Use of Neural Progenitor Cells and Attractive Proteins to Heal TBI

PUBLIC ABSTRACT

Background: During the course of normal brain development, neural progenitor cells migrate from sites of origin to specific structures where they complete their development into functional neurons. Recent evidence indicates the potential for these same neural progenitor cells to be used in the treatment of traumatic brain injury (TBI), where they may replace neurons that have destroyed by brain trauma. Accordingly, neuronal progenitor cells offer considerable promise in the treatment of TBI.

The ability of neural progenitor cells to perform their functions during development is regulated by a family of specific proteins, referred to as neuron attractive proteins. These messengers are differentially expressed by the brain throughout the course of development and act directly on progenitor cells to guide their movement to appropriate brain locations. In addition to neuronal guidance functions, these same factors also appear to promote the differentiation of neural progenitor cells such that the differentiated neurons establish appropriate functional interconnections with their neighboring neurons. Accordingly, normal brain development depends upon the proper balance of neuron attractive factors at critical stages of development. Although neural progenitor cells have the capability to repair damaged brain, improvements in the ability of transplanted cells to survive and integrate into injured brain tissue are essential to make this form of treatment clinically effective. Under present experimental conditions, only a small fraction of such cells become functional and establish proper cellular connections within the cerebral cortex. We propose that the effectiveness of neuron progenitor cell transplantation can be dramatically improved if the appropriate balance of neuronal attractive factors is also established to guide neuron migration and differentiation. Some of the neuron attractive proteins have been discovered; however, others have yet to be identified. Our ongoing research indicates that the neuron progenitor cells forming the cerebral cortex are attracted by one or more novel factors of known molecular weight. We intend to identify these neuron attractive proteins and use them in conjunction with other known substances to enhance the repair of cerebral cortex injured by TBI.

Objectives/Hypothesis: The objectives of this project are to (i) identify novel factors attracting distinct classes of neuronal progenitor cells and (ii) demonstrate their ability to facilitate neural progenitor cells in the repair of injured brain tissue in conjunction with known factors. We hypothesize that these factors can be used to create a favorable environment for repair and encourage proper reorganization in damaged cortex by transplanted neural progenitor cells. The methodological component of this proposal employs cutting-edge progenitor cell biology together with state-of-the-art biochemical and proteomic technologies for identifying the proteins that mediate the guidance of neuronal progenitor cells in the repair of injured neocortex.

Specific Aims and Study Design: The specific aims for this investigation are designed to (1) identify factors attracting developing neurons into the cerebral cortex; (2) determine the ability of the identified factors to create an optimal environment for neural progenitor cells in the repair of injured cerebral cortex; (3) use combinations of known factors in conjunction with the identified factor(s), creating an environment that will encourage proper structural and functional relationships in the repair of damaged cortex in an organotypic culture model; and (4) optimize the delivery system and repair for the identified proteins in a rat model of TBI induced by a penetrating injury to the cerebral cortex.

Impact: The impact of this project for TBI will be the discovery of important neuron attractive factor(s) and demonstration of their effectiveness, in conjunction with other known factors, to facilitate the repair of brain injury by neural progenitor cells.