Project Summary/Abstract: There are more than 11 million people in the world with keloids and more
than 425,000 associated clinic visits, yearly, in the United States. Keloids are benign fibroproliferative
tumors which cause pain, pruritus, emotional distress and loss of function. Current therapies are
unsatisfactory with unacceptably high recurrence rates, mainly because of an incomplete understanding
of keloid pathogenesis. Fibroblasts are a key player in keloid pathogenesis, but the drivers are unknown.
Keloid disease is influenced by aberrant signaling pathways. However, no clear signaling pathway has
been identified. Exosomes mediate cell-cell communication, exercising primary physiological and
pathophysiological function. Exosomal cargo, such as microRNAs (miRNAs), regulate cellular function.
Our group identified RAB27, important for exosome secretion, as being differentially hypomethylated in
keloid compared to normal skin. Our group has isolated keloid-specific exosomes. To date, there are no
published studies on keloid exosomes or the contribution of RAB27 methylation on exosome function.
We propose to test the central hypothesis that exosomes communicate critical signaling events in the
keloid microenvironment mediated by RAB27 gene methylation. Aim 1: To determine the effect of
RAB27 methylation on keloid exosome production and miRNA cargo profiles. Hypotheses: (1) Keloid
exosomal production correlates with RAB27 gene methylation. (2) Keloid exosomal cargo miRNA
expression profiles correlates with RAB27 gene methylation. (3) Keloid exosome miRNA’s putative target
genes lie within pathways essential for wound healing and/or fibrosis. Aim 2: To determine the effects
of keloid exosomes on the keloid microenvironment. Hypothesis: Keloid fibroblast exosomes compared
to normal fibroblast exosomes will cause pro-fibrotic phenotype changes in normal fibroblasts. Aim 3:
To determine the effect of keloid exosomes on scar formation in vivo. Hypothesis: Exosomes
generated in aim 1 and tested in aim 2 will increase scar formation in a rabbit ear scar model.
Significance: This project will lead to an enhanced understanding of keloid pathogenesis and the
potential for exosome-based therapy. Innovation: (i) rational progression from preliminary data
supporting the novel role of exosomes in keloid pathogenesis; (ii) investigating the influence of RAB27
methylation on the function and production of keloid exosomes would suggest a mechanistic basis for
novel epigenetic biomarkers;(iii) using unique resources which includes fibroblast cell lines from primary
untreated keloid (25) and matched normal skin (25) from a multi-ethnic group of patients and an in vivo
animal model allow for the pragmatic translational application of results; (iv) entirely new field of keloid
investigation. In summary, this project, mentoring and career development plan will position, Lamont R
Jones, MD, MBA, to become an independent clinician scientist and leader in keloid pathogenesis.