University Of Arizona

NIH Research Projects · FY 2026 · 2024-08

ABSTRACT Liver fibrosis and cirrhosis are widely prevalent globally and associated with high morbidity and mortality. A hallmark of liver fibrosis is hepatic stellate cells (HSC) activation. While there are many transcriptional and translational changes associated with HSC activation, how these changes are initiated and regulated is still not well understood. We recently demonstrated that BMP-SMAD1/5/8 signaling in hepatocytes is not only the central pathway that maintains iron homeostasis by regulating the iron hormone hepcidin, but also plays a protective role in liver fibrosis, as mice with hepatocyte SMAD1/5/8 signaling deficiency display spontaneous liver fibrosis. However, the mechanisms of hepatocyte SMAD1/5/8-mediated protection in liver fibrosis is not known. In addition, the function of SMAD1/5/8 signaling in HSC is completely missing. The overall objective of this proposal is to understand the role of SMAD1/5/8 signaling in hepatocytes and HSCs in liver fibrosis. My preliminary data suggest a role for hepatocyte SMAD1/5/8 signaling in regulating the production of wntless to control secretion of Wnt ligands, which have paracrine actions to activate HSCs. My data also suggest that intrinsic SMAD1/5/8 signaling within HSCs may also be protective against HSC activation and liver fibrosis. In Specific Aim I, I will use in vitro and in vivo approaches to determine the role of hepatocyte wntless in HSC activation and liver fibrosis in hemochromatosis and NASH models. I will also perform secretomics to identify the hepatocytes secreted paracrine modulators that activate HSCs. In Specific Aim II, I will used primary HSCs and HSC specific conditional knockout mice to investigate the intrinsic role of SMAD1/5/8 in HSC activation and liver fibrosis. This proposal will not only fill in the gaps in understanding the pathology of liver fibrosis in hemochromatosis but will also advance the liver fibrosis field more broadly by providing new insights into hepatocyte-HSCs intercellular communication and HSCs biology, more importantly, will pave the way for new clinical treatments for liver fibrosis and cirrhosis. My long-term career goal is to successfully establish a research group and obtain a tenure-track faculty position in a leading academic or hospital-based research institute. My future research goals are to bridge the gaps between iron disorders and chronic liver diseases through investigating the direct biological mechanisms by combining my expertise in iron homeostasis with the new training opportunities in liver histopathology, gene editing and proteomics techniques described in this proposal.

NIH Research Projects · FY 2024 · 2024-08

Abstract Carpal tunnel syndrome is the most common compressive neuropathy. The need for advancement in therapeutic treatment modalities is evidenced by the disease prevalence, potential for surgical complications and disparities in surgical availability amongst certain populations, particularly Hispanic women. Addressing this area of need is critical for regions such as Tucson, Arizona, which has a Hispanic population that is nearly half of the overall population. Non-surgical carpal arch space augmentation (CASA) is a treatment modality for carpal tunnel syndrome developed by our Hand Research Laboratory. This supplement has two specific aims. The first aim is to demonstrate treatment efficacy of the CASA intervention for symptom relief and hand function improvement in Hispanic women afflicted with carpal tunnel syndrome. The second aim is to compare the CASA intervention and standard-of-care (SOC) brace treatment for symptom relief and hand function improvement in Hispanic women with carpal tunnel syndrome. Hispanic women participants with carpal tunnel syndrome will be randomized into CASA and SOC groups. The study design is composed of a 4-week intervention phase and a 4-week follow-up phase. Patient-reported symptom and function outcomes will be collected over the 8 weeks. We hypothesize that the CASA treatment will alleviate symptoms and improve hand function of the carpal tunnel syndrome participants. Furthermore, we hypothesize that CASA treatment will be more effective than the SOC in relieving symptoms and improving hand function. Demonstrating the effectiveness of CASA in relieving symptoms and improving hand function in Hispanic women will provide a contribution to advancing treatment options of carpal tunnel syndrome for populations with evidenced healthcare disparities.

NSF Awards · FY 2024 · 2024-08

Currently, researchers generate large amounts of data that capture many features of physical plants and bring that data into computer systems in order to understand and reveal complex biological processes and interactions. However, extracting meaningful information from this data requires advanced technical skills such as algorithm development, programming, and statistics. The VR-Bio-Talk project will develop a life-like virtual reality (VR) visual analytics system, which will be controlled by voice. The user will be immersed in a field of scanned plants and will be able to interact with it verbally. For example, the command “show me all plants older than four weeks and their average leaf area.” will display only the correct plants and their leaf area as a label and a graph above them showing how the value is changing over time. At its core, this project will develop novel algorithms for artificial intelligence (AI)-based interaction and advanced processing, reconstruction, and visualization of large plant datasets. The overall aim is to bridge the domain gap of current data analytics systems. The anticipated impact will be support for the development of a data-enabled biology workforce capable of advancing the understanding of plant biology and contributing to innovations by deriving insights from data using novel systems and algorithms for interaction with large phenotypic data. Special attention will be given to including potentially disadvantaged users through built-in robustness to accents and support of learners with limited English proficiency and through VR data interaction designed to be accessible to users with limited motor skills. The novel AI-based voice-controlled VR interaction and visualization algorithms will have a broad impact that extends beyond the life sciences. This project has three main aims. (1) Development of novel AI-based algorithms for the reconstruction of the vast, rich, but often underused data from phenotyping facilities into plant digital twins that respond to the environment by providing highly detailed 3D geometry and light interaction. In particular, the project will use the rich data acquired by the University of Arizona field scanner. The plants will be rendered with high visual plausibility and photorealism. They will also be rendered in more salient false colors as needed for analysis and AI training. (2) The second aim is the development of a voice-controlled VR user interface that interprets complex compound commands. The interface will be connected to an AI-based voice recognition system and voice-to-text encoder, which will generate code and executable commands. The control will be tuned to respond to a wide variety of accents and commands. (3) The third aim will focus on the deployment and evaluation of a set of carefully designed experiments with participants ranging from novices to experts. The users will use intuitive, natural interaction via dialogue with an AI-enabled data analytics system. 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 · 2024-08

