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Dr. Liebl


 
Research Interests

 

 

Affiliations

 

 

Publications

 

 

 Lab Members
 


Contact Information:


 

The Miami Project
to Cure Paralysis

 

1095 NW 14th Terrace

 

Locator Code R-48

 

Miami, Florida 33136

 

 

Tel:  (305) 243-8183
Fax: (305) 243-3914

 

 

dliebl@med.miami.edu

 

Home Our Research Faculty > Daniel J. Liebl, Ph.D.


 

DANIEL J. LIEBL, PH.D.

Professor, Department of Neurological Surgery

 

Molecular Mechanisms that Regulate Cellular Dysfunction and Death Following CNS Injury, and Mechanisms to Promote Regeneration and Recovery

 

Research Interests

 

 

Our overall goal is to achieve a better understanding of how the CNS develops and regenerates following injury and disease. We have focused on a family of molecules, ephrins and Eph receptors, since they have been shown to have a dynamic influence in regulating developmental functions, including axonal growth and guidance, synaptic formation and function, angiogenesis, bone morphogenesis, and neurogenesis. We believe that studying the developing nervous systems can provide important insight to mechanisms that would regulate regeneration after injury. A choice tool in my laboratory are gene-targeted knockout mice, where alterations in CNS develop can provide an understanding of gene functions. We also attempt to take a comprehensive approach to each of our experimental goals, which include molecular, biochemical, genetic, cellular, behavioral, and physiological analyzes. We believe that a well-rounded approach to anyone question will provide a better understanding of gene function. The goals of my laboratory are divided into three areas:

 

  • (1)Neurogenesis:We have recently demonstrated new and novel functions for ephrins and Eph receptors in adult neurogenesis, where they function to maintain proper stem/progenitor cell and neuroblast numbers by regulating proliferation and survival. Current studies are continuing to dissect the mechanisms involved in these studies. In addition, we are employing high-throughput methods of siRNA knockdown to examine potential intracellular signaling intermediates that may participate in these functions. We are complementing these studies by examining whether ephrins and Eph receptors regulated endogenous or transplanted stem cell functions after traumatic brain or spinal cord injury.

 

  • (2)Axon growth and guidance: Ephrins and Eph receptors are well known for their role in regulating growth and guidance, classically through repulsion of developing growth cones. Our indepth studies have extended our knowledge on the molecules that control forebrain midline pathfinding, and found that also function to attract developing growth cones. There are dynamic choice point cues on the developing CNS midline that signal a axon to either cross or not cross the midline. We have determined that the family of ephrins and Eph receptors play a significant role in this choice determination, and genetic analysis has shown that there is a complex interplay between the role of growth and guidance molecules on both the growing axon sprout and the positioning of the local guideposts. When ephrins and/or Eph receptors are absent (i.e. knockout mice) corpus callosum axons fail to transverse the CNS midline, and instead form swirls of axon bundles called Probst’s bundles. In human, corpus callosum defects are found in many disorders and syndromes. We are currently investigating whether individual ephrins and Eph receptors map to specific chromosomal disease regions with the hope to identify the genetic basis for CNS defects associated with these diseases. As well, we are continuing to employ animal models to examine the molecular mechanism by which these molecules regulate these events.

 

  • (3)Synaptic formation and function: Ephrins and Eph receptors are known to regulate the synaptic formation and efficacy in the developing brain. We are extending our findings to investigate three different questions: (a) How ephrins and Eph receptor regulate NMDA receptor levels in the synaptic membrane?; (b) What role ephrins and Eph receptor have in glia-neural interactions and how they affect synaptic formation and function?; (c) What role ephrins and Eph receptor play on synaptic function after traumatic brain injury? Understanding these functions will better enable us to investigate how regenerating axons can form functional contacts after injury.

 

In summary, our studies evaluate all aspects of the neuronal life from early stem cell differentiation to axonal growth to synaptic formation and function to cell death and injury. We hope to improve basic understanding of the mechanisms involved as well as develop therapeutic strategies to promote recovery. Our long-term goal for all these projects are to develop strategies that will lead to clinical trials and patient recovery.

