The role of fatty fibrosis in chronic limb threatening ischemia pathobiology

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.