Diao receives $3 million grant from 4D Nucleome Consortium

September 23, 2020

Yarui Diao, Ph.D. received a U01 grant, totaling $3 million in research funding for 5 years, from 4D Nucleome Consortium (phase 2) through the NIH Common fund. Diao aims to determine the function and regulation of high-order chromatin structure on gene regulation and skeletal muscle regeneration in response to ischemia induced limb damage and recovery.

Ischemia, caused by restriction of blood flow, often results in severe tissue damage. Critical limb ischemia (CLI) is a serious condition in which peripheral artery disease (PAD) leads to irreversible limb muscle damage. About 40% of CLI patients undergo limb amputation one year after diagnosis, and 50% die after five years.

Current treatment options focus on improving limb perfusion, but these often fail to prevent disease progression, pointing to a critical need for a deeper understanding of the basic mechanisms that regulate human muscle regeneration in response to ischemic injury.

Recent studies suggest that failing to regenerate skeletal muscle is key to determining tissue loss in CLI versus repair. Successful muscle regeneration requires the orchestrated activation, proliferation and differentiation of muscle stem cells (MuSCs, also known as satellite cells) that are normally dormant.

Diao and team's preliminary analysis of MuSCs from one representative CLI patient found that the transcription of genes important for MuSC regeneration are dysregulated in ischemia; these changes are associated with rearrangements in 3D chromatin organization. These finding support the hypothesis that CLI involves a failure in the normal dynamic reorganization of 3D chromatin structure that orchestrates the regeneration of MuSCs.

Their overall objectives are to identify the spatial-temporal changes of chromatin organization (the 4D nucleome, or "4DN") normally associated with regenerative human MuSCs, and understand the functional consequences of defects in this mechanism for muscle damage in CLI. In the long-term, this information may lead to new regenerative treatment strategies for limb salvage that are independent of limb perfusion. This is a collaborative project with Kevin Southerland, M.D. at Duke Surgery and Feng Yue, Ph.D. at Northwestern University.