PROJECT SUMMARY/ABSTRACT
Chronic limb threatening ischemia (CLTI) is the most severe manifestation of peripheral artery disease (PAD)
and is characterized by the presence of ischemic rest pain, with or without gangrene, and often requires limb
amputation. Analysis of CLTI patient muscle specimens has identified fatty fibrosis, the replacement of muscle
with intramuscular fat and fibrotic scar tissue, as a prominent feature. Recent evidence points to ciliary Hedgehog
signaling as a potent anti-adipogenic signal that suppresses the differentiation of fibro-adipogenic progenitors
(FAPs), the cellular origin of fatty fibrosis, into adipocytes. Using pre-clinical rodent studies and translational
experiments in patient tissues and cells, we have uncovered mis-regulated Hedgehog signaling within the CLTI
limb. Preliminary experiments indicate that genetically or pharmacologically altering the Hedgehog pathway in
the ischemic limb modulates fatty fibrosis, perfusion recovery/angiogenesis, and muscle function – indicating
therapeutic potential of this pathway. This proposal will use innovative and powerful mouse models involving
cell-specific gain- and loss-of-function approaches to identify and define the cellular and molecular mechanisms
by which intramuscular fat forms within the CLTI microenvironment, and the functional consequences of
intramuscular fat and fibrosis on CLTI limb hemodynamics and function. Success in these studies will provide
mechanistic insight into the impact of fatty fibrosis on PAD/CLTI pathobiology, and would aide in the search for
novel targets for therapeutic development aimed to treat a patient population that currently has few available
options.