Awardees, Research, Stories

STAC Support Along the Time Continuum: Investigating Anti-Inflammatory Intervention with IAIP

Steven Threlkeld PhD
Assistant Professor, Department of Psychology, Rhode Island College

STAC Makes RI More Competitive

STAC was established nearly a decade ago at Commerce RI around the idea that supporting scientific and technological innovation across Rhode Island would lead to widespread economic growth. This thinking has been borne out by a long series of STAC-funded successes that have earned follow-on grants, awards, and venture capital investors.

A core part of STAC’s strategy has involved encouraging collaborations between different in-state science and technology entities. Many such efforts have been direct collaborations-industry-academic partnerships, for example, allowing scientists at biotech startups to share physical resources and experience with scientists working in university laboratories. Other STAC collaborations have involved various groups — academic labs and hospital researchers, for example — divvying up the painstaking, step-by-step work involved in the scientific process. In one such case, a university lab, a hospital researcher, and an in-state manufacturer joined forces to refine a laboratory device, the 3-D petri dish, that went on to earn world renown — a three-way collaboration nurtured by STAC.

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Dr. Threlkeld and his RIC Students at North East Undergraduate Research on Neuroscience (NEURON) Conference (left to right: Zahra Melendez, Steven Threlkeld, Keyshla Melendez, Cynthia Gaudet, Travis Dumais). Photo by: RI STAC

With the inception of the Rhode Island Research Alliance in 2007, STAC created a competitive, merit-based award program to support projects that promote inter-organizational, multi-disciplinary collaboration, which are positioned to attract follow-on funding from out-of-state sources. To date, STAC has invested $8.5 million in collaborative research projects that have yielded a return of $36 million back to the state in the form of grants for continued research, new federal programs, infrastructure improvements, commercialization of new products and venture funding for new companies.

In addition to funding direct collaborations, over the years STAC has provided opportunities for “follow-up” collaborations, collaborations that evolve over time, rather than in sync: an innovation originating in one laboratory that inspires scientists in another to investigate its potential applications.

Collaboration 2 Innovation: Brain Science Research Thriving at RIC

STAC funding got the ball rolling on critical brain science research in Rhode Island, and collaborative support and federal funding support has kept it going.

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A 2010 STAC-funded team from Prothera Biologics in East Providence and Women’s & Infants Hospital (WIH) in Providence examined strategies for preventing brain damage in premature infants. Steven Threlkeld PhD, now an Assistant Professor in the Department of Psychology at Rhode Island College (RIC) was involved in the research while at WIH. Since moving to RIC and becoming involved in the RI INBRE program, his current work has built on the efforts of the previous STAC team.

In 2011, Threlkeld received a two-year, $220,000 RI INBRE grant, allowing him to continue the research. He and his students have made maximum use of the award. In the last three years 11 RIC students have received paid summer fellowships to participate in this research. It is impressive to see how fully Threlkeld and his students utilize the 150 square-foot RIC Behavioral Neuroscience lab, reconfiguring the small space into four different laboratory set-ups. The RIC team’s hard work and innovation have not gone unnoticed. They recently published (the article was officially published in December 2013) a methods article in the Journal of Visualized Experiments. While science and technology research funding is increasingly scarce, brain science research in Rhode Island has overcome the odds and is thriving at RIC. As RIC’s Threlkeld observes, “Collaboration is key, you can do a lot if you have different skill sets contributing to a project.”

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Dr. Steven Threlkeld explains how the modified acoustic startle paradigm works. Photo by: RI STAC

The NIH subsequently awarded a prestigious R15 grant to Threlkeld and his Rhode Island College team of undergraduate and graduate students. The project’s goal is to determine if combining early life behavioral training with anti-inflammatory treatment can improve long-term outcomes following neonatal brain hypoxia/ischemia (a significant neurological problem in term and very low birth weight infants). “I am so proud of Steven Threlkeld,” said Rhode Island College President Nancy Carriuolo.  “He is a young professor (and father) with an NIH grant that may shed light on problems that develop in the brains of infants.  Infants have their whole lives stretching ahead of them, so their early health is especially important.”

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Steven Threlkeld PhD, Assistant Professor in the Department of Psychology at Rhode Island College (RIC), cites his own recent success as an example of this “historical” style of collaboration. Threlkeld points out that all scientific discovery has historical roots: “Scientists base all of our work on the efforts of those who came before us.” His own work has been based on the efforts of two previous STAC awardees, Yow-Pin Lim, MD, PhD, founder of Prothera Biologics in East Providence, and Dr. Barbara Stonestreet, Director of the Fellowship in Neonatal-Perinatal Medicine at Women & Infant’s Hospital. Both were part of the 2010 STAC-funded team that examined strategies for preventing brain damage in premature infants. (Over 50 percent of premature infants who sustain brain trauma go on to exhibit disabilities.)

