Project Summary/Abstract
Keloids are dermal lesions that grow beyond the margin of the original wound in a tumor-like manner. Keloids
can expand for several years, grow to large size and be painful, itchy and inflamed. Despite of the severe
physical, psychological and social impact on patients, keloids are understudied and the treatment is
unsatisfactory with high recurrence rates. Keloids also contribute to racial disparity in research and health care
because prevalence is highest in populations of African ancestry. There is strong evidence for a genetically
diverse basis for keloids. However, gene mutations that make patients susceptible and initiate keloids have not
been identified. Identifying such causative genetic variants is fundamental for the understanding of keloid
pathoetiology and for the identification of potential therapeutic targets. We previously identified several keloid
candidate variants by linkage analysis and whole exome sequencing in a large cohort of 103 ethnic Yoruba
families from Nigeria with heritable keloid formation. We prioritized four candidate genes variants that segregate
in families, are expressed in skin and associated with other fibroproliferative disorders or are involved in wound
healing.
In this application we aim to determine whether the downstream effects of these four candidate gene variants
induce a keloid-like phenotype in skin cells or in organotypic skin equivalents. We will investigate pathways by
which the candidate variants act on skin cells.
In Aim 1, we will study the roles of keloid candidate gene variants on individual skin cell types derived from
human isogenic induced pluripotent stem cells (hiPSCs) carrying the respective gene mutations. We minimize
background noise from biological variability by comparing isogenic mutant and wild type cells that differ only by
the variant to be investigated.
In Aim 2, we examine interactions between mutant fibroblasts, keratinocytes and macrophages that lead to
paracrine effects guiding epithelial-mesenchymal transition and fibrosis during wound healing, using co-cultures,
organotypic skin equivalents and xenotransplant mouse models.
We expect that investigating the role of genes that have not been investigated in keloids will bridge knowledge
gaps in keloid and wound healing research and will identify novel factors that put individuals at risk for keloid
development.