 

Interview with Marc A. Buoniconti, President, The Miami Project to Cure Paralysis

 

Dr. Dan Liebl has been leading his own lab within The Miami Project for the past ten years.  He recently sat down for a quick conversation with Marc Buoniconti to discuss his introduction to neurosciences, his work here at The Miami Project and the importance of the steps The Project is taking to move the field forward.

 

Marc: Everyone has a point in their life they decide what they want to do, was there somebody or something that turned you on to a career in science?

 

Dr. Liebl:  I’d have to go back to my childhood and describe why I did not chose other more obvious pathways. I grew up in the heart of the Midwest, Wisconsin, where my entire relation continues to reside.  My father owned a machine shop that focused on metal working, and I was raised in a very ‘blue collar’ environment.  I worked in the machine shop for four summers through college, which confirmed my desire to do something other then work in a factory.  Surprisingly, I had no examples of higher education, in that, I was the first member of my entire extended family to enter college.  At the University of Wisconsin, I started as pre-med since Medicine was a profession that interested me. In fact, becoming a Scientist was not even on my radar, since I really had no exposure to the Scientific community.

 

Marc: So why not pre-law or business?

 

Dr. Liebl:  I’ve always enjoyed science and math, and at that time in my life medicine was attractive.  I didn’t know it then, but as I went through college I realized that working in medicine wasn’t really my ball of wax either. After college, I decided to go out and explore the world and that exploratory nature is what really attracted me to science, since science is ultimately about exploration.

 

Marc: So what did you do after college?

 

Dr. Liebl:  After college, I took a couple of years off and I worked in a research lab at Baylor College of Medicine in Houston, Texas.  At Baylor, I worked on facial nerve regeneration, which exposed me to neuroscience and the regeneration field. This ultimately stimulated my desire to go to graduate school.  I went to graduate school at Kent State University and I worked in a very small laboratory.  It was just myself and my principal investigator.  We worked on a family of macroglobulin molecules that regulated neurotrophins in the brain, which led me to the most important jump in my career.  Namely, a postdoctoral fellowship with Dr. Luis Parada at University of Texas Southwestern Medical Center.  He’s a well-known developmental biologist, which was the area of science I was initially attracted towards.

 

Marc: How did that path lead you to join our group here at The Miami Project?

 

Dr. Liebl:  While working in Dr. Parada’s laboratory, the American Paralysis Association (now known as the Christopher and Dana Reeve Foundation) approached a number of scientists from around the world to be a part of a consortium and my mentor, Dr. Parada, and Dr. Mary Bunge were both asked to be consortium members.  Each member would invite a junior associate scientist to accompany them, which met an important goal of the consortium. Specifically, to expose and train the next generation of spinal cord injury (SCI) scientists.   This was my first exposure to the SCI field, which blossomed to the career you see today.

 

Marc: So you and Dr. Parada weren’t really working in SCI at all at the time?

 

Dr. Liebl: Right, we both worked in the developmental field.  It was and still is an attractive concept to merge developmental biology with regenerative biology, since many of the factors that regulate the developing brain also play a role in regeneration of the nervous system.  This was one of the strengths that Dr. Parada and myself brought to the consortium. So how did we get so involved so quickly?  Well, all the associates got together and preformed large complex experiments as part of the consortium goals.  This exposure to the field and scientists, and most importantly the close friendships formed between the associates solidified my interest in SCI research. During this period, The Miami Project was searching for new junior faculty, and Dr. Bunge suggested that I apply. I was interviewed in 2000 and hired shortly afterwards. I am very happy with the career choices I had made, and feel lucky that the timing was just right.

 

Marc: So you’ve been here 10 years now.  How would you describe you time here?

 

Dr. Liebl: Amazing. Wonderful. Whenever you start a new lab as a junior faculty member there are many challenges.  You are suddenly a leader of the lab and you don’t necessarily know how to lead a lab.  You need to learn how to hire, manage, and possibly fire people, as well as mediate personal issues on top of the scientific work you are trying to accomplish.  You have to develop your scientific goals and accomplish those goals to be successful. I’m very pleased where my laboratory and research goals have gone these past ten years; however, as a scientist we are never completely satisfied.  There are always more studies that need to be completed, as well as a desire to improve ourselves and be more successful. Our success is what will drive discovery and advancement of this very important field of science.

