Browsing by Subject "Skin"

Now showing 1 - 4 of 4
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    A comparative approach to deciphering the molecular mechanisms of scar-free wound healing
    (2017-02) Erickson, Jami
    Although mammals form scars upon skin wound healing, the Mexican “Axolotl” salamander has the extraordinary ability to heal wounds scar-free. While axolotl skin histologically resembles mammalian skin, molecular details that prevent scar formation during axolotl wound healing are largely unknown. To address this knowledge gap, we performed transcriptional profiling during axolotl cutaneous wound healing. We analyzed genes that displayed differential gene expression during axolotl wound healing compared to previously published human gene expression profiling data. We found that Sal-like 4 (Sall4) expression was increased early during axolotl skin regeneration, but did not increase in humans until later time points. We hypothesize that early increase in expression of SALL4 after injury is required for scar-free wound healing. To test this hypothesis, we depleted SALL4 in vivo during wound healing. We found that when SALL4 is depleted, we see excessive Collagen I and XII deposition that occurs earlier and is not fully remodeled, resulting in a scar-like phenotype. To determine how SALL4 expression is regulated during wound healing, we sought to identify which microRNAs post-transcriptionally regulate SALL4. We found that miR-219 is able to regulate expression of axolotl SALL4 during wound healing. Further, when we ectopically increase miR-219 levels during axolotl wound healing, we find early excessive collagen deposition, mirroring the SALL4 depletion phenotype. Additionally, we found that miR-103, not miR-219, is able to regulate human SALL4. Thus, revealing one mechanism that could explain the different SALL4 expression profiles seen in axolotls vs. humans. Lastly, we describe how to use a Dual-Fluorescent green fluorescent protein (GFP)-Reporter/ monomeric red fluorescent protein (mRFP)- Sensor (DFRS) plasmid to quantitate the dynamics of specific miRNAs over time. This system allows researchers to obtain relative quantifications for microRNA levels during biological processes over time. This will allow researchers explore the expression dynamics of any microRNA over time in vivo.
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    Expanding Paradigms of Recessive Dystrophic Epidermolysis Bullosa-Associated Cancer Development and Treatment
    (2023-12) Macaulay, Allison
    Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genodermatosis with no cure. Patients suffer from a wide range of internal and external complications: mechanically induced blistering, chronic wounds, systemic inflammation, among others. Squamous cell carcinoma (SCC) frequently arises at chronic wound sites, where fibrosis and inflammation drive its progression. RDEB-associated SCC is treatment-resistant and highly metastatic, rendering it the major cause of death for patients with RDEB. In this thesis, I present research that encompasses the spectrum of RDEB advancement, from clinical management of cutaneous wounds to RDEB-associated SCC. The central theme of this work is expanding current paradigms of RDEB-associated SCC development and progression, with the ultimate goal of improving strategies available for clinical care. I begin with a general overview of cancer development, metastasis, and treatment. The three manuscripts constituting the primary chapters include a review of drug, cell, and gene therapies for junctional epidermolysis bullosa; a comprehensive analysis of single-cell RNA sequencing from RDEB skin and non-RDEB SCC tumors; and a research paper describing a potentially targetable biomarker of invasion in RDEB-associated SCC. In the conclusion, I consider future prospects of RDEB-focused research and reflect on the evolution of my scientific philosophy.
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    Learning your ABCDE’s: When To Worry About a Mole
    (2012-07-24) Majerus, Matt
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    Perception and Mechanical Properties of the Pacinian Corpuscle
    (2020-05) Held, Tiffany
    The sense of touch is processed by the somatosensory system in which mechanoreceptors are the sensory neurons that translate mechanical stimuli into neural impulses by using specialized mechanoreceptive end organs. Pacinian corpuscles (PCs), located primarily in the hairless skin of the hands and feet, are the mechanoreceptor responsible for sensing low--amplitude, high--frequency vibrations (80-1000 Hz). In this thesis, I explored how vibrotactile perception is mediated by the PCs using a combination of computational modeling, benchtop experiments on donor tissue, and psychophysical tests. There are several mechanical models of the PC, and the first part of this thesis demonstrated that a multiphysics model of a single PC contained enough details to recapitulate the trend of observed discriminability of human subjects. We showed that discriminability of sinusoidal vibrations increases as the frequency difference between the pairs increase, and we found that complex waveforms with two frequency components were more difficult to discriminate and did not follow a discernible trend. Next, we investigated the effect that Dupuytren disease (DD) has on vibrotactile perception at frequencies within the PC's range. Dupuytren disease is a progressive hand disorder in which growth and densitification of fibrous tissue in the palms eventually causes the affected fingers to bend irreversibly. DD usually presents clinically after the age of 50, affects about 3 per 10,000 adults, and is associated with alterations to the size and the internal structure of PCs. By measuring vibrotactile sensitivity in healthy and DD subjects, we found that women are more sensitive to high--frequency vibrations than men and that men with DD may exhibit reduced sensitivity compared to men without DD. We also found that, for patients in which DD presents unilaterally, the finger with DD is less sensitive than the corresponding finger on the unaffected hand. These data may serve as a useful reference to future DD researchers and may facilitate development of novel diagnostic or prognostic protocols. Finally, we designed a system to measure the viscoelastic properties of the PC and tested isolated human cadaveric PCs from donors with and without DD to better understand how the mechanoreceptor's viscoelastic properties affect vibrotactile perception.