Get to Know Dr. Bernadette Holdener: HA 2019 Innovator Award Grantee

In January, we announced our 2019 Innovator Award grantees. The Innovator Award is designed to provide seed funding for bold and innovative work with the potential to transform hydrocephalus research. In this first installment of our Meet the Innovator Awardees Blog Series, we interviewed Dr. Bernadette Holdener, one of four scientists who received an Innovator Award grant. Dr. Holdener is an Associate Professor in the department of Biochemistry and Cell Biology at Stony Brook University. Her research aims to understand how changes in the way the brain produces and uses energy are related to the development of hydrocephalus in both children and adults.

What sparked your interest in hydrocephalus research?
My first experience with hydrocephalus was as a child. I had a friend who needed shunts replaced, but I got into the hydrocephalus research field by accident. I’ve always been interested in human development and was using mice to understand the cause of birth defects. We had made a mouse model for another human disorder called Peters Plus Syndrome and these mice developed hydrocephalus. Children with Peters Plus Syndrome don’t usually have hydrocephalus, so this was a surprise. We started looking at mutations in proteins affected by the first mutation and we discovered that some of these mice also developed hydrocephalus.

What do you find most interesting about hydrocephalus research?
There is a lot known but also still a lot of unanswered questions. What I love about hydrocephalus research is that it brings together investigators from many fields working on this common problem and they are all very collaborative. People are willing to talk about it and hash out ideas.

How long have you been researching hydrocephalus?
About two years in total and we’ve just barely started scratching the surface. We set up a collaboration with Dr. June Goto, another HA award recipient, who has been a great mentor in the field and has helped us to set up connections to other people.

What do you hope to learn from your research? What questions do you hope your research will answer?
This mouse mutation is a little different from most other hydrocephalus mutations that have been described in the medical literature. It’s a mutation in an enzyme that adds a sugar molecule onto a class of proteins with a protein fold called a thrombospondin type 1 motif. We think that the hydrocephalus results from defects in a limited subset of the proteins modified with the sugar. Our first goal is to define the actual defect that’s causing hydrocephalus in our mutant mice. The second goal is to determine precisely where in the brain/vasculature the modified proteins are expressed, which will also help us define the defect.

What makes your project unique?
What makes this project unique is that we are looking at sugar modifications on proteins that are nonstructural components of extracellular matrix. These are new molecules that haven’t really been considered before in the hydrocephalus field. Loss of the sugar modification on these matrix proteins could alter other features that scientists are currently working on, such as the arrangement of cells in the ventricles or the integrity of the brain circulatory system. There are some papers in the medical literature that reported that the fetus had a higher possibility of developing hydrocephalus if the mother had diabetes or if a patient was diabetic, they had a higher susceptibility to developing hydrocephalus later on. We do not know if the expression or activity of the enzyme we are studying is impacted by abnormal glucose metabolism. It’s not the typical things that are known to cause hydrocephalus, so it opens up a whole lot of doors.

How important is HA’s Innovator Award grant for your project?
The HA Innovator Award has allowed us the financial flexibility to pursue a new research direction outside the specific aims of our current NIH funding. With the funding we received from the Hydrocephalus Association, we have already been able to make headway into determining where the candidate affected genes are expressed in the brain at a level of resolution, previously unreported. We were excited about our findings, and with the Innovator Award we are energized!

What is the long-term plan for the project?
Ultimately, our project is about providing a foundation for understanding how disturbances in the way the brain produces and uses energy are related to the development of hydrocephalus in both children and adults. Identification of affected target proteins and tissues in our mutants will allow us to submit focused grant proposals that investigate the molecular mechanism leading to hydrocephalus in our mouse models. The studies also will set up a baseline on top of which we can then begin to evaluate the effects of disturbances in metabolism on the susceptibility to hydrocephalus. We hope that these basic research studies will ultimately identify new molecules that will prove to be therapeutic for reversing hydrocephalus, and also lead to a better understanding of the causes of hydrocephalus that will help to reduce the occurrence of hydrocephalus.

The research team involved in this project (pictured from L to R): Dr. Bernadette Holdener, Dr. Sanjiv Neupane, Ms. Sulan Xu, Mr. Richard Grady, and Mr. Daniel Cameron.

Posted 2-10-2020

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