University Of Missouri-Columbia

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Broad/Long Term Objectives: The goals of this application are to: 1) conduct a novel test of the Acquired Preparedness Model (APM) examining the moderating role of reward-related impulsivity on the relationship between familial alcohol exposure and alcohol expectancies in early adolescence and 2) utilize advanced statistics to identify latent profiles of trait, behavioral, and neural indicators of impulsivity in early adolescence. Specific Aims: The proposed project aims to 1) identify the latent structure of a reward-related impulsivity neuroimaging measure in early adolescence, 2) test the role of reward-related impulsivity in the proposed developmental pathway of the APM, and 3) utilize person-centered heterogeneity analyses to identify distinct profiles of impulsivity in early adolescence. To complete the proposed project, the applicant will receive training in multivariate statistical methods, secondary neuroimaging analysis, and scientific writing. Training will be obtained via 1) meetings with expert consultants, 2) coursework, and 3) conference and workshop attendance. Method: The project will consist of secondary data analysis of the Adolescent Brain Cognitive Development (ABCD) study dataset. Latent variable modeling will be utilized to examine the latent structure of the Monetary Incentive Delay (MID) task in the ABCD sample and identify neural coactivation patterns associated with developmental risk factors for AUD. Structural equation models will be used to test the APM, looking at multi- method reward-related impulsivity variables as moderators of the relationship between familial alcohol exposure and alcohol expectancies. Supplementary analyses will also be conducted with all available questionnaire, behavioral, and neural indicators of impulsivity to explore distinct profiles of impulsivity in the ABCD sample. Significance: The proposed project will advance understanding of the developmental mechanisms contributing to risk for early alcohol use initiation, clarify the organization of heterogeneous impulsivity constructs in early adolescence, and identify distinct neural underpinnings of reward impulsivity in early adolescence associated with alcohol risk. The results of the project will allow for more effective tailoring of prevention and intervention efforts for adolescent alcohol use. Training Plan and Environment: The training plan will provide the applicant with quantitative, substantive, and practical training to facilitate a successful career as an independent addiction scientist. The applicant will receive training in developmental neuroscience, advanced multivariate statistics, and scientific writing. Training will take place at the University of Missouri’s Department of Psychological Sciences, which has an outstanding addiction training program funded by an NIAAA training grant (T32 AA013526; PI: Denis McCarthy). The mentoring team consists of experts in developmental psychopathology (Dr. McCarthy), neuroimaging (Drs. Froeliger, Squeglia) and quantitative (Dr. Steinley) research on addiction, providing a strong collaborative training experience for the applicant.

NSF Awards · FY 2024 · 2024-09

STEM teachers play instrumental roles in shaping students' STEM learning experiences and aspirations. This CAREER research has several broad impacts - national policy, national and local recruitment strategies, and student access to educational opportunities. In the course of this CAREER award the principal investigator (PI) will carefully investigate the STEM teacher pipeline, and examine qualifications from teacher candidates who express interest in teaching STEM through to the eventual career paths of teachers in the workforce. In doing so, the project examines how the supply of STEM teachers has changed over time, whether the supply is adequate in meeting the needs of a changing nation, the qualifications and credentials of STEM teachers, and the implications of the STEM teacher career paths for equity and serving high needs contexts and students. The PI will use multiple extant data sets at the national level as well as data from the State of Kansas to support both national and local inferences. The project contributes to the STEM pipeline research by examining STEM teachers in several novel and important ways. Using regression and multi-level regression analyses, the PI will examine the early STEM teacher pipeline, undergraduate and graduate students who express an interest in STEM teaching. Second, the PI will provide the most current investigation into STEM teacher qualifications, credentials, turnover intentions, and actual turnover using up-to-date nationally representative data. Third, the PI will explore how STEM teacher qualifications, credentials, turnover intentions, and actual turnover have changed at the national level due to the Great Recession and the COVID-19 pandemic. Fourth, using longitudinal administrative data from Kansas, the PI will examine STEM teachers in often-neglected contexts, a state from the Midwest and a state with large rural areas. Fifth, the PI will consider the career paths or mobility of STEM teachers who switch from one school to another and the characteristics of the schools where STEM teachers move to. This is a Faculty Early Career Development Program (CAREER) proposal responsive to Program Solicitation NSF 22-586 and funded jointly by the Discovery Research PreK-12 program, which seeks to significantly enhance the learning and teaching of science, technology, engineering, mathematics, and computer science (STEM) by preK-12 students and teachers, through research and development of STEM education innovations and approaches, and NSF's EDU Core Research (ECR) program. The ECR program emphasizes fundamental STEM education research that generates foundational knowledge in the field. Investments are made in critical areas that are essential, broad, and enduring: STEM learning and STEM learning environments, broadening participation in STEM, and STEM workforce development. 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 · 2024-09

