal article fj.15-279554

From “Studying both sexes: a guiding principle for biomedicine,” by Janine Clayton; The FASEB Journal article fj.15-279554

Still confused? Check out NIH’s guidance or ask questions here.

 

Researchers discover a network of genes that control when puberty begins

Confocal microscopy image of the medial basal hypothalamus

Confocal microscopy image of the medial basal hypothalamus

Researchers at OHSU and the University of Pittsburgh have identified members of an elaborate superfamily of genes that regulate the timing of puberty in highly evolved nonhuman primates.

The Zinc finger, or ZNF, gene family comprises approximately 800 individual genes. A handful of genes in this network serve as a “neurobiological brake” that delay the activation of hypothalamic genes responsible for launching puberty until the end of childhood, thereby preventing the premature awakening of the process. The researchers’ insights better position scientists to decipher whether environmental factors push the start of puberty to younger ages.

ZNFs exert their inhibitory effect by setting in motion mechanisms that modify gene activity without changing the sequence of DNA. Because of this, the ZNFs are considered to act “epigenetically;” conveying to genes information from the environment without changing the genetic code itself.

The team was led by Alejandro Lomniczi, Ph.D., assistant scientist at the ONPRC. Their paper, “Epigenetic regulation of puberty via Zinc-finger protein-mediated transcriptional repression,” was published this week in the journal Nature Communications.

NIH up for budget increase, releases strategic plan

NIH to receive $2 billion budget increase

A massive federal spending bill released on Dec. 16 provides the National Institutes of Health with a $2 billion funding increase, the agency’s first raise in more than 12 years. The bill was passed on Dec. 18.

The bill provides the following for medical and healthcare-related research:

  • $200 million to the Obama administration’s Precision Medicine Initiative
  • $350 million increase for Alzheimer’s disease research
  • $85 million increase for the BRAIN Initiative
  • $303 million additional funds towards efforts to fight antibiotic-resistant bacteria
  • $91 million, a nearly 300 percent increase, toward programs to reduce opioid abuse

A few key elements of the bill were changed from the initial proposal after a period of negotiation. The version released today puts the Affordable Care Act’s medical device tax on hold for two years; excludes a provision to reign in FDA regulation on e-cigarettes by limiting pre-market reviews, designed to determine whether a product is safe; and leaves restrictions on CDC gun violence research in place.

Several other federal agencies involved in medical or healthcare related research received funding increases. For a full report, click here.

NIH Strategic Plan

The National Institutes of Health also released the NIH –Wide Strategic Plan, Fiscal Years 2016-2020: Turning Discovery Into Health. The strategic plan was  developed in consultation with a wide range of stakeholders, scientific advisors, and NIH leadership. NIH solicited input through a Request for Information, which generated more than 450 responses; a series of interactive webinars, which attracted more than 750 participants; and meetings with 21 NIH advisory councils, including the Advisory Committee to the NIH Director. (The plan was written before the funding increase was announced and does not spell out how the funds could be used and distributed.)

The four main objectives of the plan are to:

  • Continue to advance biomedical research in fundamental science, treatment and cures, and health promotion and disease prevention
  • Foster innovation by setting NIH priorities to enhance nimbleness and high risk, high reward research opportunities
  • Enhance and expand a diverse, well-educated and -trained biomedical research workforce
  • Strengthen NIH as a federal science agency by applying the scientific method to itself – learning and implementing in a rigorous way how best to support biomedical research.

The plan also lays out specific achievements that NIH will be working toward over the next five years:

  • NIH-supported clinical trials will show that at least half-dozen interventions thought to be clinically beneficial actually have no value.
  • A pivotal efficacy trial of a novel HIV vaccine, expected to begin in the Republic of South African in 2016, will confer at least 50% protection against the acquisition of HIV.
  • A wearable biosensor for monitoring blood-alcohol levels in real time will be developed and show efficacy for preventing alcohol-related injury and disease.

According to the NIH, this strategic plan is considered a living document that is open to changes as NIH leadership evaluates progress in meeting these objectives and achievements.  Download the plan here.

 

The call to modernize graduate education

In a Nov. 30, Feedback Loop Blog post, National Institute of General Medical Sciences (NIGMS) leadership detailed the need to modernize how graduate students in biomedical research are educated and trained. Drs. Shiva Singh, Alison Gammie, and Director Dr. Jon Lorsch announced efforts NIGMS is undertaking to catalyze an education system that has remained virtually unchanged in 30 years, even as science has evolved at an unprecedented rate.

The authors make the case that the growth of interdisciplinary research, Big Data, and diverse careers in research and related sectors necessitate an overhaul of graduate student education. In addition, growing problems related to reproducibility and scientific rigor must be addressed at the earliest stages of an investigator’s training. NIGMS and other NIH institutes and centers are developing and incorporating training modules that address these problems in the research endeavor, including blinding, selection of exclusion criteria, and awareness of bias. NIGMS also recently issued administrative supplements to some of their T32 predoctoral training grants to enable the development of new curricular components that address the full spectrum of skills students need to develop to become outstanding scientists.
skillrange

These activities are only part of a larger effort to promote a complete revitalization and reworking of the biomedical research graduate education system and NIGMS would like to hear from the community about potential challenges, opportunities, and strategies to help inform this effort. Leave your comments and learn more about the specific issues NIGMS aims to address here.

Collaboration accelerates research for acute myeloid leukemia

Less than 25 percent of patients newly diagnosed with acute myeloid leukemia (AML) survive beyond five years. The disease causes more than 10,000 deaths a year in the U.S., and treatment options have remained largely unchanged in 30 years.

In 2013, OHSU’s Knight Cancer Institute teamed up with The Leukemia & Lymphoma Society to find a path to treatment for this complex form of leukemia. Their research initiative, Beat AML, brought together nine drug companies and six universities to collaboratively zero in on potential drivers of the disease. They did so by sequencing cancer cell DNA from hundreds of patients who volunteered samples. In  the past two years, the project has generated a number of treatment ideas and supplied a stock of drug candidates. Beat AML findings were presented on Dec. 5-8 at the American Society of Hematology Annual Meeting in Orlando, FL. Learn more here about these findings and see which OHSU researchers have made significant contributions.

Construction notice: Vollum exterior removal begins Dec. 14

vollum_instituteThe aging, terracotta facade of the Vollum Institute will be removed from the south side of the building, facing the research courtyard. Work to be done during this phase of construction includes:

  • Installation of covered scaffolding for access and protection from falling debris
  • Removal of all existing terracotta on the Vollum facade
  • Installation of a new weather barrier
  • Replacement of all windows on the courtyard side of the building

Safety and minimizing impacts to daily operations are the top priorities during this time. The work begins Monday, Dec. 14 at 3:30 p.m.

Is your work impacted by planned or ongoing construction? Contact OHSU Project Manager Lee Weidman at weidman@ohsu.edu or Turner Construction Superintendent Randal Lutes at rlutes@tcco.com.

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Welcome to the Research News Blog

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