The proposed research seeks to continue to develop lasers for measurement of rare varieties of certain common elements of carbon and oxygen. Historically, these measurements have been done by mass spectrometry but recent successes in our laboratory suggest that lasers are a faster and more effective approach. Rare varieties (technically called isotopes) of many elements provide important data of significant interest to earth science, atmospheric and ocean chemistry, and biology. The research team at the University of Arizona has completed development of an automated, tunable infrared laser direct absorption spectroscopy (TILDAS) system that measures multiply substituted or “clumped” isotopologues of CO2 as precisely as existing methods using mass spectrometry, but at lower cost, using small samples, and much more rapidly. This proposal includes the purchase of the prototype instrument and expansion of it by adding a new laser unit to perform δ17O measurements. The sample preparation line will be modified to split a CO2 sample and deliver it to both laser systems. The result is an integrated laser monitor system that can measure clumped ∆638 (≈∆47), δ18O, δ13C, and d17O of carbonate at high precision in less than 50 minutes on a single sample aliquot of ~2mg. Combining these measurements in one instrument is unprecedented and will significantly benefit the scientific community. 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 2026 · 2024-07

PROJECT ABSTRACT Asthma is a heterogenous disease that impacts ~10% of the US population. It presents as a syndrome of non- specific airway hyperresponsiveness, inflammation and intermittent respiratory symptoms. Even though more than half of patients receiving standard asthma medication remain uncontrolled, mainstay treatments have been largely unchanged for several decades. While the introduction of the asthma-specific biologics in the last several years has improved asthma for some, those treatments are extremely costly and are typically reserved for the most severe of patients. For most asthma patients, responses are mediated by environmental allergens which frequently possess potent protease activity. These allergen proteases provoke an increased allergen response, in part by the direct activation of protease-activated receptor-2 (PAR2). PAR2 is a newly established target for development of novel analgesics and therapeutics for inflammatory diseases, including asthma. We have developed novel antagonists to PAR2 that in preliminary experiments using pre-clinical models have proven to be effective in inhibiting or reducing the detrimental physiological changes associated with allergen-induce asthma. Our central hypothesis for this application is: Small molecule pharmacological control of airway epithelial and/or nociceptor PAR2 signaling provides a novel strategy for asthma protection that can be demonstrated in vivo. We propose 3 specific aims, in which we will use a combination of in vitro and in vivo approaches to uncover a mechanistic understanding for the roles for epithelial- and neuronal-expressed PAR2 in allergic asthma. These studies will specify pharmacological impact of PAR2 modulation on airway epithelial cells and sensory neurons in vitro and in pre-clinical asthma models with human validation and will provide mechanistic understanding and cellular targeting for development of novel asthma drugs for clinical trials.

NIH Research Projects · FY 2026 · 2024-07

Project Summary/Abstract The environmental justice (EJ) framework highlights the social, political, and economic assumptions contributing to and producing unequal protection in EJ communities; highlighting that understanding a community's perspectives is crucial to conducting impactful environmental health research and literacy initiatives. There remains a need for novel research that facilitates responsible reporting back of research results (RBRR) in a manner that raises data and environmental health literacy (D/EHL) and supports communities striving for environmental health and structural change. Despite recent progress in addressing longstanding EJ issues, the bioethics literature focuses on: (a) harm, not beneficence or justice; (b) underestimates opportunities to raise D/EHL among communities; and (c) commonly employs risk communication strategies that are technical, and not based in a cultural model. The project goal is to create and pilot a national model of report back that engages diverse rural and urban EJ communities to ensure that RBRR reaches all populations in a manner tailored to their individual needs, including culture, life stage, language, and design. Rooted in bioethics, the program focuses on how to report back social determinants of health and soil and air quality data in rural and urban communities that are disproportionately impacted by pollution. Building upon trusted and established long-term partnerships and leveraging existing datasets, this project addresses cross- cutting research themes anchored in health equity, communication approaches, and the use of data report back. Through partnerships with community-based organizations and local government agencies, this project will address community concerns and social/EJ challenges in both rural, predominately Hispanic mining communities and urban, Black/African American communities. The specific aims of this proposal include: (1) Using an equity-centered community design approach to develop different design types and identify what influences preferred report back strategies, (2) Within the context of specific populations (cultural identity) and groups (life stage), elucidate key D/EHL learning outcomes by design type, (3) Identify, evaluate, and mitigate the unintentional consequences of environmental health report back by working with both rural and urban EJ communities, and (4) Develop capacity building tools for RBRR, train knowledge mediators/brokers and evaluate the efficacy of these tools to support the role of “environmental counselors”.

NSF Awards · FY 2024 · 2024-07

Today, the vast majority of Indigenous Peoples’ data are held by non-Indigenous entities that continue to produce knowledge across fields of medicine, public health, genomics, earth sciences, and the social sciences. However, Indigenous data are often organized into Western classification and naming systems that not only disconnect such data from the Indigenous contexts that give them meaning but also make it difficult for Indigenous Peoples to find their data. Indigenous data are any data, information, and knowledge that impact Indigenous Peoples at individual and collective levels, including: (1) information about lands, skies, waters, and more than human relations; (2) data about Indigenous Peoples and their communities; and (3) knowledge such as oral histories, languages, belongings, and cultural information. This project will establish and grow the international CARE (Collective benefit, Authority to control, Responsibility, and Ethics) Network-of-Networks (NoN) with the goal of fostering responsible and respectful knowledge exchange, training, and connections globally for researchers who collect, use, and store Indigenous data. The CARE NoN will forge international-scale collaboration among the Global Indigenous Data Alliance, five national/regional Indigenous Data Sovereignty networks (US, Aotearoa New Zealand, Australia, Canada, and Sapmí in Norway, Sweden, Finland), and three international Indigenous Data Governance collectives (the NSF-funded Center for Braiding Indigenous Knowledges and Science, the Equity for Indigenous Research and Innovation Coordinating Hub, and the Collaboratory for Indigenous Data Governance), promoting Indigenous leadership and design for Indigenous data futures. It is critical for the CARE NoN to develop targeted mechanisms and tools that will reveal biases in data collection, storage, and circulation, then intervene with solutions to advance science in service to communities. The CARE NoN will develop and drive (A) innovation, (B) ethical and responsible science, (C) technology theory around collaborative and participative international research, and (D) social science theory. Expected outputs from the CARE AccelNet NoN will inform digital design, research ethics, data governance, and data responsibility for Indigenous Data Sovereignty and Indigenous Data Governance across multiple domains. 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 · 2024-07

