Browsing by Author "Ali, Asim"

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    72. The Role of TrkA And P75NTR NGF Receptors in Corneal Wound Healing
    (Wolters Kluwer, 2022) Tajdaran, Kiana; Feinberg, Konstantin; Mirmoeini, Seyed K.; Zhang, Jennifer; Gordon, Tessa; Ali, Asim; Borschel, Gregory; Surgery, School of Medicine
    Purpose: The cornea is the window through which we see the world and is one of the most densely innervated structures in the body. Besides providing protective sensory input, corneal nerves may also stimulate limbal stem cells (LSCs), governing corneal epithelial maintenance and recovery. Loss of corneal innervation, through injury, diabetes, tumors, infections, and even improper contact lens use, leads to neurotrophic keratopathy (NK), a degenerative corneal disease that is characterized by corneal epithelial breakdown, scarring, and permanent vision loss1. The only non-invasive treatment option for NK is human recombinant nerve growth factor (rhNGF), but the short half-life of exogenous neurotrophins-based therapies limits their effecacy2. Development of small molecule ligands for neurotrophin receptors that have more favorable pharmacokinetics and plasma stability showed promising results in the treatment of several neurodegenerative conditions in recent years3. In this study, we investigated the molecular mechanism of NK and the role of the NGF receptors, TrkA and p75NTR, in corneal healing. We hypothesized that TrkA inhibition would delay corneal wound healing and p75NTR inhibition would accelerate corneal healing. Establishing the roles of these receptors may enable novel topical therapeutics for NK. Methods: We used commercially available Ntrk1 mutant mice, whose TrkA receptors are inhibited by a mammalian kinase inhibitor (1-NM-PP1)4. Ntrk1 mice (n=20) were divided into three groups, which received saline injection as a control. In one experimental group animals received TrkA inhibitor and the other group received both TrkA and p75 inhibitor for 5 days. On day six we removed the corneal epithelium with a 0.5 mm rotating brush. To measure epithelial healing, we performed digital imaging of fluorescein staining daily for four days after injury. We then harvested the corneas for immunofluorescent and biochemical analyses. Results: We observed a significant delay in corneal epithelial healing following TrkA inhibition. Further, we observed that topical p75NTR inhibition accelerated corneal wound healing. Conclusion: A selective TrkA agonist or p75NTR inhibition could represent new topical therapeutics for NK.
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    Corneal Nerve Assessment by Aesthesiometry: History, Advancements, and Future Directions
    (MDPI, 2024-05-12) Crabtree, Jordan R.; Tannir, Shadia; Tran, Khoa; Boente, Charline S.; Ali, Asim; Borschel, Gregory H.; Surgery, School of Medicine
    The measurement of corneal sensation allows clinicians to assess the status of corneal innervation and serves as a crucial indicator of corneal disease and eye health. Many devices are available to assess corneal sensation, including the Cochet–Bonnet aesthesiometer, the Belmonte Aesthesiometer, the Swiss Liquid Jet Aesthesiometer, and the newly introduced Corneal Esthesiometer Brill. Increasing the clinical use of in vivo confocal microscopy and optical coherence tomography will allow for greater insight into the diagnosis, classification, and monitoring of ocular surface diseases such as neurotrophic keratopathy; however, formal esthesiometric measurement remains necessary to assess the functional status of corneal nerves. These aesthesiometers vary widely in their mode of corneal stimulus generation and their relative accessibility, precision, and ease of clinical use. The development of future devices to optimize these characteristics, as well as further comparative studies between device types should enable more accurate and precise diagnosis and treatment of corneal innervation deficits. The purpose of this narrative review is to describe the advancements in the use of aesthesiometers since their introduction to clinical practice, compare currently available devices for assessing corneal innervation and their relative limitations, and discuss how the assessment of corneal innervation is crucial to understanding and treating pathologies of the ocular surface.
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    Corneal Neurotization: Preoperative Patient Workup and Surgical Decision-making
    (Wolters Kluwer, 2023-10-11) Daeschler, Simeon C.; Woo, Jyh Haur; Hussein, Isra; Ali, Asim; Borschel, Gregory H.; Surgery, School of Medicine
    Background: The use of sensory nerve transfers to the anesthetic cornea has transformed the treatment of neurotrophic keratopathy by restoring ocular surface sensation and activating dysfunctional epithelial repair mechanisms. However, despite numerous reports on surgical techniques, there is a scarcity of information on the interdisciplinary management, preoperative assessment, and surgical decision-making, which are equally critical to treatment success. Methods: This Special Topic presents a standardized, interdisciplinary preoperative workup based on our 10-year experience with corneal neurotization in 32 eyes of patients with neurotrophic keratopathy. Results: Our assessment includes a medical history review, ophthalmic evaluation, and systematic facial sensory donor nerve mapping for light touch and pain modalities. This approach enables evidence-based patient selection, optimal surgery timing, and suitable donor nerve identification, including backup options. Conclusions: Based on a decade-long experience, this special topic highlights the importance of interdisciplinary collaboration and provides a practical roadmap for optimizing patient selection and surgical decision-making in patients undergoing corneal neurotization.
