Colorado School Of Mines

NIH Research Projects · FY 2025 · 2024-07

Project Summary: Type 1 diabetes (T1D) is characterized by the immune-mediated loss of insulin-producing β-cells in the islet. Loss of the peri-islet ECM has been well documented in recently diagnosed patients with T1D and is associated with increased insulitis and β-cell death. In pre-symptomatic T1D, β-cell dysfunction and ER stress occur prior to significant immune cell infiltration. Our preliminary results indicate that cytokine-stressed β- cells express ECM degrading enzymes (including MMPs) that may contribute to loss of the peri-islet ECM prior to the onset of insulitis and may facilitate infiltration of autoreactive immune cells and β-cell death. In the early stages of T1D, islet infiltration correlates with loss of peri-islet laminin-10. Our preliminary data suggests that loss of islet interactions with laminin-10 increases cytokine-induced death and increases the activity of protein kinase C δ (PKCδ), where we have recently identified increases in PKCδ activity as a critical mediator of β-cell death. Additionally, previous studies have shown that islet interactions with laminin increase glucose stimulated insulin secretion (GSIS) via increased expression of glycolytic enzymes and mediate mitochondrial morphology and function. Taken all together, this supports a role for loss of peri-islet laminin-10 in contributing to T1D pathogenesis. We hypothesize that cytokine-stressed β-cells contribute to loss of the peri-islet ECM in early T1D leading to decreases in β-cell function and survival. We propose the following 2 aims: 1) Determine if cytokine-stressed β-cells degrade the peri-islet ECM in early T1D, and 2) Determine if loss of laminin-10 interactions regulates islet survival and function in early T1D. Experiments for both aims will utilize mouse and human islets encapsulated in a novel 3D biomimetic scaffold with laminin-10, as well as human pancreas sections from the nPOD program. Aim 1 will determine if β-cell mediated degradation of the peri-islet ECM precedes the onset of T1D. Aim 2 will determine the molecular mechanisms underlying islet dysfunction and death with loss of peri-islet laminin-10 in T1D. The successful completion of this project will define a new role for the β-cell in degrading the peri-islet ECM in early T1D that contributes to altered islet function and survival. Our results will challenge the current paradigm that β-cells are innocent bystanders in T1D onset and will provide novel therapeutic targets to halt immune infiltration of the islet and improve islet function and survival.

NSF Awards · FY 2024 · 2024-07

Climate change is resulting in warming of the permafrost across the Arctic and sub-Arctic, which results in changes in the geological and mechanical properties of soils. Quantifying the changes in soil properties are critical for both understanding the natural environment and assessing the effects of these changes on the existing and future built infrastructure, both of which have long-lasting societal impacts. This project will embed fiber optic sensing cables into the ground in an Alaskan coastal community. Fiber-optic-sensed signals will be converted into the geological and geomechanical properties of the ground material and then used to quantitatively forecast future impacts on permafrost properties. The project outcomes will enable realistic evaluation of the performances of infrastructure in Arctic Alaska and improve the design of more robust infrastructure in the Arctic. The research team will actively recruit and train women scientists and engineers through convergent research, and the research team will be involved in educational and outreach activities in Utqiaġvik, Alaska’s indigenous community. The goal of this project is to understand and forecast long-term variations of in-situ geophysical and geomechanical characteristics of the active layer and permafrost in Arctic Alaska using an innovative sensing technology, data transmission and analysis, and modeling. Through advances in sensor systems and modeling, the project will transform existing capabilities for understanding dynamic, near-surface soil processes in the active layer and permafrost in an Arctic coastal community, thus generating quantitative knowledge of long-term and in-situ permafrost degradation in the Arctic due to climate change. Five tasks will be conducted: (1) develop and deploy a 1.5-kilometer-long fiber-optic distributed acoustic sensing (DAS) array in Utqiaġvik, Alaska for long-term in-situ permafrost monitoring; (2) develop innovative data transmission and analysis of DAS signals in permafrost and derive temperature-dependent S-wave and P-wave velocity profiles of changing permafrost in spatial and temporal scales; (3) obtain ground-truth measurements of geophysical and geomechanical properties through in-situ and laboratory characterizations; (4) develop correlations between geophysical and geomechanical properties of permafrost and S- and P-wave velocities as well as between permafrost temperature and S- and P-wave velocities; and (5) forecast future changes of geophysical and geomechanical properties of degrading permafrost. Research outcomes will directly inform current infrastructure evaluation and future infrastructure development in the North Slope Borough, Alaska. Methodology developed in this project will provide transformative and cost-effective geophysical and geotechnical monitoring in the Arctic and sub-Arctic regions. This award was made through the "Signals in the Soil (SitS)" solicitation, a collaborative partnership between the National Science Foundation and the United States Department of Agriculture National Institute of Food and Agriculture (USDA NIFA). This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-06

