Anatomy, Physiology & Genetics (APG)
Uniformed Services University of the Health Sciences
4301 Jones Bridge Road
Bethesda, Maryland 20814
Martin Doughty, Ph.D.
Associate Professor Anatomy, Physiology and Genetics
- University College London, 1995
We are interested in understanding the processes that regulate neurogenesis and neuro-differentiation in the injured and developing brain. Current research projects in the lab focus on two topic areas: 1) regenerative medicine approaches to treat traumatic brain injury; 2) transcription factor programs regulating neurogenesis, circuitry organization and function in the developing cerebellum. The laboratory uses multi-disciplinary approaches including induced pluripotent stem cells, conditional gene fate mapping and gene targeting, gene expression screening, histology, confocal imaging, stereology, electrophysiology and mouse behavior testing.
Induced Pluripotent Stem Cell (iPSC) Approaches to Treat Traumatic Brain Injury (TBI)
Current treatments for traumatic brain injury (TBI) are incapable of restoring many brain functions lost to injury and TBI patients suffer lifetime deficits in their quality of life. Regenerative medicine approaches for TBI have the potential to restore brain circuits and functions lost to injury. However, to be effective stem cell grafts must evade rejection by the host immune system, integrate and differentiate in hosts to regenerate tissue lost to trauma, and all this must be achieved without the risk of uncontrolled stem cell proliferation leading to the development of tumors. Stem cells derived from the host patient offer the most promising solution to these challenges. In this strategy, a patient's somatic cells such as skin fibroblasts or blood cells are reverse engineered to induce pluripotent stem cells (iPSCs). These iPSCs are in turn differentiation to defined cell types for autologous transplantation.
Our goal is to optimize iPSC states for transplantation strategies to treat TBI using pre-clinical animal models of brain injury. Current work focuses on the efficacy of using mixed iPSC-derived neuron and glial cell engraftment strategies to enhance the integration of grafted cells and improve functional recovery after injury.
Developmental Neurogenesis in the Cerebellum
A major challenge to understanding the signals that control neurodevelopment is the sheer numbers and intricacy of neuronal organization in the brain. While the functional organization of the cerebellum is as complicated as elsewhere in the brain, there is a simplifying structural plan that suggests the possibility of truly understanding how this part of the brain is formed.
Our goal is to identify the signaling pathways that generate the cellular and functional specificity of the cerebellum. Neurons are generated from two germinative zones in the developing cerebellum, the rhombic lip and ventricular zone. These zones are defined by distinct basic helix-loop-helix (bHLH) transcription factor activities and cell fate mapping and gene deletion studies demonstrate a requirement for bHLH gene activity in the specification of cerebellar cell types.
We investigate bHLH gene function in mouse cerebellar development using transgenic mice technologies to label or delete gene activity in mice. Conventional and conditional gene deletion strategies are used to determine the role of bHLH transcription factors during pre- and postnatal mouse development. The consequences of loss of gene function on cerebellar anatomy and motor behaviors controlled by this part of the brain are measured.
Our objective is to determine the relationship between genetic determination programs in development and adult cerebellar organization and motor behaviors in mice. Understanding the genetic link between brain morphogenesis, function and behaviors is a fundamental goal of neuroscience.