Chronic wounds induced by the impaired wound healing especially in diabetic patients and aged individuals are still a major unsolved biomedical challenge. This has highlighted the importance and urgency of studying the novel mechanisms of the impaired wound healing and exploring now therapeutic options. MicroRNAs (miRNAs) have emerged as a novel class of noncoding RNAs with tremendous biological functions. The goals of this project are to determine the miRNA mechanism and therapeutics of impaired wound healing. Using RCR based array and deep-sequencing analysis as well as qRT-PCR, we identified a group of miRNAs that are aberrantly expressed in bone marrow (BM)-derived endothelial progenitor cells (EPCs) isolated from diabetic and aged individuals and mice. Among them, let-7 family members, let-7b, let-7c, let-7d, and let-7d* are significantly increased. The hypothesis of this proposal is that Let-7 family members play important roles in the impaired cellular functions of EPCs and impaired wound healing in diabetes and aged individuals via their target genes. miRNA-reprogrammed "smart" EPCs via modulators of let-7 family may represent a novel effective therapy for chronic wounds. We will test our hypothesis via three specific aims:
Aim 1 will determine the effects of let-7 family members on the migration, proliferation and apoptosis of EPCs in vitro.
Aim 2 will determine the effects of let-7-reprogrammed autologous EPCs on wound angiogenesis and wound healing in diabetic and aged mice in vivo.
Aim 3 will determine the molecular mechanisms of let-7-mediated biological effects. The biological role of let-7 family on refractory wounds via gene reprogramming in EPCs is an unexplored research field. The proposed study will utilize the latest cellular, molecular, and whole animal approaches to target the major unsolved biomedical challenge: chronic wounds. Uncovering the novel molecular mechanisms and therapeutics of the impaired wound healing at translational level via miRNAs may open a new scientific paradigm in chronic wounds.

Public Health Relevance

The biological role of let-7 family on refractory wound via gene reprogramming in endothelial progenitor cells (EPCs) is an unexplored research field. The goal of this project is to test our hypothesis: Let-7 family members play important roles in impaired cellular functions of EPCs and impaired wound healing via their target genes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Nursing Research (NINR)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NR013876-02
Application #
8501695
Study Section
Special Emphasis Panel (ZNR1-REV-T (11))
Program Officer
Tully, Lois
Project Start
2012-07-01
Project End
2014-06-30
Budget Start
2013-07-12
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$217,566
Indirect Cost
$75,366
Name
Rush University Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
068610245
City
Chicago
State
IL
Country
United States
Zip Code
60612
Wood, Stephen; Jayaraman, Vijayakumar; Huelsmann, Erica J et al. (2014) Pro-inflammatory chemokine CCL2 (MCP-1) promotes healing in diabetic wounds by restoring the macrophage response. PLoS One 9:e91574
Liu, Xiaojun; Cheng, Yunhui; Yang, Jian et al. (2013) Flank sequences of miR-145/143 and their aberrant expression in vascular disease: mechanism and therapeutic application. J Am Heart Assoc 2:e000407
Li, Jingyuan; Li, Jing; Liu, Xiaojun et al. (2013) MicroRNA expression profile and functional analysis reveal that miR-382 is a critical novel gene of alcohol addiction. EMBO Mol Med 5:1402-14