Mobile devices, such as smartphones and tablets, embed multiple processors to efficiently carry different types of computation. In such systems, applications running on different processors store their data on a single shared memory. This project uncovers certain security vulnerabilities that mobile systems with shared memories possess. Leveraging these vulnerabilities, a malicious party could circumvent existing protection mechanisms and extract sensitive information by monitoring data access patterns. The research will develop a framework to better understand potential attacks and investigate several protection mechanisms. Broader comprehension and mitigation of these attacks hold crucial importance in protecting intellectual property and user privacy in mobile devices. The award contributes to enabling a more secure operation of billions of mobile devices used daily around the globe. This project investigates a critical side-channel leakage mechanism based on the memory-access contention occurring when multiple applications execute together in a multi-processor system with shared memory. An adversary could exploit this leakage to build attacks and extract intellectual property, such as the hyper-parameters of neural networks used in biometric authentication, without requiring special privileges or comprised hardware. This project builds upon an attacker framework to extract unique memory-contention-based signatures of victim applications. New profiling and analysis techniques are developed to capture non-linear memory access characteristics of machine learning and artificial intelligence workloads. The signatures are then used to create reverse-engineering, information extraction and denial-of-service based attacks. Finally, various countermeasures at architecture- and system-level are developed against the new attacks. The research team investigates the security, performance, area, and energy implications of new memory controller scheduling policies and randomization-based solutions. This project unveils a previously overlooked class of cybersecurity threats with financial and privacy-related impacts. The awareness and mitigation of the new security issues strengthen the trustworthy operation of billions of mobile devices. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY/ABSTRACT Antibiotic resistance is becoming increasingly catastrophic. Developing novel drugs that target essential ma- chinery in bacteria for which there is not yet resistance is critical to expanding treatment options and reducing the toll of infections. The long-term goal of this work is to develop drug candidates that target the SUF-like pathway of iron-sulfur (Fe-S) cluster biosynthesis as a novel treatment for drug resistant infections caused by Gram-positive bacteria. The SUF-like pathway was recently identified as a viable drug target, but a systematic screen against any SUF proteins remains lacking. The overall objectives of this proposal, which build off a library screen, are to characterize and optimize three structural classes of inhibitors of the SUF-like pathway that pos- sess favorable pharmacokinetic and ADME properties and are effective against S. aureus, E. faecalis, and S. pneumoniae. The specific target in the proposed research is the cysteine desulfurase from the SUF-like pathway, SufS, which has >60% sequence identity between the three named species. The central hypothesis is that small molecules can selectively occupy the SufS active site and alkylate the catalytic cysteine residue, thereby inhib- iting cysteine desulfurase activity and causing reduced cell viability in Gram-positive bacteria. This hypothesis is supported by preliminary data, including the screening of an acrylamide compound library against SufS from S. aureus, which identified 18 hits that covalently modify SufS and inhibit cysteine desulfurase activity. The central hypothesis will be tested through three specific aims: assess the (1) bioactivity and (2) biochemistry of the 18 hits and (3) synthetically modify the hits to improve potency and drug-likeness. In Aim 1, the inhibitors will be assessed for their efficacy against S. aureus, E. faecalis, and S. pneumoniae; their specificity in S. aureus; and their drug metabolism and pharmacokinetic properties. In Aim 2, the binding residue and binding mode of the inhibitors will be determined using X-ray crystallography, and potency will be assessed using dose response assays. In Aim 3, the best inhibitors will be synthetically modified to increase their potency and selectivity using structure-guided drug design. The proposed research is innovative because it is the first known effort dedicated to pursuing the SUF-like pathway as a drug target for new antibacterial agents, and it involves the first systematic screening of a compound library against the SUF-like pathway. The proposed research is significant because the results will provide a framework for developing novel broad-spectrum antibacterial agents, for which there is not yet resistance, to treat infections from three Gram-positive infections, including S. aureus, E. faecalis, and S. pneumoniae, which are all listed as serious threats by the Centers of Disease Control and Prevention. Addi- tionally, this work will enhance our understanding of the effects of modulating the SUF-like pathway and lay the foundation for identifying other targets that rely on the SUF-like pathway, such as M. tuberculosis and parasites that causes malaria, thereby adding a powerful new tool to improve human health and well-being.

