Research Update

Research to Create Tomorrow's Advances

Several major grants were awarded to Kellogg faculty in 2018, including the renewal of two major institutional grants and five significant new individual investigator awards, continuing to place Kellogg among the leading centers in the nation in ophthalmic research funding.

Kellogg’s National Institutes of Health/National Eye Institute sponsored K12 grant, supporting the Michigan Vision Clinician-Scientist Development Program, was renewed for five more years. Overseen by Professors Thomas Gardner, MD, MS, and Paul Lee MD, JD, the program provides resources and mentorship to help launch the research of promising early-career investigators. “At any given time, up to two investigators are funded by the K12 grant,” explains Dr. Gardner, “giving them the time, resources and mentorship to reach a point where they can compete for individual K grant funding.” Abigail Fahim, MD, PhD, is the newest investigator supported by the K12.

Currently, nine Michigan Medicine researchers are funded by individual K grants, including Yannis Paulus, MD, who received a K08 grant, and Lindsay DeLott, MD, who received a K23 grant, both in 2018. Both Dr. Paulus and Dr. DeLott were previously funded by the K12 grant.

The unrestricted grant funding Kellogg receives from Research to Prevent Blindness (RPB) was also renewed for another five years. In addition, Dr. Jillian Pearring received a 2018 RPB Career Development Award. RPB is the leading non-governmental funder of research into conditions that threaten sight. Its researchers have been associated with nearly every major breakthrough in this arena in the past 50 years.

“These grants support the full spectrum of research from genetics to health policy, enabling us to push the frontiers of vision research to treat, cure and prevent vision loss.” explains Director Paul P. Lee, MD, JD.

Abigail Fahim, MD, PhD

Abigail Fahim, MD, PhD

Clinical Scientist Institutional Career Development Program Award

Kellogg Clinical Assistant Professor Abigail Fahim, MD, PhD, has been awarded a Clinical Scientist Institutional Career Development Program Award from the National Institutes of Health. With this award, which supports early-career investigators working within interdisciplinary research programs, Dr. Fahim will occupy one of two positions in the Michigan Vision Clinician Scientist Development Program K12 grant overseen by Professor Thomas Gardner, MD.

Dr. Fahim’s lab is investigating the connection between the retinal pigment epithelium (RPE) and the development of inherited diseases of the retina, notably choroideremia, an early onset blinding disease for which there is no treatment.

The RPE is a layer of cells situated between the light-sensing photoreceptor cells and the choroid, a collection of blood vessels that supplies oxygen and nutrients to the retina. While much is known about the many ways the RPE supports photoreceptor cells, far less is known about how the RPE interacts with the choroid.

Choroideremia is caused by defects in a single gene, CHM, which helps transport proteins to the correct locations in cells. “Our hypothesis is that a disruption in this transport process changes the characteristics of RPE cells in choroideremia,” explains Dr. Fahim. Using a technology for the genetic manipulation of stem cells called clustered regularly interspaced short palindromic repeats, her team has generated RPE cells with a choroideremia defect to compare their function with that of normal cells.

“I see patients who will be blinded by inherited retinal diseases like choroideremia for which I can do nothing,” Dr. Fahim says. “This research will help us understand the genetic changes that drive these diseases, and will provide a platform for testing new treatment strategies—it’s the next step in giving these patients hope.”

Steven Abcouwer, PhD, and David Antonetti, PhD

Steven Abcouwer, PhD, and David Antonetti, PhD

NIH Research Project Grant (R01): Inflammatory Resolution and Vascular Restoration in Diabetic Retinopathy

Diabetic retinopathy and associated diabetic macular edema are leading causes of blindness in the United States. David Antonetti, PhD, and Steven Abcouwer, PhD, have proposed an unique platform for studying how these diseases progress and conducting preclinical testing of potential treatments.

Their research focuses on how diabetes impairs the retina’s ability to resolve inflammation and repair itself—specifically, to restore normal blood vessel function after injury. The inability to heal properly may be responsible for the buildup of damage in the diabetic retina. Drs. Antonetti and Abcouwer draw a parallel between this and another common consequence of diabetes: poor wound healing that leads to chronic foot ulcers.

This approach is novel in the field of diabetic retinopathy. To date, research has focused on how diabetes damages the retina. These U-M researchers are instead exploring how inadequate healing may contribute to the disease process. Unlike impaired foot wound healing in diabetes, however, the retinal vasculature also requires a functioning blood-retinal barrier (BRB) that must be restored for proper vessel function. This BRB protects the retina by tightly controlling what can enter and leave. By comparing the healing mechanisms of normal and diabetic rodents following retinal injury, they hope to identify strategies for overcoming the destructive impact of diabetes on the retina’s ability to combat inflammation and restore the BRB.

This effort leverages the special expertise of the Abcouwer and Antonetti laboratories in retinal inflammation and the blood-retinal barrier, respectively. The close collaboration of these laboratories is expected to uncover new insights into the mechanisms of disease progression and identify new therapeutic options to reverse the devastating effects of diabetic retinopathy.

Rajesh C. Rao, MD

Rajesh C. Rao, MD

NIH Mentored Clinical Scientist Development Award (K08): Understanding the Epigenetic Mechanisms That Drive Retinal Development

Degenerative retinal diseases like age-related macular degeneration (AMD) are blinding disorders with few treatment options. In AMD, a disease that affects 10 million Americans, degeneration of photoreceptor cells leads to vision loss.

