Advance-CTR

Advance RI-CTR Pilot Projects Program (Cycle 10)

"Enhancing Tendon Repair through Genetically Modified Human Tenocytes"

Musculoskeletal injuries are the most common type of non-fatal occupation-related injuries reported in Rhode Island with tendon and ligament injuries being most common amongst them. Degenerative Patellar tendinopathy (PT) is a chronic and debilitating condition characterized by pain, inflammation, and progressive tissue degeneration, leading to significant functional impairment.

Current treatment modalities, including physical therapy, corticosteroid injections, and surgical interventions, often result in incomplete recovery, long rehabilitation periods, and high recurrence rates. The lack of effective regenerative therapies highlights an urgent need for novel, targeted approaches to improve patient outcomes. This project focuses on developing genetically modified human tenocytes (hTNCL-CXCR4) as a cell-based therapy for PT. These tenocytes overexpress the CXCR4 receptor, which plays a pivotal role in cell migration and tissue repair by responding to stromal cell-derived factor-1 (SDF-1) signals at injury sites. CXCR4 overexpression is hypothesized to enhance tenocyte retention, reduce inflammation, and promote anti-catabolic signaling, resulting in improved tendon healing. 

The specific aims of the study are:

1. Elucidate the impact of CXCR4 overexpression on the transcriptomic landscape of hTNCL-CXCR4: RNA sequencing and bioinformatic analysis will identify differentially expressed genes and pathways related to cell migration, inflammation and wound healing modulated by CXCR4 overexpression. Functional assays, including scratch and proliferation assays, will validate key targets of interest.
2. Investigate the migration efficiency of hTNCL-CXCR4 toward injured tissue ex vivo: Cell migration assays using human tendon explants will quantify the movement and retention of hTNCL-CXCR4 cells at injury sites in response to SDF-1, simulating the biological environment of tendon injuries.
3. Evaluate the therapeutic efficacy of hTNCL-CXCR4 in a rat model of degenerative PT: A well-established rat model of degenerative PT will be employed to evaluate the in vivo healing capacity of hTNCL-CXCR4.

Minimally invasive injections of hTNCL-CXCR4 will be performed and cells will be regularly monitored via live imaging. Histological analyses will be used to assess tissue regeneration, cell retention, and inflammation reduction.

This innovative study integrates advanced techniques such as GFP-tagged cell tracking, transcriptomic profiling, and cutting-edge spatial molecular imaging to uncover the molecular mechanisms underlying CXCR4-mediated tendon repair. The expected outcomes include proof-of-concept data on the safety, efficacy, and scalability of hTNCL-CXCR4 therapy, with significant implications for clinical translation. The health relevance of this research lies in its potential to revolutionize treatment for PT and other soft tissue injuries by providing a minimally invasive, cell-based regenerative therapy.

Beyond PT, the therapeutic principles and methods developed in this study could be adapted for broader applications in musculoskeletal injury repair, including ligament and intervertebral disc repair. This work directly aligns with the Advance-CTR’s mission to advance innovative clinical and translational that address the broad-spectrum challenges faced by the population in Rhode Island. As a junior investigator, I firmly believe that this pilot project funding will provide me with the necessary support to launch my independent research career (Please refer to the support letters from the Department Chair and other relevant individuals).

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