Humanity is characterized by complex behaviors and social interactions. Understanding what fueled these developments, and when and how they enabled people to migrate, adapt, and thrive in new and changing environments are topics of importance. To examine these themes, archaeologists often turn to artifact provenance and materials characterization studies to ask questions about mobility, resource use, symbolic expression, and the development of social networks. Dr. Brandi L. MacDonald’s program focuses on two interrelated areas of materials research: the procurement, exchange, and use of ochre mineral pigments, and the properties and materiality of those pigments used in social and symbolic expressions, such as rock art. Despite having much to offer, rock art and ochre provenance research have been underutilized for reconstructing object biographies and social networks. Studies have been limited in scope by small sample sizes, slow advancements in minimally-destructive methods, a dearth of expertise in understanding geochemical constraints for provenance, and an overall lack of theorizing on the role of ochre mineral pigments in social and symbolic contexts. The scientific objectives of this program are to apply archaeometric techniques for ochre provenance and rock art analysis to enhance the research outcomes in two collaborative projects in contexts of multiple geographic regions and time periods. This research uses novel scientific and community-engaged approaches for understanding complex behaviors and social networks. By integrating several case studies, this project produces the datasets needed to reconstruct ochre mineral pigment provenance, and social contexts of its exchange and use for creating rock art. Conventional research on ochre has centralized its focus on early human cognition and symbolically mediated behaviors, often overlooking its utility as a proxy for mobility, social exchanges, and long-term human-environment adaptations. Yet, geochemical datasets are important to the study of social networks and communities of practice because the ability to reconstruct the ochre production procedures as one way to identify behavioral patterns over time, signaling sustained or changing social contexts. Through the lens of archaeological science, geochemical datasets can produce specific and accurate descriptions of social networks, thus advancing theoretical understandings of cultural adaptations and preferences. The scope of this project sets several new benchmarks for ochre provenance and rock art research. The educational goals of this CAREER award are to integrate this research with early scholar training to: (1) support graduate and undergraduate educational training of US scholars; (2) make leading-edge, NSF-supported analytical infrastructure and expertise available to early scholars in archaeology; (3) deliver a series of outreach events and educational training to relevant local communities; and (4) improve public perceptions of science through community engagement, including the scientific methods used to study rock art and mineral pigments in the past and present. 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 · 2024-08

PROJECT SUMMARY/ABSTRACT This K99/R00 NIH Pathway to Independence Award will provide Dr. Cofresí, trained as a preclinical neuroscientist, with a two-year intensive, mentored training and research experience in translational neuroscience and three-years of research support that will launch his career as an independent investigator. The training and research program focuses on bidirectional translation between preclinical and human laboratory models of neurobehavioral mechanisms that promote alcohol use disorder (AUD). The K99 career development plan will provide training in AUD psychopathology, human alcohol administration, human cognitive/affective neuroscience, and human functional neuroimaging methods. Training will include coursework, conferences, individualized one-on-one mentoring, seminars, and workshops. The K99 research focuses on a neurobehavioral domain of the Addictions Neuroclinical Assessment believed to be critical to the Addiction/AUD Cycle: the attribution of incentive salience (IS) to alcohol cues. Preclinical and human neurobehavioral evidence suggests that repeated alcohol intoxication can sensitize IS attribution to alcohol cues, which may drive the Addiction/AUD Cycle in some individuals. To begin testing this possibility, Dr. Cofresí will translate a preclinical model of individual differences in propensity to attribute IS to reward- predictive cues into a human laboratory model of individual differences in propensity to attribute IS to alcohol intoxication-predictive vs. natural reward-predictive cues, and examine how these individual differences are associated with future problematic alcohol use. Dr. Cofresí’s development will be facilitated by a team with collective expertise spanning the areas of training (Drs. Bruce Bartholow, Shelly Flagel, Brett Froeliger, David Kareken, Denis McCarthy, Ed Merkle, Thomas Piasecki, Kenneth Sher, Todd Schachtman). The K99 phase will take place at the University of Missouri, a world-class research institution, in the Department of Psychological Sciences, home to renowned faculty in alcohol and addiction research with human participants and a premier alcohol research training program (T32-AA013526). The R00 research will take place at a to-be- determined R1 institution, and will focus on continued testing of IS attribution to alcohol-predictive cues and its sensitization in the human laboratory. This K99/R00 award will produce research that advances Goal 1 Objective 1a of the 2017-2021 NIAAA Strategic Plan, which involves identifying behavioral and neurobiological mechanisms underlying AUD, and explaining heterogeneity in how people progress through the Addiction/AUD Cycle, in order to inform the development of AUD prevention and treatment. This K99/R00 award will also produce an independent scientist able and committed to conducting basic behavioral and neurobiological research with human participants that will continue to advance NIAAA’s mission to improve diagnosis, prevention, and treatment of alcohol-related problems, including AUD.