Proteostasis comprises the processes governing the life cycle of proteins from synthesis to degradation. Imbalanced proteostasis contributes to numerous pathologies, including those affecting the heart. Proteostasis in the sarco/endoplasmic reticulum (ER) of cardiac myocytes is important since proteins involved in contractile Ca handling, as well as receptors and secreted proteins, are synthesized on ER-bound ribosomes. We found that cardiac pathology imbalances ER proteostasis, causing ER stress and misfolded proteins that must be degraded to avoid toxicity. This proposal concerns one such degradation process, ER associated protein degradation (ERAD), which is the mechanism responsible for proteasome-mediated degradation of ER proteins. We found that in mice cardiac ischemia/reperfusion (I/R) increases ROS and activates the ER stress response, which induces several previously uncharacterized antioxidant proteins, including the trans-ER membrane selenoprotein, Vimp, which has not been studied in the ischemic heart. We found that Vimp knockdown in mice increased I/R-generated ROS and infarct size in in vivo I/R, consistent with a role for Vimp as an antioxidant. In addition to its antioxidant activity, Vimp has been shown in model cell lines to be important for assembly of the ERAD complex, the function of which is not known to require antioxidants or Se. Vimp overexpression in cultured cardiac myocytes increased ERAD, consistent with Vimp’s function as a key regulator of ERAD in the heart. Our hypothesis is that Vimp mitigates ROS and misfolded protein accumulation, both of which protect against I/R damage. Moreover, the unique dual roles of Vimp are mechanistically linked to the antioxidant function of its Se and the protein degradation function of its ERAD domain. Finally, endogenous proteins in the heart are degraded by ERAD as part of their life cycle, which is essential for balancing proteostasis and optimizing heart function. Our specific aims are to: 1- determine the effects of AAV9-sh-RNA-mediated knockdown of endogenous Vimp, which is very effective in vivo, on cardiac structure and function, infarct size and remodeling, as well as ROS, ERAD and molecular sensors of cardiac pathology and ER protein misfolding in mice subjected to I/R, 2- mechanistically dissect roles for the Se and the ERAD-enabling domain of Vimp using AAV9 encoding wild type Vimp (Vimp-WT), Vimp lacking Se (Vimp-Se), and Vimp with a mutated, dysfunctional ERAD domain (Vimp-ERAD), allof which we have already prepared, in mice subjected to I/R, and 3- use three complementary approaches to examine how ERAD affects endogenous proteins in the mouse heart, in vivo, investigating 1- ERAD-mediated degradation of Serca2a, 2- ER proteome dynamics using ER-targeted proximity biotin labeling and quantitative proteomics, and 3- ER proteome dynamics using stable isotope labeling mass spectrometry. In terms of relevance to heart disease or significance, our concept that ERAD is critical for the protein degradation component of proteostasis is innovative. Examining this concept is expected to provide new avenues for exploring the development of novel therapies for ischemic heart disease.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY Herpes simplex virus (HSV) keratitis is the leading cause of corneal ulcers and infection-associated blindness in the United States. The existing antiviral therapies for the topical management of ocular herpes infections include nucleoside analogs such as ganciclovir and trifluridine which need to be administered 5-8 times a day to control the infection. Hence, current topical therapies have patient adherence issues which impact therapeutic outcomes. In addition to the limited topical bioavailability, the emergence of drug resistance to acyclic nucleosides has necessitated the development of long-acting antiviral therapies for the topical treatment of ocular herpes infections. Our preliminary data show that adefovir dipivoxil (ADV), an off-patent, FDA-approved hepatitis B virus DNA polymerase inhibitor, is well tolerated by the human corneal epithelial cells and is significantly more active against HSV-1 and HSV-2 when compared to acyclovir, other acyclic nucleoside phosphonates such as tenofovir, cidofovir, and their prodrugs. Our preliminary data further showed that thrice daily topical administration of 1% ADV solution has a robust antiviral effect in a murine ocular herpes model compared to once daily 1% ADV solution and thrice daily 0.15% ADV solution. Thus, strategies are needed to reduce the dosing frequency of ADV to further improve ocular herpes therapy and patient compliance. We previously demonstrated that hydrophilic ionizable antibiotics such as moxifloxacin can be converted to hydrophobic moxifloxacin salt and its subsequent formulation into a mucoinert nanosuspension augmented the topical delivery and reduced the administration frequency. Here, we extend this approach to improve ocular delivery of hydrophilic ionizable antiviral drug, ADV. We hypothesize that the development of hydrophobic salts of ADV and their transformation into mucoinert nanosuspensions (NS) will improve ocular delivery and prolong the release of ADV with a concomitant reduction in dosing frequency. Aim 1 will focus on the evaluation of ADV solution compared to currently approved topical anti-herpetic drugs, ganciclovir, and trifluridine using ex-vivo ocular permeability studies, ocular PK in rabbits, and in vivo efficacy in a mouse model of ocular herpes. Aim 2 will focus on the development and characterization of NS of various ADV hydrophobic salts followed by evaluation of their in vitro cytocompatibility, in vitro antiviral activity, ex vivo corneal permeability, ocular PK in rabbits and in vivo efficacy in a rabbit model of ocular herpes. We have already generated NS of ADV pamoate, a hydrophobic salt of ADV. Our preliminary data show that once-daily topical ADV pamoate NS was significantly more effective than once daily 1% ADV solution but equally effective as thrice daily 1% ADV solution in a murine model of ocular herpes infection. We will evaluate selected nanoformulations of ADV hydrophobic salt in the rabbit model of ocular herpes infection. Finally, we will evaluate the long-term safety of ADV solution and ADV nanoformulation in rabbits. The successful completion of this project will lead to the development of clinically viable, patient-friendly long-acting topical nanomedicine for the effective management of ocular herpes infections.

