Our research represents interdisciplinary biomedical and engineering approaches aimed at the functional clinical regeneration of the central nervous system (CNS), and an understading of how the CNS represents and processes information; with a particular focus on the neural retina (which is an extension of the brain and an excellent model for the CNS). We are essentially focusing on three broad approaches to achieve these clinical goals: 1. The use of quantum dot nanotechnology to study the molecular and cellular biology of neurons and glia (the two main cell types in the CNS ). We are developing and applying technologies that allow us to quantitatively measure and track the dynamics of cell signaling processes using functionalized quantum dots and advanced imaging, combined with computational modeling of the data. 2. The study of how complex biological neural (i.e. again both neuronal and glial) networks in the CNS change following CNS injury.  We are interested in understanding quantitatively how remodeling of connections between CNS cells can lead to the induction and maintenance of disease.  Our approach is to use advanced forms of cellular imaging to accumulate data that can than be studied quantitatively using network theory and related mathematical and computational tools.  3. The development of cellular replacement and transplantation strategies that make use of stem cells as the source of donor cells, and the development and integration of molecular bioengineering approaches for their ex vivo differentiation and delivery (i.e. transplantation) into target CNS sites of injury.  In particular, we are focusing on the differentiation and in vivo delivery of adult stem cells into retinal photoreceptor neurons, which are lost following degenerative retinal disorders, and how engineered stem cells can protect cells following injury (i.e. neuroprotection). In particular, our work focuses on the molecular details of a neuropathological process called reactive gliosis , which is a biochemical and physical barrier to neuronal regeneration following essentially every form of CNS trauma and degeneration.  We are attempting to understand how it is initiated, how it is maintained, and how it contributes to the disease process by studying intracellular molecular details using quantum dots, and by studying large interacting networks of cells quantitatively.

To achieve these scientific and clinical objectives we are developing two major sets of tools, which in themselves represent major scientific objectives in our group. 1. Quantum dot nanotechnologies specific for neural cells.  Because nanoscience focuses on engineering materials and devices in a controlled way at spatial scales that are similar to those of the constituent building blocks of cells themselves (i.e. a physical scale that is on par with the molecular scale of proteins, receptors, DNA, RNA, etc.), this approach represents a very powerful way of integrating technology and physiological systems in order to study and reverse underlying disease processes. 2. We are developing high throughput algorithms and programming for mapping the functional network structure and architecture of large groups of neurons and macroglial cells.  This is not trivial, since functional connections and signaling between CNS cells do not necessarily require physical contact between cells, so that it is difficult to trace and map their network structures in a high throughput way (i.e. for large numbers of statistically meaningful cells in a fast way).  To achieve this, we are combining our quantum dot nanotechnology with confocal microscopy and the development of computational methods.  In particular, we developing software that will automate the detection and mapping of complex cellular networks, and even allow their analysis and characterization within the mathematical structure of network theory.  By studying both healthy CNS networks and networks following injury or degenerative events (first in vitro- based on cell culture models being developed in our lab that mimic pathological processes such as gliosis, and later in vivo in rodent models of CNS disorders), we will be able to gain an understanding of how complex neural cellular networks participate in disease and develop approaches to reverse this, regenerate the CNS, and develop novel clinical strategies to treat neurological and neural retinal disorders.

Applications of the technologies and experimental approaches we are developing are ultimately applied in situ in an attempt to develop new approaches to treating degenerative neural retinal disorders and reducing CNS reactive gliosis. This movie shows how we can visualize physiologically intact structures using fluorescence and confocal imaging. Shown here is a flat mount whole neural retina preparation stained with the non-specific nuclear stain Dapi. As the plane of focus goes through the retina three distinctive cell retinal cell layers can be seen in their intact physiological organization, which preserves the cytoarchitecture and functional anatomy of the retina.