Christian P Petersen - US grants

DESCRIPTION (provided by applicant): Pluripotent stem cells offer great promise for regenerative medicine, but it remains a significant challenge to finely control their activities to build complex organs de novo. Tissue engineering has approached this problem by designing synthetic scaffolds to control stem cell function, but production of true tissue mimics in this fashion is a daunting task. Animals that have evolved mechanisms of adult tissue regeneration provide an opportunity to discover how stem cells can be naturally instructed to undergo post-embryonic organogenesis. Planarian flatworms are famous for their ability to regenerate any missing tissue by controlling the activity of pluripotent stem cells termed neoblasts. Because such animals can engage a multitude of different regenerative programs dependent on the nature and extent of injury, they require exquisite control over the utilization of stem cells. Thi ability likely either resides in novel signaling pathways or in a unique use for well-described signaling pathways. This proposal describes a strategy for specific identification of the regulatory molecules that control regenerative growth by stem cells in planarians. The analysis of the function of these genes using RNA interference will describe pathways that control regenerative growth. Ultimately, a quantitative understanding of stem cell control in regeneration will be necessary to efficiently adapt natural regenerative mechanisms to the enhancement of human tissue repair. The proposal further describes the application of single-molecule fluorescence in situ hybridization to quantitatively analyze the spatial and temporal dynamics of Wnt, BMP and hedgehog signaling in planarian regeneration. This approach will allow a systems-level identification of signal control mechanisms that underlie stem cell-mediated organogenesis through regeneration. It is likely that stem cells and tissue repair mechanisms are ancient. Therefore, these studies have the potential to identify novel conserved proteins that could be modulated to enhance tissue repair and uncover basic principles of tissue restoration that could be applied to regenerative medicine.

Project Summary/Abstract Organisms with regenerative abilities have been informative models for uncovering natural mechanisms by which tissue damage activates stem or progenitor cells for injury repair. The timing, location, and extent of injuries are not predetermined, requiring the existence of mechanisms that instruct tissue restoration activities that perfectly counter the effects of damage. A key question to understand this process is how regenerative tissue redefines territories removed by injury, and it is hypothesized this is related to as-yet undiscovered systems that robustly regulate tissue proportionality across large length scales. To begin to address this question, it is essential to define the cell signaling systems that underlie regional identity and proportional growth. While regenerative tissues have been extensively probed for the roles of injury-induced signals and the involvement of stem or progenitor cells, much less is known about the molecular and developmental processes that enable the restoration of form after injury and its maintenance through adult growth. In the aims of this grant, this deficit is addressed by leveraging expertise in the planarian system, which uniquely allows for the study of signaling that regulates re-scaling of tissues through regeneration, to elucidate the regulatory and developmental mechanism that generates and restores tissue proportionality after injury. Uncovering fundamental mechanisms used by organisms to control tissue proportionality will provide foundational insights into understanding diseases of growth misregulation, the nature of proportional growth, and the control of stem cells for tissue regeneration.

Project Summary/Abstract Organisms with regenerative abilities have been informative models for uncovering natural mechanisms by which nervous system damage activates stem or progenitor cells for injury repair. The timing, location, and extent of injuries are not predetermined, requiring the existence of mechanisms that instruct tissue restoration activities that perfectly counter the effects of damage. A key question to understand this process is how cessation of regenerative growth is accomplished. To begin to address this question, it is essential to define the transcriptional and cell signaling systems that negatively regulate adult regenerative neurogenesis. While regenerative tissues have been extensively probed for positive regulators of regeneration, much less is known about factors that act in opposition and whose inhibition could lead to enhanced neural regeneration. In the aims of this grant, this deficit is addressed by leveraging expertise in the planarian system, which uniquely allows access to the biology of complete adult brain regeneration. Uncovering the conserved and fundamental mechanisms used by organisms to limit the extent and rate of tissue regeneration and cell turnover will provide foundational insights into understanding and ultimately treating diseases characterized by an inability to undergo sufficient neural repair.