NSF Awards · FY 2024 · 2024-07

This research asks how the words that children already know help them to learn new words. That is, is it easier or harder to learn a new word that either sounds like or is similar in meaning to words the child already knows? Answering this question benefits parents and educators with information about how best to expose children to new words. Children are tested online and do not need to come to a university campus; therefore, this project expands knowledge on language development in children who come from a wide range of socioeconomic, educational, ethnic, and racial backgrounds. This research also provides opportunities for training two graduate students from groups traditionally underrepresented in science. These students are role models for students from similar backgrounds who make up a large proportion of the undergraduate student population where the research is conducted. Finally, this research involves many undergraduate student researchers (including from groups underrepresented in science), who gain important skills for career readiness in the workforce through their work on this project. The exposure that students get to young children also provides them with information about whether they would like a career working with or studying this population. This project uses priming methods with 24-month-old children to ask if a newly learned word is affected if we "prime" children’s memory of it by preceding the new word with a word that the child already knows that shares either meaning or sound with the new word. Researchers teach children new words for objects from familiar categories, such as vehicles and animals, for which individual children produce many words. If a word for a new animal (e.g., raccoon) connects with a child’s existing knowledge of animals, then hearing a related word first (e.g., dog) should affect how much time it takes for children to identify a picture for a newly learned word (e.g., raccoon) compared to a picture of another newly learned word (e.g., carriage), relative to being primed with an unrelated word (e.g., cup). Similarly, if a new word (e.g., carriage) sounds like a word that the child already knows (e.g., cat which starts with the same sound), then seeing a picture of a cat before seeing a picture of the newly learned carriage should affect how much time it takes the child to identify the picture of the carriage vs. another newly learned word that starts with a different sound. This research not only asks how words that children already know affect how they learn new words but it also seeks to determine the time course of new words as they become connected with toddlers’ existing vocabulary. Research has already shown that adults more readily connect new words with known words that share meaning or sound if they learn words through contrastive labeling (which is learning a new word in the context of a known word) compared to direct labeling (which is simply showing a new object and saying its name). This project asks if toddlers are similar to adults in this regard, thereby providing a life-span view of language learning. Comparing these word teaching methods provides further information to parents and educators about how to expose young children to new words for greatest success in language learning. 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 2026 · 2024-07

Heart failure is the leading cause of mortality, and about 6.2 million adults in the United States have heart failure. Heart failure with preserved ejection fraction (HFpEF) has typical heart failure symptoms with mostly diastolic LV dysfunction but preserved ejection fraction. HFpEF is characterized by pronounced coronary microvascular dysfunction (CMD), the causal contribution of which is unclear. CMD is associated with coronary artery diseases (CAD), diabetic cardiomyopathy (DCM), ischemia with the non- obstructive coronary artery (INOCA), and HFpEF. Patients with CMD exhibit impaired acetylcholine-induced endothelial-dependent relaxation. Impaired endothelium- dependent vasodilation (EDD) decreases coronary blood flow and myocardium perfusion and might lead to myocardial ischemia even without an obstructive coronary artery. We hypothesize that the myocardial deficiency perfusion caused by CMD will lead to myocardial ischemia, diastolic cardiac dysfunction, and fibrosis in HFpEF. So CMD plays a critical role in HFpEF. Moreover, our ex vivo study shows a deficiency of miR-21 that restores the NO- dependent coronary vasodilation. This application will address the underlying mechanism of how miR-21 regulates the coronary microvascular function, cardiac function and remodeling in HFpEF in a mouse model of HFpEF induced by a long-term high fat and high sugar diet. Such a preclinical modelof HFpEF has been validated in our preliminary data. We hypothesize that restoring “normal” coronary microvascular function (restoring endothelial-dependent dilation) by modulating miR-21can ameliorate HFpEF. We will test our hypothesis by an interdisciplinary approach encompassing a range of approaches and disciplines from molecular and cell analyses, vascular biology to physiology and pathophysiology, engendering the study of a novel mechanism of coronary microvascular dysfunction, such as tissue-specific knockouts and lineage tracing with 3D fluorescent imaging, measurement of vasodilation and myocardial blood flow in vivo by contrast echocardiography and cardiac function by echocardiography along with RNA-seq, sc RNA-seq, etc. Completing this project may lead to a new strategy to treat microvascular dysfunction and HFpEF and improve the cardiovascular prognosis of HFpEF.

NIH Research Projects · FY 2025 · 2024-07

Heart failure (HF) is a common cause of progressive disability and death. Increased plasma renin activity (PRA) levels are among the earliest biomarkers and modulators of HF with reduced ejection fraction (rEF). Renin is a protease that activates the renin-angiotensin-aldosterone system (RAAS) to regulate salt-water homeostasis, myocardial contractility, blood pressure, and vascular wall integrity. Chronic overactivation of the RAAS harms the heart and circulatory system, promotes salt-water retention (edema) and cardiac remodeling, and contributes to early mortality in HFrEF. Renin itself is activated by the cleavage of pro-renin, but despite its crucial role as a master regulator of RAAS, the mechanism(s) responsible for pro-renin activation in the circulation remain unknown. Insights into the mechanism of systemic renin activation could lead to novel strategies to prevent HFrEF progression and death. We recently discovered a novel harmful role of proteinase Factor XIIa (FXIIa) in HFrEF. We hypothesized that in dilated cardiomyopathy (DCM), FXIIa contributes to the development of progressive HF in vivo and that the adverse effects of FXIIa may be mediated through its enzymatic cleavage of pro-renin in circulation. To confirm or refute our hypotheses, we will combine enzymology, biomarker analysis, and HFrEF modeling in vivo with relevance to human disease. To understand the mechanism of FXIIa in DCM- HF, we will imply FXII-targeting molecular interventions and perform randomized, blinded trials to longitudinally evaluate cardiac dysfunction, edema, cachexia, and other detrimental physiological outcomes and clinically- relative biomarkers of HFrEF. We will explore our hypotheses in two Specific Aims: 1) define the newly discovered role of FXIIa in modulating the progression of DCM and HFrEF; 2) test the hypothesis that in DCM, FXIIa enhances the progression of HFrEF through increased levels of PRA to activate RAAS. Completing the proposed study will define the mechanisms of FXIIa’s contribution to HFrEF and discover novel therapeutic strategies needed to block or prevent the progression of HFrEF.

NIH Research Projects · FY 2025 · 2024-07

Project Summary Approximately 4 million amputees globally, a number estimated to grow 200,000 annually. Upper limb amputees traditionally use passive, body powered, or electrically powered prostheses that use surface Electromyographic (EMG) signals from intact muscles in the residual limb for movement, despite the motion artifacts, variability and need of visual and/or surrogate sensory control by the user. Advanced peripheral nervous system (PNS) interfaces have been proposed as a viable mechanism to improve the control by amputees, by reading naturalistic sensory feedback from the robotic prosthetics. Unfortunately, current neural interfaces suffer from common challenges, and electrode failure, signal deterioration over time, EMG contamination and electrical and unstable sensory percepts, including “stings or tingles” remain a challenge. This study is uses two novel strategies designed to increase the selectivity of recording/stimulation at the PNS interface: 1) The use of an innovative regenerative multi-electrode interface with ultra-small recording sites using our recently developed ultra-thin multielectrode array , and 2) incorporation of molecular guidance cues to influence the type of sensory neurons at the neural interface. This selectivity Regenerative Ultramicro Multielectrode Array (RUMEA) is designed to discriminate between motor and cutaneous neural interfacing by combining it with molecular guidance to biologically engineer the content of sensory-motor axons at the electrode interface. Three specific aims are included: In SA1 36-electrode RUMAs, straight and Y-shape devices, will be fabricated and electrochemical and mechanical tested. In SA2 we seek to demonstrate selective recording from motor axons and evoke touch percepts using the RUMA. In SA3, we will demonstrate selective interfacing of motor and tactile axons in an upper limb amputee rat model of bidirectional Nerve Machine Interface using molecularly guided RUMAs. If successful, this strategy will demonstrate the benefit for using RUMA for selective recording from motor axons, and stimulation of sensory modality axons that evoke naturalistic sensory percepts. This advancement in peripheral neural interfaces for amputees, will reduce the cognitive burden for users of robotic prosthetics, and decrease the abnormal sensations associated with electrical stimulation in the PNS.