NIH Research Projects · FY 2025 · 2024-06

Meibomian gland dysfunction (MGD) is the leading cause of the dry eye disease which affects 6 to 7 million people in the United States. The Meibomian glands in MGD dry eye patients are unable to secrete oily lipids resulting in loss of the lipid layer on the surface of tears, leading to an increase in tear evaporation. Current treatments for patients with MGD include warming of the glands to temperature higher than melting point of the meibomian in MGD patients to increase secretion of the lipids, which will increase tear volume and reduce dry eyes symptoms. Most commercial therapies for the warming- treatment heat eyelids from the outside even though the glands are located close to the inner surface of the eyelids in contact with tears. Warming from outside requires heat to be applied at about 45 oC which can cause discomfort and burns. Additionally, heat supplied to the eyelids can reach the cornea which can also damage the cornea, particularly in conjunction with applied massage. We are proposing a novel approach for warming the eyelids from inside by designing gold nanoparticle loaded contact lenses (GoldInLens) which can be warmed by exposure to a low intensity light source due to the absorption of light by gold nanoparticles due to surface plasmon resonance (SPR) effect. To use the GoldInLens treatment, patients will insert the lens, and then keep their eyes open while the lens is exposed to the light source for about 10 s to increase lens temperature to the targeted 40 oC. The patients will then close the eyes to warm the Meibomian glands. The lens will cool during this phase and so after certain time, which will be determined in this study, the patients will open eyes for subsequent exposure to the light source to warm the lens. This cycle of warming of lens during open eyes followed by warming of the glands during closed eyes will be repeated for 10 min. To eliminate the potential for cornea damage, we will design a piggyback system by placing the GoldInLens on top of a low thermal conductivity polymethyl methacrylate contact lens which will act as an insulator to minimize exposure of the cornea to the elevated temperatures. Additionally, gradient lenses with gold nanoparticles located only near the front surface will be prepared to produce the benefits of the piggyback design but with a simpler manufacturing process. Lenses will be tested extensively in vitro for transparency, warming, and proof-of-concept in vivo studies will be conducted in rabbits to explore feasibility. The overall hypothesis of this study is that gradient or piggyback lenses of gold nanoparticles will warm the inner eyelid preferentially, relative to the ocular surface. The hypothesis will be tested in the following two aims. 1) To design gradient and piggyback lenses for unidirectional delivery of heat to the eyelids. 2) To test directional delivery of heat in vivo in the rabbit. Successful completion of this research will lead to the development of a novel platform for providing affordable, at-home warming therapy for treating MGD. In future, we will expand the platform to include directional release of anti-inflammatory drugs to the eyelid while minimizing corneal toxicity. 2

