In the United States, impaired wound healing represents a major public health problem that is rapidly growing because of soaring health care costs, an aging population and a sharp rise in the incidence of diabetes and obesity. Development of a comprehensive understanding of the molecular mechanisms that regulate wound healing is therefore necessary. As much as 97% of human DNA does not encode for protein and has been called """"""""junk"""""""". microRNAs (miRs) are evolutionary conserved, approximately 22-nucleotide single-stranded RNAs that do not encode protein but determine the functional fate of coding genes. Thus, miRs represent a class of non-coding (nc) genes that can not only be no more regarded as """"""""junk"""""""" but are of such extraordinary significance that their discovery has led to the 2006 Nobel Prize and the 2008 Lasker Award. Our group has published first report proposing a key role of miRs in cutaneous wound repair. This proposal is based on preliminary data demonstrating that miRs are highly responsive to wounding. These results, and outcomes of proposed studies, represent a missing piece of the wound healing biology puzzle that has so far taken shape without the consideration of miRs. Defects in one or multiple keratinocyte function(s) related to re- epithelialization can have pleiotropic effects, ranging from excessive scarring to the formation of chronic ulcers. We have thus chosen to focus on understanding how miRs regulate wound re-epithelialization. The following three aims are proposed:
AIM1 : Establish the significance of mature miR in wound re- epithelialization. Hypothesis 1.1: Keratin-14 (K14) directed conditional ablation of Dicer in mice (K14CreERtam Dicer-/-) results in depletion of mature miRs in the skin epidermis and compromises re-epithelialization of excisional wounds. Hypothesis 1.2: Injury-induced cutaneous epithelial cell proliferation is compromised in K14CreERtam Dicer-/- mice. Hypothesis 1.3: Dicer knockdown compromises proliferation and migration of keratinocytes.
AIM2 : Determine the significance of miR-1 dependent molecular mechanisms regulating wound re-epithelialization. Hypothesis 2.1: miR-1 expression is acutely down-regulated in the wound-edge tissue following excisional cutaneous wounding. Hypothesis 2.2: Wound-induced down-regulation of miR-1 results in induction of the target gene Dll1. Hypothesis 2.3: In keratinocytes, miR-1 and Wnt signaling pathway regulate a common target Dll1.
AIM3 : Determine the significance of miR-21 dependent molecular mechanisms in regulating wound re-epithelialization. Hypothesis 3.1: miR-21 expression is up-regulated in the wound-edge tissue following excisional cutaneous wounding. Hypothesis 3.2: Wound-induced up-regulation of miR-21 results in silencing of the target gene PTEN. Hypothesis 3.3: Wound-induced miR-21 dependent silencing of PTEN drives Akt signaling and epithelial cell proliferation. Hypothesis 3.4-3.5: In keratinocytes, elevated levels of miR-21 support cell proliferation (3.4) and migration (3.5) via a PTEN dependent pathway.
In the United States, skin wounds affect 6.5 million patients placing a major burden, estimated at US$25 billion annually, on society. The proposed project aims at developing a clear understanding of the fundamental mechanisms that influence wound closure in new light. This light originates from recent breakthrough discoveries recognizing a novel class of genes - previously thought to be junk - called microRNAs as being of critical significance in health and disease.
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