NIH Research Projects · FY 2024 · 2024-06

To facilitate research endeavors at the University of Arizona (UA), we seek funding for the acquisition of the Nanoscribe Quantum X Shape 3D microfabrication system from Nanoscribe GmbH & Co. KG. This system will be integrated into the Precision Freeform-optics Design, Fabrication, and Testing (PF-DFT) Facility at the College of Optical Sciences (COS), with the objective of advancing current and future NIH projects in basic, translational, and clinical biomedical research. The Nanoscribe Quantum X Shape system is purposefully designed for fabricating high-precision components used in various fields, including biomedical imaging, microfluidics, life sciences, micromechanics, and material engineering. It excels in the microfabrication of 2.5D and 3D objects with submicrometer precision on areas up to 25 cm2. Notably, it enables feature size control down to 100 nm, enabling nano and microscale printing, as well as mesoscale printing for objects up to 50 mm in size. Furthermore, the system offers an extensive selection of printing materials, including those suitable for printing glass elements used in micro-optics and microfluidics, as well as biocompatible materials essential for printing parts utilized in microfluidic devices and drug delivery systems. Since its establishment, the PF-DFT Facility has been dedicated to supporting both internal and external users in advancing their NIH-funded projects. The acquisition of the Nanoscribe Quantum X Shape system will significantly enhance PF-DFT's capacity to assist a broader range of users in biomedical optical imaging and other fields that were previously inaccessible, such as microfluidics. This advanced equipment will empower researchers in these areas to achieve breakthroughs and explore new avenues of inquiry. Our overarching goal in requesting this funding is to establish a robust micro-fabrication capability that enables the rapid prototyping of biomedical optical devices, microfluidic devices, and other novel components for NIH- funded projects. Integrating the Nanoscribe Quantum X Shape 3D microfabrication system into the PF-DFT Facility will provide investigators with the means to explore previously inaccessible design spaces and fabricate intricate precision components and systems. To further support our efforts, Nanoscribe is considering the establishment of a Center of Excellence (COE) at UA, catering specifically to users in the southwestern region. This envisioned COE would provide valuable expertise and support to researchers utilizing the Nanoscribe Quantum X Shape system, further enhancing the success and impact of micro-fabrication endeavors in the region.

NSF Awards · FY 2024 · 2024-06

Nitrogen is an essential nutrient for all life on earth. It is also the most abundant element in the atmosphere, but most organisms cannot access it from the air directly. Only certain specialized microbes have the ability to convert nitrogen in the atmosphere into a biologically useful form in a process known as nitrogen fixation. Some of these microbes are free-living, but most live in a close symbiotic association within the roots of plants, exchanging nitrogen for carbon. This nitrogen-fixing symbiosis is a central component of the global nitrogen cycle, and it is central to agricultural systems because nitrogen is often the limiting factor for crop growth. It is therefore imperative to understand how nitrogen-fixing plant-bacterial partnerships form in nature and how they respond to an environment filled with challenges and in constant flux. The purpose of this project is to provide a data-intensive framework to learn how plants and bacteria choose their partners and how this choice influences and responds to surrounding species, soil, and climate. A second purpose of the project is to train students from groups underrepresented in science. Students will be prepared for the data-intensive careers now needed across STEM disciplines using an innovative mentorship program and interdisciplinary research including fieldwork, laboratory work, and computational biology. The project will investigate the diversity of nitrogen-fixing bacteria and other microbes associating with plant roots across the North American continent using NSF-sponsored ecological monitoring resources through NEON (the National Ecological Observatory Network). At each of 45 NEON sites, environmental data will be combined with data on the nitrogen-fixing symbiosis. Specifically, investigators will sample the microbiome in the soil and root nodules, and will assay leaf isotopes to determine the level of function of nitrogen-fixing symbionts. Leveraging data from these different sources, the PIs will be able to determine whether microorganisms and plant partners are each limited by the same environmental factors, such as aridity. They will also be able to determine the extent to which choosiness of plant or microbe partners limit the extent of the association. In addition, by examining patterns in the tree of life, the PIs will be able to infer whether highly specific partnerships have persisted across evolutionary time. Finally, models will be used to address synthetic questions across all data sources. For example, a model can test the prediction that arid environments favor highly specific associations, in which both microbes and plants choose specific partners in those stressful settings. This project is jointly funded by the BIO Emerging Frontiers Program and the Established Program to Stimulate Competitive Research (EPSCoR). 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 2026 · 2024-06

