February 21, 2020

Anatomy of a grant: Ashley Kramer’s yearlong journey to finding her doctoral thesis

He asked her for a list of dream projects she would love to investigate. What followed was a year of challenges, stresses and the ultimate reward – guided intellectual freedom toward scientific discovery.

Ashley Kramer
Ashley Kramer

Ashley Kramer, a student at the Wayne State University School of Medicine, is enrolled in the school’s M.D./Ph.D. program, an eight-year commitment broken down into three parts – the first two years of medical school, four years of graduate school, then the final two years of medical school. Like all M.D./Ph.D. students at the medical school, Kramer had to complete research rotations with faculty she thought would make good dissertation advisors.

“Because I have always loved stem cell biology and had experience working with zebrafish in the past, I decided to do an eight-week rotation in Dr. Thummel’s lab between my medical year one and medical year two, and made the decision that this was absolutely the perfect lab for me,” she said.

Ryan Thummel, Ph.D., is an associate professor of Ophthalmology, Visual and Anatomical Sciences. His lab focuses on retinal development and regeneration, myelination disorders affecting vision, and zebrafish models of cancer. Zebrafish are an attractive model to study neurodegenerative diseases because of their ability to regenerate neuronal tissues. Zebrafish fully regenerate their retinas in just a matter of weeks, an ability mammals lack For lab details, visit www.thummellab.com

Zebrafish and mammals both have a cell called Müller glia that supports retinal neurons. In zebrafish, however, these cells convert to stem cells and are responsible for retinal regeneration.

At the end of the rotation, Dr. Thummel “floated the crazy idea of starting to work on this grant, a 70-plus page monster undertaking, during my M2 year, and I immediately jumped at the opportunity. I was excited at the idea of having a four-year research project completely planned out by the time I started my Ph.D. after M2 so I could hit the ground running after the dreaded STEP 1,” Kramer said.

“I came to him two days later with a nine-page document of project ideas. We sat down for three hours discussing projects and came up with a ‘top-two’ list of cohesive projects for me to move forward with as a grant and thesis,” she said. “From there, it was a nearly yearlong process of writing, meeting, revising and repeating for each of the many sections of the grant.”

The effort was worth it. Kramer secured a five-year, $294,102 grant from the National Eye Institute of the National Institutes of Health last year to study the molecular mechanisms of retinal regeneration in zebrafish, an organism that exhibits a remarkable capacity for regeneration.

"Ashley is a dedicated young scientist and worked very hard on this grant application," Dr. Thummel said.

The grant is one of the NIH’s Ruth L. Kirschstein National Research Service awards, also known as an F30. The project, “Elucidating the role of DNA methyltransferases in epigenetic regulation of retinal regeneration in the zebrafish,” started last month. She is the principal investigator.

“This was an incredibly challenging experience that allowed me to grow immensely as a scientist. Grant writing, planning effective and novel longitudinal scientific investigations, and time management will all be critical skills for me moving forward in my career as a physician scientist,” she said. “I cannot thank Dr. Thummel and my past advisors enough for all of their mentoring and support in the last ten years who have gotten me to where I am today, and I am looking forward to the rest of my training here at Wayne State and beyond.”

Kramer earned her bachelor’s degree in Genetics, Cell Biology and Development from the University of Minnesota in 2014. Her love of research and stem cell biology started when she was an undergraduate research assistant there.

Nearly a decade later, she is studying how epigenetic marks are added to, and removed from, genes in zebrafish retinal stem cells during the process of retinal regeneration. The role of epigenetics in the body is akin to traffic signs on the road.

“If roads had no traffic lights, stop signs or barricades, it would be complete chaos. The same is true for your cells. If you used every single gene encoded in your DNA 100% of the time, your cells would be chaos. Epigenetics is what is responsible for telling your skin cell to be a skin cell and your liver cell to be a liver cell, while they both have the exact same underlying DNA sequence,” Kramer said. “There are various different epigenetic marks that decorate the DNA without actually changing the sequence. These marks come in many forms and can act to either start, stop or change the amount that a particular gene is used, similar to how a green light, road block or stop sign direct traffic rules.”

The process is critical for normal embryonic development and everyday cell processes.

“If we can gain a deeper understanding of how species like the zebrafish are able to regenerate tissues when mammals cannot, despite having the same cell types, we may be able to start working to translate those mechanisms to mammals,” she said. “It is possible that certain regeneration pathways have been epigenetically silenced through evolution and we may be able to use modern advances in gene therapy techniques to ‘unlock’ regenerative capacity in mammals.”

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