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    Schwann Cells Are Key Regulators of Corneal Epithelial Renewal
    (Association for Research in Vision and Ophthalmology (ARVO), 2023) Mirmoeini, Kaveh; Tajdaran, Kiana; Zhang, Jennifer; Gordon, Tessa; Ali, Asim; Kaplan, David R.; Feinberg, Konstantin; Borschel, Gregory H.; Surgery, School of Medicine
    Purpose: Corneal sensory nerves protect the cornea from injury. They are also thought to stimulate limbal stem cells (LSCs) to produce transparent epithelial cells constantly, enabling vision. In other organs, Schwann cells (SCs) associated with tissue-innervating axon terminals mediate tissue regeneration. This study defines the critical role of the corneal axon-ensheathing SCs in homeostatic and regenerative corneal epithelial cell renewal. Methods: SC localization in the cornea was determined by in situ hybridization and immunohistochemistry with SC markers. In vivo SC visualization and/or ablation were performed in mice with inducible corneal SC-specific expression of tdTomato and/or Diphtheria toxin, respectively. The relative locations of SCs and LSCs were observed with immunohistochemical analysis of harvested genetically SC-prelabeled mouse corneas with LSC-specific antibodies. The correlation between cornea-innervating axons and the appearance of SCs was ascertained using corneal denervation in rats. To determine the limbal niche cellular composition and gene expression changes associated with innervation-dependent epithelial renewal, single-cell RNA sequencing (scRNA-seq) of dissociated healthy, de-epithelized, and denervated cornea limbi was performed. Results: We observed limbal enrichment of corneal axon-associated myelinating and non-myelinating SCs. Induced local genetic ablation of SCs, although leaving corneal sensory innervation intact, markedly inhibited corneal epithelial renewal. scRNA-seq analysis (1) highlighted the transcriptional heterogenicity of cells populating the limbal niche, and (2) identified transcriptional changes associated with corneal innervation and during wound healing that model potential regulatory paracrine interactions between SCs and LSCs. Conclusions: Limbal SCs are required for innervation-dependent corneal epithelial renewal.
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    Sustained Release of Tacrolimus From a Topical Drug Delivery System Promotes Corneal Reinnervation
    (Association for Research in Vision and Ophthalmology (ARVO), 2022) Daeschler, Simeon C.; Mirmoeini, Kaveh; Gordon, Tessa; Chan, Katelyn; Zhang, Jennifer; Ali, Asim; Feinberg, Konstantin; Borschel, Gregory H.; Surgery, School of Medicine
    Purpose: Corneal nerve fibers provide sensation and maintain the epithelial renewal process. Insufficient corneal innervation can cause neurotrophic keratopathy. Here, topically delivered tacrolimus is evaluated for its therapeutic potential to promote corneal reinnervation in rats. Methods: A compartmentalized neuronal cell culture was used to determine the effect of locally delivered tacrolimus on sensory axon regeneration in vitro. The regenerating axons but not the cell bodies were exposed to tacrolimus (50 ng/mL), nerve growth factor (50 ng/mL), or a vehicle control. Axon area and length were measured after 48 hours. Then, a biodegradable nanofiber drug delivery system was fabricated via electrospinning of a tacrolimus-loaded polycarbonate-urethane polymer. Biocompatibility, degradation, drug biodistribution, and therapeutic effectiveness were tested in a rat model of neurotrophic keratopathy induced by stereotactic trigeminal nerve ablation. Results: Sensory neurons whose axons were exposed to tacrolimus regenerated significantly more and longer axons compared to vehicle-treated cultures. Trigeminal nerve ablation in rats reliably induced corneal denervation. Four weeks after denervation, rats that had received tacrolimus topically showed similar limbal innervation but a significantly higher nerve fiber density in the center of the cornea compared to the non-treated control. Topically applied tacrolimus was detectable in the ipsilateral vitreal body, the plasma, and the ipsilateral trigeminal ganglion but not in their contralateral counterparts and vital organs after 4 weeks of topical release. Conclusions: Locally delivered tacrolimus promotes axonal regeneration in vitro and corneal reinnervation in vivo with minimal systemic drug exposure. Translational relevance: Topically applied tacrolimus may provide a readily translatable approach to promote corneal reinnervation.
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    The Role of Sensory Innervation in Homeostatic and Injury-Induced Corneal Epithelial Renewal
    (MDPI, 2023-08-09) Feinberg, Konstantin; Tajdaran, Kiana; Mirmoeini, Kaveh; Daeschler, Simeon C.; Henriquez, Mario A.; Stevens, Katelyn E.; Mulenga, Chilando M.; Hussain, Arif; Hamrah, Pedram; Ali, Asim; Gordon, Tessa; Borschel, Gregory H.; Surgery, School of Medicine
    The cornea is the window through which we see the world. Corneal clarity is required for vision, and blindness occurs when the cornea becomes opaque. The cornea is covered by unique transparent epithelial cells that serve as an outermost cellular barrier bordering between the cornea and the external environment. Corneal sensory nerves protect the cornea from injury by triggering tearing and blink reflexes, and are also thought to regulate corneal epithelial renewal via unknown mechanism(s). When protective corneal sensory innervation is absent due to infection, trauma, intracranial tumors, surgery, or congenital causes, permanent blindness results from repetitive epithelial microtraumas and failure to heal. The condition is termed neurotrophic keratopathy (NK), with an incidence of 5:10,000 people worldwide. In this report, we review the currently available therapeutic solutions for NK and discuss the progress in our understanding of how the sensory nerves induce corneal epithelial renewal.