PROJECT SUMMARY Basic research has fueled a revolution in how complex diseases are treated. As our understanding of T cell activation improves, so will our ability to leverage the latest findings for translational purposes. For example, synthetic receptors could be used to redirect T cell specificity and functions to treat numerous diseases if they are able to integrate with a T cell’s intracellular signaling machinery in a way that mimics the native 5-module receptor complexes that naturally drive T cell responses to peptide antigens presented by MHC molecules [receptor module = the T cell receptor (TCR); signaling modules = CD3γε, CD3δε, CD3ζζ; coreceptor module = CD4/CD8]. We have therefore advocated for biomimetic engineering of synthetic receptors. However, our basic and translational work in this space, along with the basic research from other labs, have taught us that doing so requires a better understanding of coreceptor function. At present, controversy surrounds how the TCR-CD3 complex and CD4 work together on the outside of a CD4+ T cells to relay pMHCII-specific information across the cell membrane. And, on the inside of CD4+ T cells, the dominant paradigm that is thought to describe pMHCII-specific signal initiation is not supported by recent results of experiments that were designed to directly test this model. The current proposal will therefore interrogate the molecular mechanisms, both outside and inside of CD4+ T cells, by which CD4 contributes to pMHCII-specific responses. We will leverage advances in computational analysis of protein evolution, and co-evolution, to guide structure-function analysis of the putative docking site for CD4 and TCR-CD3-pMHCII units. We will also work to purify TCR- CD3-pMHCII-CD4 assemblies for structural characterization. Finally, we will investigate the molecular mechanisms by which motifs in CD4’s transmembrane, cytoplasmic juxtamembrane, and intracellular regions work to help initiate and regulate pMHCII-specific responses. Our results will inform our basic understanding of CD4+ T cell activation, and therefore guide biomimetic engineering of synthetic receptors for therapeutic purposes.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY/ABSTRACT In a recent multi-cohort discovery study, we reported for the first time that serum levels and whole blood gene expression of creatine kinase (CK) are decreased in childhood asthma. CK is an enzyme that – by catalyzing the reversible reaction of creatine and ATP to phosphocreatine and ADP – plays a vital role in cellular energy homeostasis and buffering. Further, in preliminary studies on a subset of participants with asthma from the TCRS birth cohort we observed that, among 6-years old children with asthma, those with high circulating levels of CK had a striking 80% reduction in their risk of persistent disease into adult life. These results, together with those from experimental studies that we have completed, indicate that CK may play a protective role in asthma. However, multiple elements of this association remain to be elucidated and this R21 application will use observational data from multiple cohorts to address two critical questions. First, although our preliminary data indicate that, among school-age children with asthma, high levels of circulating CK may confer protection against persistence of disease, these studies are based on a single cohort, a single CK measurement, and a small number of asthmatics and require validation in a larger consortium. Second, it remains unknown whether, in addition to circulation, CK deficits are also present in the airways of individuals with asthma, a question of critical importance because of the role of CK in sustaining the ciliary beat and, in turn, enhancing the first defensive mechanism of the lungs. This R21 application seeks to overcome these knowledge gaps through the following specific aims: Specific aim 1: To determine whether circulating levels of CK predict persistence of childhood asthma into adult life in multiple population-based cohorts. Specific aim 2: To characterize and compare CK gene expression in airway epithelial cells from individuals with and without asthma.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY There is an unmet clinical need for accurate, minimally invasive strategies to diagnose endometriosis, a debilitating disease which affects 10% of reproductive-aged women and frequently results in chronic pain, infertility, or even cancer. Diagnosis is often delayed due to seemingly invisible and vague symptoms and the lack of definitive diagnostic methods except invasive surgery. This project aims to study the uterotubal junction (UTJ), the proximal, contractile segment of the fallopian tubes. Despite the protective role of the UTJ in retrograde menstruation, and the fact that it is structurally altered in women with endometriosis, this region is understudied. I hypothesize that there are structural and functional differences in the UTJs of women with and without endometriosis, which can be visualized with three dimensional minimally invasive imaging. My goal is to evaluate and compare these differences using optical coherence tomography (OCT), and to develop a miniature endoscope to access the UTJ through the uterus. OCT is a novel, non-destructive imaging technique capable of providing depth-based microstructural information at micron-scale resolution. Previous work has indicated the ability of OCT to define the organization of smooth muscle and collagen in tissue, differentiate endometriosis from normal tissue, and inform the functional status of tubal cilia in live mouse studies. I propose the first comparative study of the structure and function of the UTJ in the setting of endometriosis using high-resolution, volumetric imaging. Through Specific Aim 1, I will compare functional and morphological measures of explanted UTJs from women with and without endometriosis on volumetric OCT images. I will develop novel algorithms to extract quantitative measures, including texture features, the quantity and orientation of collagen (structure), and ciliary beat frequency (function). In the short term, I aim to provide effective and accurate diagnostic information which can differentiate individuals with endometriosis from controls, as well as advance our current understanding of the understudied UTJ. Through Specific Aim 2, I will design, build, and test a minimally invasive, miniature endoscope capable of providing depth-resolved structural-functional information to demonstrate that OCT can be made suitable for imaging the UTJ. In the long term, I hope to prove that a simple, low-cost office-based imaging procedure, using an OCT endoscope, can provide accurate diagnostic information to identify endometriosis at an early stage. This device could overcome limitations in current diagnostic methods by providing a means for repetitive surveillance, informing prognostic markers of endometriosis susceptibility, and improving detection times and accuracy. The proposed research will generate the preliminary data needed to design a larger in vivo study to prove the diagnostic capability of our endoscope.

NIH Research Projects · FY 2025 · 2024-05

PROJECT SUMMARY/ABSTRACT Secreted and membrane proteins are important for cell survival and crosstalk. The rough endoplasmic reticulum (ER) is a dynamic organelle that adjusts to changes in protein folding demand by regulating secretory protein throughput. While recent studies examined transcriptional regulation of genes encoding secretory proteins in the heart, post-transcriptional regulation of protein expression remains largely unstudied. Here, post-transcriptional regulation genes encoding secretory proteins will be studied, which we found to be an important layer of gene expression control. ER-associated RNA-binding proteins that bind targeting elements in transcripts may orchestrate post-transcriptional regulation of gene expression at the ER. Our pilot data identified ribosome-binding protein 1 (RRBP1) as a novel protein that binds RNA at the ER of cardiac myocytes, which we found to be necessary for secretory protein expression. We demonstrated that RRBP1 increased in cardiac disease settings that affect the ER secretory capacity. We also revealed that RRBP1 expression decreased during postnatal development, coordinate with decline in ER secretory capacity. When RRBP1 expression was increased in cardiac myocytes, transcripts encoding ER-targeted proteins increased and cardiac structure and function after myocardial infarction improved. Our concept is that RRBP1 localizes specific mRNAs that encode secretory proteins to the ER, and that this localization is important for the synthesis of proteins that improve ER secretory capacity, as well as secreted proteins. This has led to the hypothesis that RRBP1 mechanistically links post-transcriptional control of secretory protein expression and ER secretory capacity, which we posit to be adaptive in the heart. This hypothesis will be addressed in three specific aims: 1) Assess the effects of RRBP1 on mRNA metabolism, 2) Examine the effects of RRBP1 on secretory protein synthesis and cellular crosstalk, and 3) Determine the protective potential of increasing RRBP1. These studies will be performed using an innovative molecular strategy for endogenous re-expression of a gene that is downregulated specifically in cardiac myocytes to mechanistically dissect roles for RRBP1 as a regulator of gene expression and response to injury. Impact: Coupling this strategy with cardiac myocyte- specific RNA profiling and ribosome profiling will enable us to determine the effects of RRBP1 on all aspects of RNA metabolism dynamics in cardiac myocytes, in vivo. These studies will reveal previously unappreciated roles for RRBP-1 mediated post-transcriptional regulation of ER-localized mRNAs in cardiac myocyte viability and cardioprotection.