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Graduate and undergraduate members of Dr. Threlkeld’s lab at Rhode Island College. Photo by: RI STAC

NIH R15 academic research enhancement grants are intended to “support meritorious research, expose students to research, and strengthen the research environment of the institution.” The NIH scored on all fronts this year by awarding a prestigious R15 grant to Threlkeld and his Rhode Island College team of undergraduate and graduate students. The excellence of their proposal made an impression: NIH reviewers gave a perfect score to their proposal to “assess the relative influences of anti-inflammatory intervention with IAIP (Inter-Alpha-Inhibitor Protein), early behavioral experience and maturation on adult behavioral and anatomical outcomes in rats following neonatal brain injury.” The project’s goal is to determine if combining early life behavioral training with anti-inflammatory treatment (IAIP) can improve long-term outcomes following neonatal brain hypoxia/ischemia (a significant neurological problem in term and very low birth weight infants).

It was Lim who provided the origins of Threlkeld’s research. Lim developed a groundbreaking method for purifying the protein from human blood plasma. His method demonstrates unrivaled efficacy compared with other purified forms of IAIP. Asian labs have succeeded in isolating a urine-derived form of IAIP that demonstrates 15 minutes of efficacy. Lim’s plasma-derived process has demonstrated more then 12 hours of efficacy.

After Lim demonstrated IAIP’s potential as a biomarker for inflammation in mice, Dr. Stonestreet began to contemplate the protein’s potential for helping to protect her neonatal patients from inflammation/infection. “Inflammation is a hallmark of mortality in neonatal patients,” explains Threlkeld, who worked with Dr. Stonestreet as part of his post-doctoral work, contributing to her research on IAIP and neonatal brain injury in 2009-2010. That study examined IAIP’s neuroprotective potential in sheep. Their work involved administering the protein prophylactically to sheep fetuses with brain injury.

Threlkeld says that working with Dr. Stonestreet expanded his understanding of the neurobiology of brain injury, as well as his facility with neuroscience research methodologies. In 2011, with encouragement from Stonestreet, Threlkeld applied for and received, a two-year, $220,000 RI INBRE grant, allowing him to continue the research.

Thanks in part to neurobiology expertise honed during his time working with Dr. Stonestreet, Threlkeld was hired at Rhode Island College. The dearth of resources there was greatly offset by Threlkeld’s INBRE grant. “We don’t have a huge amount of resources at our state institutions,” Threlkeld notes, but “The INBRE thing was a great option in getting, basically, start-up money for putting a lab together.” He and his students have made maximum use of the award.

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Configuring one of the four laboratory setups, the behavioral assessment water maze. Photo by: RI STAC

It is impressive to see how fully Threlkeld and his students utilize the 150 square-foot RIC Behavioral Neuroscience lab. They figured out how to break down and reconfigure the small space into four different laboratory set-ups: a learning assessment lab; an auditory processing lab; a neuroanatomy lab; and a microscopy lab.

The behavioral assessment lab is particularly fascinating. It’s a rodent-sized water maze used to test the rats’ spatial learning. Also impressive is the modified acoustic startle paradigm the team devised to measure the rats’ auditory processing of complex sounds, which in humans relate with language proficiency. Threlkeld claims only one other lab in the country is doing similar testing, which involves measuring rats’ ability to learn patterns in auditory signals. Processing of complex auditory information is frequently impaired in human infants with brain injury. Therefore, assessing this function along with experimental treatment may shed light on possible behavioral protection afforded to humans with neurodevelopmental injury.

The RIC team’s hard work and innovation have not gone unnoticed. They have recently published a methods article in the Journal of Visualized Experiments. It features video of rats moving through the water maze, and text protocol of how to perform the spatial learning experiment. The RIC neurobiology lab supports its own website, which can be accessed here.

The results of the RIC team’s hard work have been gratifying. Threlkeld reports they were able to demonstrate strong evidence of IAIP’s neuroprotective potential. “We’re working on publications that show IAIP prevents cell death within 72 hours of treatment.” The research has come a long way, and Threlkeld credits his mentors with feeding its progress. “Dr. Stonestreet encouraged me to pursue the RI INBRE grant,” he says. “My advisor has been good about letting me in on how to keep a lab viable, how to write grants, and showing how they beget more grants.” Science and technology research funding is increasingly scarce. Yet IAIP research in Rhode Island has overcome the odds and is thriving at RIC. STAC award recipients got the ball rolling, and collaborative support kept it in play. As RIC’s Threlkeld observes, “Collaboration is key, you can do a lot if you have different skill sets contributing to a project.”