NSF Awards · FY 2024 · 2024-08

It is essential to make programs more accessible to everyone, even individuals with disabilities to broaden the STEM enterprise and workforce. Despite rising awareness of barriers in STEM for those with disabilities most efforts have centered on physical disabilities, often overlooking neurodiverse learners. To address the issues of neurodiverse learners, this project leverages game development innovations to offer an engaging STEM curriculum, available to all and tailored for individuals with disabilities, through video game design. The focus is on designing a curriculum to support the development of computational thinking skills with middle-school students to: (1) embed acquisition of computational concepts and practices within a highly engaging context; (2) complement the increasingly computational nature of STEM careers; and (3) lead to tangible representations of learning. The design, development, implementation, and evaluation of an accessible video game design curriculum using Nintendo's Game Builder Garage platform will be deployed in informal STEM environments to investigate how participation influences computational thinking skills and attitudes towards STEM. The aims of this project are to influence STEM perceptions and skills for individuals in informal STEM learning settings. The target audience are middle school students. This Integrating Research and Practice project will be guided by these research questions: 1) How can a curriculum be designed to support development of computational thinking for all including individuals with disabilities, for deployment in informal STEM learning environments? 2) How do stakeholders (e.g., individuals with disabilities, caregivers, experts) perceive the accessibility and ease-of-use of the curriculum and game development tools, and what improvements are needed? 3) What is the influence of the Gaming for Good learning experience on participants' perceptions towards STEM? 4) What is the influence of the Gaming for Good learning experience on participants' computational thinking skills? A mixed methods research design and an iterative learning experience design evaluation approach, which includes formative, summative, and remedial phases, will be employed in this project. As a result, this project will produce a co-designed inclusive digital game-based learning curriculum that addresses the following STEM topics: data, modeling & simulation, computational problem solving, and systems thinking. The broader impact of this project is that by shifting from a programming to a data focus in game making, STEM careers like computer science, game design, and instructional design will be more accessible to all including individuals with disabilities. This project is funded by the Advancing Informal STEM Learning (AISL) program, which seeks to advance new approaches to, and evidence-based understanding of, the design and development of STEM learning in informal environments. This includes providing multiple pathways for broadening access to and engagement in STEM learning experiences. 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

This award supports a research project on the interaction of algebra and geometry, and the application of commutative algebra to other areas of mathematics. A motivating problem is the existence of resolution of singularities. To resolve singularities is to smooth out, by algebraic operations, the singularities in a space defined by polynomial or analytic equations. Resolution of singularities is still open in certain cases for spaces of dimension greater than 3. It is of importance in other branches of mathematics, physics and engineering. An important focus of the project will be the training of graduate students and the mentoring of young mathematicians from diverse backgrounds. A major topic to be investigated in this project is properties and applications of filtrations in local rings. Another topic to be investigated is inseparable local uniformization, the local resolution of singularities along a valuation after taking a purely inseparable extension. The PI will also investigate the characterization of good properties of extensions of valuations. The project will explore properties of filtrations of rings, including their analytic spread, Hilbert functions and generalized multiplicities. A particular emphasis will be on divisorial filtrations which although non-Noetherian, share many good properties of the Noetherian I-adic filtrations of an ideal I. Inseparable local uniformization will be investigated. This is a local resolution of singularities, after taking a purely inseparable extension. The PI will also study extensions of valuation rings with the goal of giving valuation theoretic characterizations of when the extensions are almost finite etale, or have related good properties. 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