NSF Awards · FY 2024 · 2024-05

Earthquakes caused by human activities - such as wastewater injection, geothermal extraction, and underground carbon storage - tend to be small. With notable exceptions, such as the 2016 Pawnee Oklahoma earthquake, these earthquakes often hide below cultural seismic noise. This presents a challenge for both monitoring and detecting them. It impedes studying their causes and assessing corresponding hazards. In the U.S., regions that have been free of earthquakes are now pressed to find reliable ways to address earthquake risks. Research on induced seismicity has expanded in the last decade; but studies have mostly focused on known hotspots in Arkansas, Colorado, Kansas, Ohio, Oklahoma, Texas, and Wyoming. Yet, it is expected that induced earthquakes will occur in regions which did not face this threat before. It is, thus, critical to monitor and catalog the natural baseline seismicity in these regions before induced earthquakes happen; this allows detecting when seismicity rises above background levels and assessing the risks. One such location is the State of Louisiana. It is currently at the threshold of implementing CO2 storage and increased oil and gas exploration. However, Louisiana lacks a statewide seismic network and monitoring program to assess seismic hazards. Here, the researchers integrate research and education in the aim to understand human-driven changes in Louisiana. Deploying geophysical and seismic instruments, they study three key locations related to human activities and resources. These locations are: 1) in northwest Louisiana, a region with high wastewater injection rates; 2) an underground storage cavern, where ground motions have been reported and nearby sinkhole formation has occurred (with precursor earthquake activity); 3) across the Baton Rouge fault that also acts as a patchy barrier for salt water. Integrating multiple data types, the team gradually unveils the new threats Louisiana is facing. The project also provides support to an early-career female scientist, one postdoctoral researcher, and graduate and undergraduate students. It includes the establishment of student-focused regional workshops, notably on Machine Learning applications in Geophysics. The project also fosters broadening participation in science, e.g., by involving students from the Southern University at Baton Rouge, a Historically Black University. This project is jointly funded by the Geophysics Program and the Established Program to Stimulate Competitive Research (EPSCoR). The project is an integrated geophysical study of multiple data types. It produces a detailed characterization of fluid-involved crustal deformation. The results have important societal implications for energy corridors undergoing rapid human change. They characterize the largely unknown deformation of the subsurface beneath a region that supplies a major part of the U.S. oil and gas. This region is challenged by ongoing subsidence, groundwater salinization, and increasing seismicity associated with wastewater disposal from hydrocarbon exploration. The seismic arrays installed at three key locations not only measure the levels of seismicity, but also constrain the poorly understood aseismic deformation. Indeed, innovative techniques are applied, such as Fracture Seismic imaging, that image fluid-filled networks by using harmonic resonances within fractures. Seismological methods are integrated with GPS data analysis to understand the deformation budget of the crust. This approach provides insight into the pattern of crustal deformation driven by human activities. One expected outcome is the first high-resolution mapping of fracture geometry and connectivity, subsurface material properties, and seismic and aseismic deformation in the region. The study, thus, has far-reaching impacts on our general understanding of fluid-driven processes and their effects on crustal deformation. 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 · 2024-04

PROJECT SUMMARY Systematic reviews (SRs) and meta-analyses (MAs) are essential tools in evidence-based medicine and comparative effectiveness research, enabling thorough evaluations of treatment benefits and risks. In the context of the COVID-19 pandemic, SRs and MAs have been extensively utilized to provide timely insights on preventive interventions, therapeutic medications, and vaccines, aiding informed decision-making and response strategies. However, traditional SRs have limitations such as redundant publications, inconsistent inclusion criteria, and inadequate investigation of evidence accumulation. Living systematic reviews (LSRs) have emerged as a dynamic approach to continuously update and synthesize evidence, addressing these limitations. LSRs offer benefits such as timeliness, reduction of research waste, identification of research gaps, and integration of the latest evidence. Trial sequential analysis (TSA) is a valuable tool to derive conclusive evidence for assessing the adequacy of studies in LSRs. By providing monitoring and futility boundaries, TSA ensures reliable decision- making regarding a treatment’s effectiveness or futility. Conclusive evidence can save patients from harmful treatments or placebos, and redirect resources to other research areas. However, the current TSA methods have significant limitations, mainly stemming from their heavy reliance on interim analyses of RCTs, where patients tend to be more homogeneous than those in MAs that consist of multiple studies on different populations. This proposed project aims to advance TSA methods by developing innovative approaches to establishing decision boundaries, specifically targeting the improvement of early-stage TSAs and reducing the risk of premature termination of LSRs. By addressing between-study heterogeneity and enhancing statistical methods, this project seeks to enhance the reliability and timeliness of living evidence. Rigorous validation of the proposed methods for TSAs will be conducted through extensive simulation studies carefully designed to evaluate the overall type I and type II error rates of treatment effect estimates. Additionally, the performance of the proposed methods will be assessed using diverse real-world datasets. Furthermore, user-friendly, open-source software will be developed, accompanied by comprehensive instructions and examples, ensuring accessibility and ease of implementation for biostatisticians and clinicians. In conclusion, these novel TSA methods hold broad applicability across medical fields, including infectious diseases and cancers, facilitating more robust assessments of existing evidence, guiding decisions regarding the necessity of new randomized controlled trials, and ultimately advancing comparative effectiveness research and evidence-based medicine.

