Grants and Contracts Details
Description
1 ABSTRACT
2 Severe burn trauma triggers profound muscle wasting and dysfunction which persists for years following injury.
3 To date, the vast majority of studies have focused on elucidating hypermetabolic and catabolic signaling in
4 muscle cells consequence of burn, with few investigating non-canonical drivers. Muscle regeneration and
5 remodeling are tightly choreographed process involving several cell types in the muscle niche, such as
6 fibroblasts and immune cells. We postulate that burn injury dysregulates cell-cell signaling, leading to muscle
7 dysfunction not attributable to hypermetabolism alone. We are uniquely positioned to pursue our long-term
8 goal of unveiling cellular and molecular drivers of burn-induced myopathy to identify innovative therapeutic
9 targets aimed at preserving muscle quality, not just mitigate wasting. Over the next five years, we will pursue
10 four related but independent projects. Project 1 will investigate the cellular determinants and
11 consequences of altered extracellular matrix remodeling after burn injury. A recent report indicates
12 significant collagen deposition for up to 21-days post-murine burn injury, indicative of unresolved fibrosis which
13 may increase tissue stiffness and reduce strength. We will employ a discovery-based powerful multi-omic
14 (transcriptomic and proteomic) approach to unveil cellular and molecular determinants of burn-induced fibrosis.
15 We will investigate identified pathological mediators using transgenic and/or pharmacologic manipulation.
16 Collagen dynamics (architecture, orientation, cross-linking) will be assessed using a variety of techniques to
17 understand the remodeling potential of ECM after burn injury. Project 2 will evaluate the chronic effect of
18 burn injury on immune responses in muscle and its effect on myogenic and ECM-related processes.
19 We will assess immune cell abundance and phenotype in muscle in the days to months following burn injury.
20 We will also investigate how burn reprograms immune cells epigenetically, metabolically, and functionally.
21 Upon identification of cellular perpetuators of muscle dysfunction after burn, we may pursue cell depletion
22 strategies to directly test their role in relation to muscle function. Project 3 will elucidate the potential by
23 which immunomodulation can restore healthy muscle adaptation after burn injury. We will investigate
24 whether immunomodulation of macrophage phenotype using Toll-like receptor (TLR) agonists stimulates
25 healthy ECM turnover and improves muscle mechanics and strength. Project 4 will fill the knowledge gap
26 regarding the role of muscle MyD88 in burn-induced cachexia and muscle regeneration. The TLR adaptor
27 molecule MyD88 is expressed in muscle and has been implicated in cancer cachexia but also required for
28 myofiber regeneration. We will employ a skeletal muscle MyD88 knockout transgenic animal to determine
29 whether MyD88 is pro-restorative or pro-wasting after burn injury. These projects support the overarching goal
30 of this proposal, which is to better understand burn-induced cellular and molecular dysfunction and to identify
31 therapeutic targets that can improve muscle function after severe burn injury.
Status | Finished |
---|---|
Effective start/end date | 8/1/24 → 8/1/24 |
Funding
- National Institute of General Medical Sciences
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