 

Marc: Where do you see your specific research going in the next 5 years or so?

 

Dr. Liebl: We have two primary interests in our lab that are hopefully forging their way towards clinical trials.  One is understanding how endogenous (naturally existing in the body) stem cells within our brain can be utilized.  There are a few areas of the brain that produce stem (pluripotent) cells to become new neurons throughout our lives. We know that following brain injury the brain tries to rejuvenate itself a little bit, in other words, there is a natural increase in the production and survival of these cells; but it’s limited. We also know that these cells tend to migrate to the site of injury. After SCI, this would represent a long migratory distance for these brain-derived cells, but transplantation of these cells or other autologous stem cells may be beneficial. We feel that understanding the mechanisms that regulate endogenous stem cell functions will provide an important understanding of how stem cells work in general. We know that many transplanted cells have limited capacity as a result of excessive cell death, restricted proliferation and limited migration. If we can improve the overall survival and migration of these cells, we may be able to really improve not only endogenous neurogenesis but also cellular transplantation approaches.

 

The second area we are interested in is the survival of mature spinal cord cells after injury.  In addition to having trophic factors that are expressed to help cells survive, as you know there are also active mechanisms within cells that kill them off called apoptosis or programmed cell death.   We’ve identified a new family of molecules that regulate these functions, and in fact we find that after SCI some of the cells that die, do so because of this new mechanism.  For instance oligodendrocytes, which are the myelinating cells, undergo excessive apoptosis after SCI and this results in part from our newly described cell death mechanism.  We’ve used many molecular and biochemical tools to dissect these pathways and to understand how these mechanisms work with the hope to ultimately reverse them.  In mice we’ve been able to support oligodendrocyte survival after injury where they would normally die off.

 

Marc: So why can’t we take these stem cells from the spinal cord and use our technique for the Schwann cells and culture them?

 

Dr. Liebl: The techniques for retrieving pluripotent stem cells from the adult spinal cord is similar to our techniques in the adult brain; however, the spinal cord population is very small.  The question becomes, do we need to take them from the spinal cord?  We can take then from a lot of different tissues including the brain and transplanted these cells into the spinal cord at various times after injury. The important thing in that scenario is that you get autologous stem cells that your body is not going to reject.

 

Marc: There was always the hypothesis that if you transplant the cells in to the damaged area of the cord, the body is smart and those cells will know where to go.

 

Dr. Liebl: What I think they were talking about in that scenario was a severed axon.  When you implant a conduit for axons to grow across, the axon may eventually find its target cell.  In some senses that may occur, but I am not one hundred percent sold that that is accurate.  My thought is that it will innervate a lot of areas and the ones it shouldn’t innervate will be pruned away similar to the developing nervous system.  We need to be able to ensure that we can produce as maximum amount of growth as possible to ensure that happens.  When you are thinking of transplantation, it is a very different scenario where transplanted stem cells have to differentiate into neurons and start projecting its axon towards a target it has never seen before.  It becomes a little more difficult, but I’m a firm believer that we have some of the tools to begin addressing these possibilities, although not all of the tools needed.  As fast as science is advancing, we are continually obtaining new tools. As we develop those tools we hope to improve our ability to guide both migrating cells and growing axons.  It will also be important to ensure that these newly growing neurons survive over time to providing long-term stability to the recovery process.

 

Marc: How do you think The Miami Project overall is being received within the field?

 

Dr. Liebl: From my standpoint, and from what I hear in the scientific community, our efforts are being received well.  Most people I talk to in my travels are excited about where The Miami Project is going.  Everyone thinks the trial (Schwann cell) is extremely important.  They understand that there are challenges in what we are trying to achieve, but a successful transplantation trial in SCI is extremely exciting to everyone in the field. It’s going to forge the way for a lot of people to start thinking about SCI trials.  Overall, I think it is a very important step that we are taking.

 

Marc:   Thank you so much for your time and for giving us a little glimpse of your work.

 
 
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