NIH Research Projects · FY 2025 · 2024-03

Microbial keratitis (MK) is a serious ophthalmic infection that can cause visual impairment and even blindness. The MK infection is commonly treated by the fourth-generation fluoroquinolones such as moxifloxacin or combination therapy including tobramycin and vancomycin or gentamycin and vancomycin. The frequency of drop instillation for severe infections is every 5 min for the first 30 min followed by half-hourly drops or hourly drops for the first 24-72 hours including night. Subsequently, the frequency decreases to once every 2 or 4 hours. The high instillation frequency is required because of rapid eye drop clearance resulting in a low bioavailability of 1-5%. The total number of drops for this therapy could be as high as about 100 over 1-week of treatment. While efficacious, the patients have difficulties in complying with this high frequency application of eye drops resulting in poor prognosis. We will address this unmet need by designing a novel sustained release contact lens drug delivery system for delivering antibiotics (moxifloxacin (monotherapy) and tobramycin and vancomycin (combination therapy)) to treat MK. Contacts lenses offer many advantages over eye drops including extended release that will improve compliance by replacing 100 drops with 1-2 lenses and higher bioavailability that will lead to higher and more consistent concentrations in ocular tissues resulting in improved therapy and reducing the possibility of development of resistance that is becoming a major problem. We have developed a novel, patented approach for extended delivery by incorporation of vitamin E (a tocopherol) nanobarriers in commercial silicone hydrogel contact lenses. Use of commercial contact lenses that are already approved by the FDA reduces barriers to translation. Our preliminary results have shown that nanobarrier contact lenses (NB-CL) increase the drug release duration of moxifloxacin, while maintaining all key properties of the contact lenses including transparency, wettability, UV-blocking, oxygen and ion permeability, low protein binding, and young’s modulus. Specifically, we showed that incorporation of 20% (w/w) on dry basis of vitamin E in Acuvue Oasys lenses increases the release duration of moxifloxacin from a few hours to about 50 hours. Also, validated mathematical model suggests that an Oasys lens loaded with 30% VE and 500 µg of moxifloxacin will result in drug concentrations in aqueous humor comparable to the tedious drop regimen of numerous drops over 3 days. This research aims to manufacture and characterize the antibiotic-loaded nanobarrier lenses in Aim 1 and test pharmacokinetics and efficacy in New Zealand white rabbits in Aim 2. The approach will provide insights into sustained drug delivery and efficacy with acute wear NB-CL, and lead to a novel device to treat MK. Our approach promises to increase bioavailability, reduce dosage amount to improve compliance and minimize drug variations to reduce the potential for development of antibiotic-resistance. If successful, NB-CL for sustained drug delivery will revolutionize MK treatment by replacing about 100 drops with 1-2 contact lenses. The approach is applicable to other drugs individually or in combination for many other indications including other infections, glaucoma, wound-healing, inflammation, cystinosis, etc. The validated model will establish the fundamental design principles and serve as an optimization tool.

NIH Research Projects · FY 2026 · 2023-09

Currently most treatments for retinal diseases are based on frequent intravitreal injections, which are invasive, and could lead to serious complications such as endophthalmitis and retinal detachment. The frequent injections are necessary because the drugs delivered through the injection are cleared from the vitreous by multiple pathways. The frequency of injections in real-world experience may be lower than recommended resulting in poorer-than-expected treatment outcomes. It is ideal to administer ophthalmic drugs topically as eye drops but due to low bioavailability, they are not suitable to achieve therapeutic benefits in the back of the eye. Contact lenses have been extensively investigated for delivering drugs to treat anterior segment diseases because about 50% of the drug in the lenses permeates into the cornea compared to about 1-5% with eye drops. Delivery of drugs to the back of the eye including sustained delivery by contact lenses has received considerably less attention. Here we propose to advance contact lenses for back of the eye delivery, by determining the underlying mechanisms of delivery, evaluating enhanced and sustained delivery with the lenses relative to eye drops, developing models predictive of contact lens-based drug delivery, and developing novel lenses for delivery of biologics. We have preliminary data showing feasibility of contact lens mediated delivery of drugs to the back of the eye. The proposal will investigate two major pathways that can contribute to the back of the eye delivery from a contact lens: a) diffusion across cornea into anterior chamber followed by uveoscleral outflow into sclera-choroid and b) non-corneal transport involving diffusion into the tears followed by transverse diffusion across sclera and choroid into retina and vitreous. This proposal combines in vitro, ex vivo, in vivo and in silico studies to determine the relative importance of these pathways. We use a pharmacology-based approach in Aim 1 to evaluate the uveoscleral outflow pathway and a lens engineering-based approach entailing piggyback lenses in Aim 2 to understand the non-corneal pathway and to deliver drugs via one of the two pathways. Further, in Aim 2, we will develop and validate a novel, mechanistic, in-silico model incorporating drug and tissue properties. The model will allow design of contact lenses for delivering drugs to the back of the eye at therapeutic concentrations. In Aim 3, we will develop novel porous annulus lenses to deliver anti VEGF antibodies that are commonly used for treating wet age-related macular degeneration. All in vivo and ex vivo experiments will be conducted in New Zealand white rabbits that are commonly used for measuring ocular pharmacokinetics. In Aims 1 and 3, dexamethasone, which is used for treating diabetic macular edema is investigated, and in Aim 2, a series of corticosteroids with Log(P) ranging from 0.53 to 3.2 are used to explore the effect of hydrophobicity. In each of the Aims we use a novel approach of integrating vitamin E nanobarriers into contact lenses (NB-CL) to control the drug release kinetics. The approach will provide new fundamental insights into sustained drug delivery to the back of the eye using contact lenses. If successful, NB-CL for sustained drug delivery will become a noninvasive approach for back of the eye drug delivery to replace invasive intravitreal injections.