NIH Research Projects · FY 2026 · 2024-04

Project Summary/Abstract: The number of Native Americans (NA) entering the Science Technology Engineering and Mathematics (STEM) workforce is the smallest proportion of any ethnicity. At the same time, this group faces tremendous health disparities, with many directly linked to aging health. Education in, and awareness of, aging-related health issues in NA communities involves three inter-related challenges: lack of a workforce culturally attuned to NA communities, systemic lack of capacity for on-site biomedical research, and significant mistrust of western scientific research and researchers. The proposed programs focus on developing NA health professionals and academic researchers who possess both cultural competence and trust from their communities, elements critical to eliminating health disparities and minority representation in STEM fields. In addressing these challenges, we first recognize that many Native American students approach the world and the means to investigate it from fundamentally different philosophical perspectives. In contrast to highly reductionist Western models, traditional NA epistemological models are more holistic and narrative-based. Importantly, these models, in which animate and inanimate entities are connected and interdependent, should not be seen as pedagogic deficits, but rather as an innate strength that may allow these students to construct and expand upon sophisticated mental models of current scientific knowledge. We have developed an educational program that integrates established best pedagogical practices with aging research learning experience. By integrating the holistic perspective of the Navajo culture with the scientific problem-based approach of aging, we will advance and enrich both perspectives. The training program proposed herein is designed to create a pipeline of NA/AI students to advance from their colleges to aging programs at top tier research universities, creating a model of culturally grounded MSTEM education while bolstering NIH workforce and cultural diversity. We will accomplish this goal through a series of interrelated aims. Our first specific aim is to develop and institute a recruitment plan to attract NA/AI students interested in aging sciences. Our second specific aim is to develop a research experience and scientific training that integrates established best pedagogical practices with aging research. Specifically, we will focus on developing the scientific literacy of the students, providing them with professional development opportunities and a sense of belonging within the academic community. Our third specific aim is focused on providing a support and retention system for NA/AI students to complete their undergraduate studies and move into the workforce or enter graduate school.

NIH Research Projects · FY 2026 · 2024-04

Project Summary Osteopenic fragility fractures are a devastating result of poor bone quality secondary to high mortality and long- term patient disability. Currently there is limited understanding on the mechanistic level reflected in the relatively few available treatment and diagnostic options. Dual-energy x-ray absorptiometry (DEXA) is utilized in combination with established patient standards for diagnosis and management of osteoporosis, however its use is limited in patients. There is a clear need to improve technologies that enable bone quality measurements, especially to avoid refracture. In the proposed work we will develop technology that enables chronic insight into bone health for rodent animal models to enable real-time high-fidelity readout enabling advanced insight for the study of mechanisms and to evaluate the efficacy of new treatments. Specifically, we will build on our recently introduced device class, osseosurface electronics, which are battery free and fully implantable bone strain monitors. In aim 1 we will evaluate permanent interfacing and sensing capabilities of the platform that is grown to the bone via calcium phosphate ceramic particles on month long timescales. Data captured from daily exercise on a treadmill will enable insight in sensing fidelity and will be compared against gait parameters automatically captured by deep neural net image analysis. In aim 2 we will develop a new sensing modality, thermal conductivity measurements, that will be validated by the attachment of the biointerface to the bone, a mechanism we already characterized with strain sensors. This platform will then be used to compare the sensitivity of serial DEXA, µCT, in vivo strain and thermal conductivity measurement in detecting bone changes following administration of an anabolic medication used to treat osteoporosis in aim 3. Ovariectomy animal models with and without treatment will be evaluated by osseosurface electronics against DEXA and µCT. Successful expansion of our osseosurface electronic platform will enable new real time and high-fidelity measurement of bone health in freely moving small animal models. This capability is instrumental to explore mechanisms of chronic and acute changes attributed to fracture or disease in models that have the full genetic toolset and enable rapid test of hypothesis with little cost. The experiments will also inform the utility of the devices towards the use in patients for chronic treatment of osteoporosis.

NIH Research Projects · FY 2026 · 2024-04

Abstract Atrial fibrillation (AF) is the most common arrhythmia especially in the aging population. It is associated with increased risk of mortality and morbidity. At the present time, management of AF has focused on risk factor modification, rate or rhythm control and anticoagulation. Evolution of clinical trials in the management of AF have revealed that ablation seems superior in reducing the burden of AF and controlling the symptoms compared to pharmaceutical agents. However, the benefit of ablation decreases over time and patients frequently require more than one ablation. Earlier ablation in the course of the disease is more beneficial as failure of therapy is related to duration of AF and size of left atrium. After two decades of investigations with varying methods of ablation, we have only marginally improved the clinical outcome. The ablation procedure is time consuming and only a fraction of patients are undergoing this procedure. A robust criterion of prediction of successful ablation will be beneficial for patient selection and maximize the utilization of invasive therapies. With this highly collaborative and multiscale study, our long-term goal is to develop effective models and discover factors that indicate severity of AF that can be helpful as therapeutic targets and to predict prognosis. Our objective is to identify patients who have increased risk of recurrence after ablation for AF by taking advantage of the intracardiac electrograms from left atrial map and inflammatory biomarkers from blood samples obtained pre-procedure. The central hypothesis is that domain-specific machine learning/ artificial intelligence algorithms derived from multimodal data can predict the type of AF, severity of AF as indicated by abnormal areas in the left atrium and clinical outcomes of AF ablation. To directly test the hypothesis, we will enroll prospective consecutive consenting patients who present for AF ablation therapy. Pre-and post-ablation left atrial map and blood samples drawn for biomarker analyses will be used for study purposes.

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY Several transition metals are essential nutrients in human physiology: their acquisition and distribution are highly regulated, and alterations of metal homeostasis are associated with multiple pathological conditions including neurodegeneration and cancer. Metal-binding pharmaceuticals are employed clinically to treat metal overload; however, these chelators target systemic metals rather than intracellular metal dysregulation. Our research program aims at the design of chelation systems to increase the current understanding of metals in disease conditions and to modulate metal dysregulation for therapeutic applications in the long term. Our current experimental focus is on the role of iron in cancer progression. Because malignant cells require higher iron levels to sustain fast proliferation rates, we are engineering antiproliferative chelators that are activated upon cellular uptake to interfere with the availability of the labile iron pool. We employ disulfide bonds and arylsulfonate moieties as activation switches in prochelators that are activated following reaction with abundant thiols intracellularly. Exploiting the physiological differences between malignant and normal cells, we design bioconjugation approaches that increase the selectivity of prochelators for cancer cells. Further enhancing selectivity, we will also pursue the activation of prochelators by specific proteins that are overexpressed (or uniquely expressed) in cancer cells. In addition, we will deploy pro-oxidant strategies that enlist the redox chemistry of chelator-bound iron and copper complexes to generate reactive oxygen species in targeted cells. A new class of prochelators based on tetrazolium cations will be employed to pilot an initiative to image iron chelation via photoacoustic methods. Our experimental approach blends principles of coordination chemistry and chemical biology to produce a new generation of advanced chelation strategies. Detailed mechanistic studies will delineate the cellular uptake of our prochelators as well as their impact on cell cycle, cell death, and iron signaling. Because iron is a fundamental player in malignant behavior, this research offers opportunities to impact a broad spectrum of cancer phenotypes. These molecular design strategies are poised to enhance the scope of chelation in cancer research and potentially in other pathological conditions associated with metal dysregulation.