Friday, April 26, 2024
4/26/2024
Project Summary The heterogeneous group of inherited peripheral neuropathies referred to as Charcot-Marie Tooth disease, have an estimated prevalence of 1:25001. Among these disorders, Charcot Marie Tooth 1A (CMT1A) and Hereditary Neuropathy with Liability to Pressure Palsy (HNPP) are the most common1. These diseases result from duplication (CMT1A) or deletion (HNPP) of the gene encoding for peripheral myelin protein 22 (PMP22)2, leading to its over or underexpression in Schwann cells (SCs), respectively3,4. There are no cures for these debilitating diseases, highlighting the need to identify novel mechanisms to modulate PMP22 expression, and to elucidate the pathological mechanisms involved in peripheral nerve (PN) demyelination. Recently, the complex formed by the transcriptional coactivator with PDZ-binding motif (TAZ)5 and the transcription factor TEA domain 1 (TEAD1)6,7, was shown to positively regulate PMP22 expression8,9. Therefore, modulation of TAZ activation is an intriguing therapeutic avenue to decrease PMP22 transcription in CMT1A, or increase its transcription in HNPP. Moreover, the functions of PMP22 in SC biology include cell cycle regulation10,11, formation of cellular junctions and myelin permeability12,13, and determining the mechanical properties of myelinated PN fibers14,15. Notably, these aspects of SC biology are also regulated by TAZ, and the related transcriptional coactivator Yes- associated protein 1 (YAP)16–20; the major downstream effectors of the HIPPO pathway21,22. Activated YAP/TAZ translocate to the nucleus and associate with TEAD1-423,24, altering the transcription of many genes essential for SC proliferation and differentiation including laminin receptors, integrins, G-protein Ga, EGR2, and myelin and lipid genes8,20,25,26. Therefore, changes in the activation status of YAP/TAZ in CMT1A and HNPP may impact the physiology of SCs, contributing to demyelination. Thus, we hypothesize that modifying TAZ expression may restore proper PMP22 expression and ameliorate the phenotypes of CMT1A through direct regulation of PMP22. We also postulate that YAP/TAZ activation may be altered in mouse models and human samples of CMT1A and HNPP, potentially contributing to altered SC proliferation, myelin permeability, and mechanical properties of PNs. To determine the effects of modulating TAZ activation, genetic ablation of TAZ alleles in SCs of PMP22- overexpressing mice will be assessed for morphological, electrophysiological, sensory, and behavioral phenotypic rescue. The presence of altered YAP/TAZ activation will be assessed through immunostaining and biochemical analyses of human biopsy samples and mouse models of CMT1A and HNPP. The research for this proposed project will be conducted at the Institute for Myelin and Glia Exploration, composed of an interdisciplinary group of scientists dedicated to the study of myelin and its associated diseases. The overall training plan will emphasize the development of scientific communication skills, training in various techniques, improving critical thinking and problem-solving skills, as well as opportunities for regular clinical experiences. This will create the ideal environment for developing the skills necessary for a career as a physician-scientist.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
