Wound healing is critical for an organism to recover functionally and aesthetically from injury. The differentiated barrier epidermis of both vertebrate and Drosophila heals primarily through directed cell migration across the wound gap. Although some of the signals that initiate wound-induced cell migration and de-differentiation have been identified, mechanistic details of how these signals are presented to wound-edge epidermal cells and result in downstream pathway activation remain obscure. This research project focuses on the molecular genetic control of postembryonic wound healing. Our guiding hypothesis is that there is a conserved molecular genetic program of cell-cell signaling events that initiates, regulates, executes, and terminates the repair process. Our long-term goal is to identify the signals that control each of the steps of the process and understand at a mechanistic level how they act. Over the last grant period we used fluorescent transgenic reporter larvae and an in vivo RNAi screening approach to identify and characterize two wound-induced signaling pathways and a number of presumably downstream genes that execute the wound closure program. These studies established that Pvr, the Drosophila homolog of the PDGF/VEGF receptor tyrosine kinase (RTK), is required for wound-edge actin polymerization and the initiation of epidermal cell migration. Pvr acts in parallel to Jun N-terminal kinase (JNK) signaling, which regulates the ability of epidermal cells to dedifferentiate- an apparent prerequisite for efficient migration. Our goal over the next grant period is to further dissect thee two pathways at the mechanistic level and to characterize a newly identified and possibly mechanosensory role for Hippo signaling in larval wound closure. These short-term goals are enumerated in the following specific aims: 1. To test the hypotheses that activation of epidermal Pvr signaling is initiated by blood-borne ligand and is localized to the wound edge. 2. To test the hypotheses that Pvr-induced hemocyte spreading and epidermal wound healing require both specific structural features of the receptor and specific downstream signaling molecules. And, 3. To test the hypotheses that Hippo signaling components act downstream of JNK or Pvr signaling during wound closure. This project represents the continuation of the first systematic study of postembryonic wound closure in a model genetic organism and will unravel critical mechanistic details of wound-induced signals that control wound closure. Given the conservation of genes required for most fundamental processes we expect that this project will inform our understanding of wound closure in vertebrates and in pathophysiological states, such as cancer and a variety of skin diseases, where the wound healing response is thought to be improperly activated or regulated.

Public Health Relevance

This research project employs the fruit fly, a model genetic organism, to dissect the genetic control of postembryonic wound healing, a process of immediate relevance to human health. Wound repair is vital for recovery from the common occurrences of trauma and surgery. Given the conservation of genes required for most fundamental biological processes we expect that the findings from this project will inform our understanding of wound closure in vertebrates and in pathophysiological states, such as cancer and a variety of skin diseases, where the wound healing response is known to be improperly activated or regulated.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM083031-06
Application #
8505978
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Somers, Scott D
Project Start
2008-05-15
Project End
2017-03-31
Budget Start
2013-06-01
Budget End
2014-03-31
Support Year
6
Fiscal Year
2013
Total Cost
$320,000
Indirect Cost
$120,000
Name
University of Texas MD Anderson Cancer Center
Department
Biochemistry
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Anderson, Aimee E; Galko, Michael J (2014) Rapid clearance of epigenetic protein reporters from wound edge cells in Drosophila larvae does not depend on the JNK or PDGFR/VEGFR signaling pathways. Regeneration (Oxf) 1:11-25
Scherfer, Christoph; Han, Violet C; Wang, Yan et al. (2013) Autophagy drives epidermal deterioration in a Drosophila model of tissue aging. Aging (Albany NY) 5:276-87
Lesch, Christine; Jo, Juyeon; Wu, Yujane et al. (2010) A targeted UAS-RNAi screen in Drosophila larvae identifies wound closure genes regulating distinct cellular processes. Genetics 186:943-57
Wu, Yujane; Brock, Amanda R; Wang, Yan et al. (2009) A blood-borne PDGF/VEGF-like ligand initiates wound-induced epidermal cell migration in Drosophila larvae. Curr Biol 19:1473-7