Despite their negative reputations, parasites are important parts of healthy ecosystems. They have been shown to promote increased biodiversity in living communities and stabilize the population sizes of other species. Many parasites rely on three or more other species to complete their life cycle and their success reflects a well-functioning ecosystem. What happens to these parasites and hosts after a mass extinction? This research will evaluate the impact of a 2.5-million-year-old mass extinction on flatworm parasites and their clam hosts in the western Atlantic Ocean. Understanding parasite-host responses to this geologically recent extinction can give us insights into how economically valuable living clam populations and their parasites will respond to ongoing biodiversity loss. The Broader Impacts portion of this project will promote science education by supporting a STEM camp for elementary and middle grades students at the University of Missouri. Mass extinctions not only disrupt phylogenetic lineages but can fundamentally alter ecological interactions within the affected ecosystems. Little is known about how extinction events influenced parasite-host interactions in geologic time. A major regional extinction event took place among western Atlantic mollusks during the Plio-Pleistocene transition, and this project will utilize the well-characterized fossil record of bivalve hosts bearing traces induced by their flatworm parasites to test the following hypotheses: 1) parasite prevalence, abundance, and aggregation systematically decreased among host taxa following the extinction; 2) trematode pit size distributions (as a parasite taxonomic proxy) changed significantly following the extinction event; 3) host body size and longevity within a taxon was suppressed by high parasite prevalence and increased when released from parasitism pressure; and 4) geochemical proxies from the fossil bivalves will reveal spatial variation in the importance of multiple environmental drivers. This project will be transformative by revealing how biotic overturn has influenced parasite-host interactions in the geologically recent past and will provide insight into how currently elevated extinction rates may cause such interactions to change in the coming decades to centuries. As such, this work will be of broad interest in paleobiology, geology, ecology, parasitology, and epidemiology. The Broader Impacts plan of this project addresses scientific literacy in the areas of deep time, biological evolution, and environmental change by expanding a science day camp in collaboration with colleagues at Mizzou Paleo and the University of Missouri’s The Connector. Mizzou Rocks! is for rising 4th-6th grade students where students learn to identify minerals, rocks, and fossils common in Missouri; become familiar with the broad strokes of Earth and life history; build quantitative skills while learning about megafauna locomotion; and learn geology in the field. 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

Population growth and environmental change have increased concerns about the ability of agricultural systems to meet future food and fiber needs, and crop diversification has emerged as a favored approach to increasing agricultural resilience. Crop diversity has long been acknowledged to support greater agricultural system resilience, yet there are various barriers that pose obstacles to greater crop diversification. This project uses modeling, interviews, and historical data to investigate how self-reinforcing crop "simplification traps" develop and alter the structure of the interconnected farm-community landscapes. The project informs development of diversification strategies that build the sustainability and resilience of agricultural systems and rural communities, and develops public datasets and educational activities for college education and public engagement. Recent work suggests that socio-technical lock-in presents challenges to crop diversification efforts. However, there is little quantitative evidence documenting how crop diversity operates within a system of interdependent farms and rural communities to alter system agroecosystem resilience. This project advances knowledge by examining current conditions and historic trajectories that have influenced farm structure, crop diversity, and the rural communities to which they are tied. The project 1) identifies and characterizes "simplification traps" using change-point analysis of agricultural census and archival data, 2) explores processes that lead to the production of "simplification traps" using statistical inference, interviews, and agent-based simulation, and 3) explores changes in resilience and pathway diversity associated with "simplification traps". The project contributes to an understanding of farm-community connections and the non-linear impacts of environmental change on rural development. Findings inform development of tools for identifying and monitoring at-risk systems and contribute to the development of interventions that support greater resilience of agricultural systems and rural communities. 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 · 2024-08

