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Browsing by Author "Moyer, Kurtis E."

Now showing 1 - 4 of 4
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    Building a Better Scar: Re-engineering Extracellular Matrix Structure in Dermal Scars
    Montgomery, Jade (Virginia Tech, 2020-01-27)
    Introduction Cutaneous scars represent a common surgical complication, yet no effective drug therapy for scar treatment currently exists despite huge patient and physician demand. A connexin 43 (Cx43) carboxyl terminus (CT) mimetic peptide, alpha Connexin Carboxy-Terminus 1 (αCT1), has demonstrated efficacy in improving long-term scar appearance in pre-clinical and clinical trials. However, current understanding of the mechanism-of-action by which αCT1 improves long-term scar appearance with early intervention treatment is not well understood. Methods In vivo: Scar biopsies from 1) human, 2) Sprague-Dawley rat, and 3) IAF Hairless guinea pig trials of αCT1 were examined for collagen matrix structure at 4 weeks (all models), and 2 and 6 weeks (rat and guinea pig models only). Collagen matrix variables examined included local disorganization of the fibers, a variable that is higher in unwounded skin compared to scar tissue, and density of the fibers, which is higher in scar tissue but can also be used as an early temporal marker of the rate of healing. In vitro: Primary murine dermal fibroblasts were isolated from the whole dermis of 3-4 week old transgenic mice expressing collagen 1(α2) GFP-tpz. Cells were sorted for expression via FACS and plated on prealigned collagen substrate for 7 days under conditions favorable to generating extracellular matrix. Results: All in vivo scar biopsies demonstrated some level of altered collagen matrix structure with αCT1 treatment. Treated scars had higher local disorganization of the collagen fibers within the wound, and an increase in collagen matrix density compared to control at certain earlier timepoints that tended to decrease or disappear at later timepoints. The IAF Hairless guinea pig, a novel splinted wound healing model presented herein, was found to closely replicate the human dermal collagen profile and changes in collagen profile spurred by αCT1, significantly outperforming the traditional rat model. Primary dermal murine fibroblasts treated in vitro with αCT1 significantly increased synthesis of procollagen 1, the precursor of collagen 1 necessary for constructing the extracellular matrix, suggesting that at least part of the reason for higher collagen density at early in vivo timepoints is due to increased collagen synthesis by fibroblasts. Conclusion: αCT1 treatment in the early stages of wound healing prompts individual fibroblasts to increase their output of collagen and create a more disorganized early collagen matrix. These early changes potentially spur the long-term scar appearance improvements seen in clinical trials, and provide a basis for future work to discover the cellular pathways to alter in order to improve wound healing and cutaneous scarring outcomes.
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    Connexin 43-Based Therapeutics for Dermal Wound Healing
    Montgomery, Jade; Ghatnekar, Gautam S.; Grek, Christina L.; Moyer, Kurtis E.; Gourdie, Robert G. (MDPI, 2018-06-15)
    The most ubiquitous gap junction protein within the body, connexin 43 (Cx43), is a target of interest for modulating the dermal wound healing response. Observational studies found associations between Cx43 at the wound edge and poor healing response, and subsequent studies utilizing local knockdown of Cx43 found improvements in wound closure rate and final scar appearance. Further preclinical work conducted using Cx43-based peptide therapeutics, including alpha connexin carboxyl terminus 1 (αCT1), a peptide mimetic of the Cx43 carboxyl terminus, reported similar improvements in wound healing and scar formation. Clinical trials and further study into the mode of action have since been conducted on αCT1, and Phase III testing for treatment of diabetic foot ulcers is currently underway. Therapeutics targeting connexin activity show promise in beneficially modulating the human body’s natural healing response for improved patient outcomes across a variety of injuries.
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    Opening the Debate: How to Fulfill the Need for Physicians’ Training in Circadian-Related Topics in a Full Medical School Curriculum
    Selfridge, Julia M.; Moyer, Kurtis E.; Capelluto, Daniel G. S.; Finkielstein, Carla V. (Ubiquity Press, 2015)
    Background: Circadian rhythms are daily changes in our physiology and behavior that are manifested as patterns of brain wave activity, periodic hormone production, recurring cell regeneration, and other oscillatory biological activities. Their importance to human health is becoming apparent; they are deranged by shift work and jet-lag and in disparate conditions such as insomnia, sleep syndromes, coronary heart attacks, and depression, and are endogenous factors that contribute to cancer development and progression. Discussion: As evidence of the circadian connection to human health has grown, so has the number of Americans experiencing disruption of circadian rhythms due to the demands of an industrialized society. Today, there is a growing work force that experiences night shift work and time-zone shifts shaping the demands on physicians to best meet the needs of patients exposed to chronic circadian disruptions. The diverse range of illness associated with altered rhythms suggests that physicians in various fields will see its impact in their patients. However, medical education, with an already full curriculum, struggles to address this issue. Summary: Here, we emphasize the need for incorporating the topic of circadian rhythms in the medical curriculum and propose strategies to accomplish this goal.
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    Precision Medicine Approach to Improving Reconstructive Surgery Outcomes for Breast Cancer Survivors
    Degen, Katherine Emily (Virginia Tech, 2018-07-25)
    As the survival rate increases, the importance of quality of life post-cancer is increasing. This, in conjunction with genetic screening, has increase the number of breast reconstructions 36%. The most common complication causing revision of reconstructive surgery is the formation of a dense scar capsule around the silicone implant called capsular contracture. Nearly all patients will experience this complication, though with different degrees of response, ranging from moderate scarring to major disfigurement and pain at the implant site. Presently, there is no way to predict the degree of contraction capsule formation that individual patients will suffer prospectively, nor is there clinical approach to preventing this complication. Patient information and tissue was collected in a uniform manner to address these lingering problems. Clinical data was used to construct a predictive model which can accurately predict capsular contracture severity in breast reconstruction patients. Histological analysis demonstrated differences in structure and cell composition between different capsule severities. Of particular note, a new region was described which could serve as the communication interface between innate immune cells and fibroblasts. RNA-seq analysis identified 1029 significantly dysregulated genes in severe capsules. Pathway enrichment was then performed which highlights IL4/13 signaling, extracellular matrix organization, antigen presentation, and interferon signaling as importantly dysregulated pathways. These RNA results were also compared to various clinical and histological measurements to evaluate novel correlations. PVT-1, a long non-coding RNA associated with cancer, was strongly correlated to capsules formed after cancer removal. This suggests cancerous transformations of cell types that remain after the tumor is removed. Furthermore, transgelin and caspase 7 correlated to myofibroblasts density, suggesting an abnormal fibroblasts that are resistant to cell death and may have enhanced contractile abilities. Capsule formation is a complex process however, with well controlled clinical models quantitative differences can be found. These results serve as stepping stone for the field to move beyond retrospective clinical trials and pursue treatments and preventative measures.