One current tissue regeneration strategy for AMD is the transplantation of photoreceptors (light-sensing cells) derived from pluripotent stem cells. Pluripotent stem cells can develop into many types of cells. In this multi-step strategy, pluripotent stem cells are coaxed to specifically become retinal precursors, which later give rise to photoreceptors. But this approach is inefficient, donor-dependent and still poorly understood.

Rajesh Rao, MD, Assistant Professor of Ophthalmology and Visual Sciences and Pathology and an Emerging Scholar at the A. Alfred Taubman Medical Research Institute, has developed a three-year mentored career development project focused on gaining a better understanding of how stem cell-derived retinal precursors arise. Specifically, the project uses a stem cell-based platform to study the role of the Mll1 complex, an important epigenetic protein that “switches on” genes necessary for retinal development. It is hoped that the knowledge gained from this endeavor will lead to new stem cell-based therapies to restore vision.

Jillian Pearring, PhD

Jillian Pearring, PhD

RPB Career Develoment Award: Understanding how molecules are delivered to the light-sensing organelle of photoreceptor cells

Human vision takes shape in the retina, a thin and transparent piece of neural tissue lining the back of the eye. Light entering the eye is captured by the rod- and cone-shaped outer segments of photoreceptor cells in the retina. The light-sensing outer segment compartment contains a specific set of proteins involved in capturing light and transforming it into electrical signals to be processed by the brain. Defects in the delivery of these select proteins are responsible for many forms of inherited retinal degenerative diseases, including retinitis pigmentosa, a blinding disease affecting nearly two million people worldwide.

The lab of Dr. Jillian Pearring, PhD, is working to understand the cellular mechanisms that guide protein transport and delivery to the outer segment in healthy photoreceptors and how defects in these processes result in retinal degeneration. What her team discovers may guide the development of future therapies to treat patients with retinal disease. Her work is funded by a generous Career Development Grant from Research to Prevent Blindness (RPB).

RPB is the leading voluntary health organization supporting research to prevent, treat or eradicate all diseases that threaten vision. Researchers supported by RPB have been associated with nearly every major breakthrough in vision research in the past 50 years.

David Musch, PhD, MPH

Brenda Gillespie, PhD, David Musch, PhD, MPH, and Leslie Niziol, MS

NIH Exploratory/Developmental Research Grant Award (R21): Glaucoma progression—modeling its trajectory and contributing factors: evidence from AGIS and CIGTS

The extent and rate of visual field progression is an important measure of a glaucoma patient’s response to treatment. A panel convened by the National Eye Institute (NEI) to study glaucoma and optic neuropathies called for experts in the field to standardize instruments and data collection methods as well as improve statistical methods that determine the progression of disease.

David Musch, PhD, MPH, Professor of Ophthalmology and Visual Sciences in the Medical School and Professor of Epidemiology in the School of Public Health, is stepping up to that challenge using this grant. His team of experts includes Brenda Gillespie, PhD, Associate Professor of Biostatistics in the U-M School of Public Health and Associate Director of the U-M Center for Statistical Consultation and Research, Kellogg Senior Statistician Leslie Niziol, MS, and Paul Lichter, MD, Professor Emeritus. Joseph Caprioli, MD of UCLA and Paul Van Veldhuisen, PhD, of the Emmes Corporation are also involved.

The project, which will employ advanced statistical techniques, has two distinct aims: 1) to compare numerous methods of modeling the progression of visual field loss in order to identify the best ones; and 2) to investigate the importance of the type of visual field defects documented in two landmark NEIsupported clinical trials—the Advanced Glaucoma Intervention Study and the Collaborative Initial Glaucoma Treatment Study.

NIH Institutional Training Grant (T32)

Peter Hitchcock, PhD, with pre and post doctoral fellows

Supporting pre-and post-doctoral fellows training in vision research at the University of Michigan

This grant funding will continue to support the University of Michigan’s long-standing tradition of training graduate students and postdoctoral fellows for careers in vision research.

The centerpiece of this effort is the National Eye Institute supported Vision Research Training Program (VRTP). Recently renewed with continuous funding extended to 20 years, the VRTP serves to create a cohesive community of vision scientists at U-M, recruiting outstanding pre-and post-doctoral fellows and providing breadth in research training and professional development to keep pace with opportunities for careers in vision research. The VRTP is enhanced by the Michigan Vision Clinician Scientist Development (K12) Program, one of only six such programs in the United States.

Members of the training faculty are funded, productive scientists and experienced mentors whose research portfolios include both basic and translational projects. Most hold primary appointments in the Department of Ophthalmology and Visual Sciences, but the team also includes faculty in the departments of Cell and Developmental Biology, Biomedical Engineering, and Molecular, Cellular and Developmental Biology.

The program is directed by Peter Hitchcock, PhD, Professor of Ophthalmology and Visual Sciences and Professor of Cell and Developmental Biology in the School of Medicine and Associate Dean for Academic Programs and Initiatives in the Rackham Graduate School. In his role as graduate dean, Dr. Hitchcock provides administrative oversight for 26 bioscience PhD programs and the 1,400 postdoctoral research fellows training at U-M.