NIH Research Projects · FY 2025 · 2023-09

Project Summary/Abstract The Colorado School of Mines (CSM) Energy, Mining and Construction Industry Safety Program (EMCIS) is a well-established training organization that was initially formed in 1999 as the CSM Mine Safety and Health Program. With mining still at its core, CSM operates its training center to enhance the quality and availability of health and safety training for Western mine workers. Goals include providing workers with relevant knowledge regarding hazards associated with working on mine sites and effective controls for reducing risk for injuries and illnesses. In addition, trainees will be continuously encouraged to be active participants in improving the health and safety conditions where they work. CSM proposes to offer a comprehensive approach to meet the safety and health training needs of the Western mining industry by providing a high quality, interactive training experience that targets several audiences: mine workers, trainers, safety and health professionals, mine management, and mining engineering and geology students. In addition, CSM’s training program will service underrepresented industry sectors such as contractors, consultants, suppliers and equipment manufacturers. Courses will be taught by highly qualified, professional instructors, who are technical experts as demonstrated by academic degrees, professional certifications and licenses, and experience. Depending on the training activity, CSM will utilize a combination of teaching pedagogies, including classroom discussion, hands-on exercises, games and group activities, and participation at the Edgar Underground Mine, as well as opportunities for online delivery, for these courses which will enhance student engagement, understanding, and knowledge retention. The NORA sector that will be addressed by CSM is the Mining Sector. Primary NORA cross-sectors of Hearing Loss Prevention, Respiratory Health, Traumatic Injury Prevention, and Healthy Work Design and Well-Being are addressed indirectly by being included as topics in various training courses offered to the mining industry.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY/ABSTRACT In the pancreas the islet is surrounded by a specialized protein scaffold called the extracellular matrix (ECM) that regulates cell survival and insulin secretion. The ECM surrounding the islet consists mainly of laminin-10 and type IV collagen (COL IV) which provide mechanical and biochemical cues to the β-cells. During the onset of T1D, immune cells infiltrate the pancreas and the peri-islet ECM is degraded, leading to β-cell death. While changes to the peri-islet ECM have been well documented in T1D, the role of these ECM changes to T1D pathogenesis are largely unknown. Changes to ECM stiffness have been correlated to changes in insulin secretion; however, the mechanisms of mechanotransduction regulating insulin secretion have not been studied in the islet. Infiltrating immune cells also produce high levels of pro-inflammatory cytokines that cause islet dysfunction and death. While some studies have suggested that infiltrating immune cells degrade the peri-islet ECM, a recent study has shown that β-cell interactions with macrophages induces ECM remodeling by the β- cell. A role for the β-cell degrading the peri-islet ECM has not been established in T1D. Our overall goal is to determine the effect of changes in peri-islet ECM on islet function and to determine the role of autoreactive immune cells and cytokine stressed β-cells in remodeling the peri-islet ECM in T1D. We will utilize a novel reverse thermal gel scaffold functionalized with laminin-10 and COL IV with encapsulated mouse and human islets to accomplish this goal. Towards this goal we propose two specific aims: (1) Determine the effect of changes in ECM stiffness on islet function and insulin secretion dynamics; (2) Determine the role of autoreactive CD4+ and CD8+ T-cells and cytokine stressed β-cells in remodeling the peri-islet ECM in T1D. The results from this work will support a role for ECM mechanical properties in regulating islet function and will define a role for the β-cell in peri-islet ECM degradation and in the pathogenesis of T1D. The innovation of this work will provide useful insight into treating T1D and will help to improve diabetes therapies and the lives of patients.