“Targeting Lysophosphatidic Acid- Hippo/Yap/Taz-Connected Route as a Novel Therapeutic Strategy”

Muscular dystrophies (MDs) are a diverse group of hereditary diseases characterized by muscle debilitation that often results in a reduced lifespan and that currently have no cure. Most of the affected genes codify for proteins present in the dystrophin-associated glycoprotein complex, which is crucial for protecting the sarcolemma from the mechanical stresses of muscle contraction. Acute damage of the sarcolemma activates a series of molecular and cellular events leading to muscle fiber regeneration. Under chronic injuries, as in MDs, continuous repetition of this cycle eventually leads to a severe limitation of the skeletal muscle regeneration potential due to the exhaustion of the progenitor's cells pool, the satellite cells. As muscle fiber necrosis repeatedly occurs, a strong desynchronized and persistent inflammatory reaction is established and damaged muscle fibers end by being replaced with ECM material in a phenomenon called fibrosis. Muscle strength irreversibly decreases and overall individual performance is negatively affected. The pathophysiological mediators of muscle fibrosisare not entirely understood.
In an animal model for Duchenne MD (DMD), we have demonstrated that the Connective tissue growth factor (CTGF/CCN2) is a critical protein controlling inflammation and fibrosis, and a potential therapeutic target. Based on these findings, Phase 2 and 3 clinical trials using a CTGF/CCN2 inhibitor in DMD patients are currently in progress.
Lysophosphatidic acid (LPA) is a critical lipid factor involved in inflammation and fibrosis. It is mainly synthesized by the enzyme autotaxin (ATX) and acts via G protein-coupled receptors (LPARs), conforming the so-called ATX/LPA/LPARs axis. LPA induces the expression of CTGF/CCN2 in several cell types, including muscle cells. Among LPA multiple downstream molecular pathways, the Hippo/YAP/TAZ comprises a kinase cascade and a transcriptional module. The Hippo/YAP/TAZ pathway has three relevant characteristics: 1) YAP/TAZ are mechanosensitive proteins. 2) CTGF/CCN2 is its best-known target gene, and 3) it acts as a central node for several pathways, including integrins and ATX/LPA/LPARs. Regulation of several biological processes relevant to MDs, such as cell proliferation and differentiation, tissue regeneration, and mechanosensing of the ECM associated with fibrotic responses are among the many functions that have been described for both the ATX/LPA/LPARs axis and the Hippo/YAP/TAZ pathway.
This proposal focuses on signals involved in the common mechanisms of secondary damage found in MDs. Activation of LPARs and consequent YAP/TAZ modulation can be the potential target of pharmacological inhibition and could be an essential tool to inhibit MDs inflammation/fibrosis. We postulate that in MDs, an increased ATX/LPA/LPARs axis activates YAP/TAZ to promote inflammation and fibrosis; we propose inhibiting the LPARs-YAP/TAZ-connected route might have a promising therapeutic effect on these devastating diseases.
Hypothesis:
YAP/TAZ activity is augmented in MDs in response to increased ATX/LPA/LPARs mediated signaling. Inhibition of the LPARs-YAP/TAZ-connected route is a novel therapeutical approach for treating MDs.
The objectives of this proposal are:
1. To characterize the ATX/LPA/LPARs axis in a MD mouse model (δ-sarcoglycan-null, Sgcd-/- mice).
2. To determine if the YAP/TAZ pathway is enhanced in the Sgcd-/- mice, and if this increase depends on the ATX/LPA/LPARs activity.
3. To study the therapeutic effect of inhibiting the ATX/LPA/LPARs and the subsequent signaling mediated by the Hippo pathway in the Sgcd-/- mice phenotype.
This project is focused on the fundamental and applied study of MDs and will characterize the presence of the ATX/LPA/LPARs axis, which we believe is activated. Since the axis signals through the Hippo YAP/TAZ pathway, we expect it to be also enhanced in the Sgcd-/- mice. The applied part of this proposal focuses on using specific ATX/LPA/LPARs and YAP/TAZ inhibitors to reduce inflammation/fibrosis and improve muscle physiology.
We expect that our results in this animal model of MD may provide the first demonstration of the involvement of this complex connected route in the development of fibrosis in MDs, and become the crucial first step on the long road of translational medicine towards developing new therapies to alleviate these disabling conditions.

Estudiar el efecto del eje ATX/LPA/LPARs en la fibrosis asociada a distrofias musculares.