Research

Targeting TRCP6: A Novel Approach for Discogenic Chronic Back Pain

Discogenic chronic back pain (DCBP) is a leading cause of disability, often linked to intervertebral disc (IVD) degeneration, inflammation, and nerve and blood vessel growth. Current treatments, including opioids, are insufficient, highlighting the need for new approaches. This project focuses on TRPC6, a promising target found to be elevated in degenerated, painful IVDs. Our research investigates how TRPC6 is activated within the IVD, its effects on cell behavior, and the potential for using TRPC6 inhibitors as a treatment. By understanding how mechanical and chemical changes in the disc environment influence TRPC6 and testing inhibitors in cell and animal models, we aim to develop a non-opioid treatment for DCBP, providing effective pain relief without addiction risks. If successful, this could lead to significant advancements in treating back pain and improving patient outcomes. Currently funded by Eurospine.

Substrate Stiffness, Topography, and TRPV4 in Disc Mechanotransduction

Over the past decade(s), research has revealed that substrate stiffness and architecture/topography can be recognized by cells, serving as mechanical and topographical cues that ultimately drive cell behavior through mechanoreceptors. These substrate changes can also affect the mechanical stimulation of cells, influencing their response to loading. These responses are largely governed by mechanosensitive ion channels, such as transient receptor potential (TRP) channels. This project aims to determine the impact of substrate stiffness and topography on TRPV4 activation in intervertebral disc cells (AF cells) in response to a pharmacological TRPV4 agonist and cyclic stretching, and its relevance in regulating extracellular matrix synthesis and remodeling. Ultimately, we aim to uncover the role of cell-substrate interactions in intervertebral disc health and disease, leveraging this knowledge to develop regenerative approaches. Currently funded by NIH NIGMS R16 GM146717-01.

Investigating TRPC6 Inhibition for Treating Scleroderma

Scleroderma is a rare disease characterized by chronic tissue hardening (fibrosis), particularly affecting the skin due to excessive collagen accumulation. Despite extensive research, effective therapies for scleroderma-related skin disease remain elusive. The ion channel TRPC6 plays a significant role in various fibrotic conditions but has not been explored in scleroderma. This project aims to investigate the therapeutic potential of TRPC6 inhibition in treating scleroderma. Initial experiments will utilize classical 2D cell cultures. Concurrently, an electrospun 3D scleroderma skin model will be developed, combining standard and advanced electrospinning techniques to simulate both epidermal and dermal layers seeded with keratinocytes and dermal fibroblasts, respectively. Cellular cues will induce scleroderma-like conditions in this organotypic model before assessing TRPC6 inhibition effects. Subsequently, the efficacy of TRPC6 inhibition will be evaluated in a bleomycin-induced in vivo scleroderma model. By exploring this novel therapeutic strategy, the project aims to pioneer effective treatments for scleroderma, offering hope for patients grappling with skin hardening and tightening. Currently funded by DoD CDMRP SL20014.

Extracellular vesicles produced by CRISPR-activated MSCs

Degenerative disc disease (DDD) is a leading cause of chronic low back and neck pain, significantly impacting daily activities and work attendance, and creating substantial financial burdens. Traditional treatments, including mesenchymal stem cell (MSC) therapy, face limitations due to the harsh microenvironment of degenerated intervertebral discs (IVDs). This project explores the potential of extracellular vesicles (EVs) derived from MSCs, specifically those enhanced by CRISPR/Cas9 activation of TSG6.  By modifying MSCs to overexpress TSG6, we aim to produce EVs with increased therapeutic capacity, targeting inflammation and catabolism in IVD cells. This research aims to develop non-opioid, targeted therapies for DDD, potentially offering new hope for effective pain management and improved quality of life for patients. Currently funded by NIH NIAMS R21AR081987.

TLR-Associated MicroRNAs

Dysregulation of inflammation in degenerative disc disease, which is believed to be associated with pain development, is based on complex molecular mechanisms. One of the main regulators of inflammation are Toll-like receptors (TLRs), amongst which TLR2 is specifically relevant in disc pathophysiology. Importantly, inflammation is closely linked with mechanical loading in the IVD as high loads not only induce inflammation themselves, but also modulate TLR expression and lead to the accumulation of damage-associated molecular patterns with inflammatory/TLR activating capacity. As TLRs are an essential component to tissue inflammation, their tight control is crucial. In numerous cell types, microRNAs (= small noncoding RNAs) have been shown to modulate TLR signaling and the downstream inflammation and catabolism, both in health and disease. This project will be the first to identify and comprehensively investigate miRNAs in the context of TLR activation in the IVD and will thus elucidate posttranscriptional regulation of genes associated with IVD pathophysiology under the linked concepts of inflammation and mechanoregulation.

Electrosprayed Biomaterials for Drug Delivery

While oral delivery of pharmaceutical compounds generally has the highest compliance rates, local delivery of drugs can often be more effective. To prolong the effects of the selected therapeutics, such as substances with anti-inflammatory, anti-catabolic, and/or anti-oxidant properties, slow-release systems that provide sustained delivery and enhanced protection against degradation are needed. In this context, electrospraying is particularly useful as it is a gentle electrohydrodynamic encapsulation method that can be conducted under less harsh conditions than most other encapsulation techniques and is hence specifically suitable for sensitive substances such as natural polyphenols. In this project, we aim to create electrosprayed nano-/microparticles for improved drug delivery. We currently focus on encapsulating the polyphenol resveratrol for improved wound healing, but this approach is also relevant for other drugs and application areas.