PROJECT SUMMARY: OVERALL Advances in genome editing have paved the way for the possibility of new therapeutic strategies for treating human disease. There is a current need for animal resources and services that can assist with studies that will accelerate the translation of genome editing technology into clinical applications. In particular, the availability of a center that can provide testing not only in mice but in rats, which are often a preferred model species for validation of therapeutics, is greatly needed. The MU Rodent Testing Center for Somatic Cell Genome Editing brings together a team with longstanding and established expertise in the fields of animal modeling and comparative medicine who are equally proficient at working with both mice and rats. Additionally, strengths of the assembled collaborative team include 1) access to large numbers of rodent disease models and reporter strains and the demonstrated ability to acquire/cryorecover/make any needed mouse/rat strain, 2) expertise in the maintenance and distribution of rodents under the highest quality standards to ensure downstream research rigor and reproducibility, 3) access to established and state-of-the art infrastructure and phenotyping expertise in rodents, 4) experience operating facilities that are service-oriented and familiar with managing fee-for-service operations, and 5) the demonstrated ability to work successfully together and as part of collaborative interdisciplinary research teams. The specific goals of the MU Rodent Testing Center for Somatic Cell Genome Editing are 1) breed and maintain groups of wild-type, reporter and disease model mice and rats for in vivo testing, 2) establish assays and protocols for evaluating on and off-target genome editing, biodistribution, bioactivity, and safety using a variety of delivery methods, including in utero delivery, and 3) provide the resources and services needed by biomedical researchers to evaluate new reagents/tools related to somatic cell genome editing/gene therapy in relevant preclinical rodent models. Our collaborative group can work with investigators to provide comprehensive evaluation of somatic cell genome editing tools and delivery vehicles in whole animals and embryos as well as in all tissues and cell types. The MU Rodent Testing Center for Somatic Cell Genome Editing is ideally suited to provide the rodent-based expertise needed to facilitate the ability to evaluate new genome editing tools and technologies for future application to human disease treatments.

NIH Research Projects · FY 2025 · 2024-08

Project Summary/Abstract The long-term goal of this research is to improve self-efficacy, activity performance, and health in individuals with stroke. Current stroke rehabilitation research and practice must be addressed to shift the focus of the field from an over-emphasis on impairment reduction to management of stroke as a chronic disease. The overall hypothesis of this proposal is that a clinically feasible, self-management-based intervention, the Improving Participation after Stroke Self-Management Rehabilitation (IPASS-R) program, will produce a significant improvement on measures of self-efficacy, activity performance, quality of life, and community engagement outcomes as compared to a general health-focused self-management program, the Chronic Disease Self-Management Program (CDSMP). All assessment and intervention procedures will be conducted virtually via videoconferencing. The specific aims of this project in the subacute stroke population are to: (1) evaluate the efficacy of IPASS-R to improve self-efficacy within home, community, and work activity performance; (2) evaluate the efficacy of IPASS-R to improve activity performance and quality of life; and (3) explore the effect of IPASS-R on objective measures of in-home activity patterns and community engagement. Participants with subacute stroke living in the community will be recruited through local hospitals at two sites (n = 100). Those individuals who meet eligibility criteria will be randomized to either an IPASS-R group or to a CDSMP group. Both groups will receive six, 90-minute group sessions of self-management education. Treatment outcomes will be assessed at baseline, post-intervention, and at six-months post-intervention. Treatment efficacy outcomes will be analyzed with an intent-to-treat model with an analysis of covariance (ANCOVA). Potential covariates will include age, stroke severity, degree of cognitive impairment, and degree of motor impairment. Independent samples t-test and chi-square test will be used to ensure successful randomization and balance between groups. Group differences at baseline that are statistically significant will also be considered as covariates in the analysis. Post-hoc tests will be employed as appropriate. Significance levels, effect sizes, and confidence intervals will be reported. Completion of this study is likely to result in an efficacious, clinically feasible intervention to improve self-efficacy, activity performance, and participation in individuals with stroke that can be feasibly implemented into current systems of care. The proposed study and anticipated outcomes are consistent with the research priorities of the National Center for Medical Rehabilitation Research (NCMRR), which include which include rehabilitation interventions focused on chronic symptom management with real-world, participatory outcomes and objective markers of functional progress.

NSF Awards · FY 2024 · 2024-08

Cloud DevOps is widely adopted in industry applications for automation of data/computation-intensive workflows. However, scientific application communities (for example, in bioinformatics, health science, and geospatial analysis) are yet to see wide and large-scale adoption. The goal of this project is to benefit scientific application communities who need new comprehensive learning modules that utilize research-inspired use cases for modernizing scientific workflows using suitable Cloud DevOps tools/technologies. Consequently, the project activities are focused on training content development and training modalities that advance the adoption of Cloud DevOps in domain science communities to help improve productivity, security and collaboration. By targeting audience who may or may not have computer science backgrounds, the project activities ultimately will increase the pace of scientific discovery in multiple disciplines such as computing, industrial engineering, geography, biology, healthcare, and agriculture, which serve the national interest. Involvement of learners from under-served groups is achieved through strategic partnerships with Minority Serving Institutions and NSF REU Programs to deliver webinar talks and tutorials, and for strategic participant recruitment in the training activities. The “Mizzou Cloud DevOps” learning modules from this CyberTraining project are application-inspired to enable learners to learn about important Cloud DevOps tools/technologies, and help them benefit in diverse scientific application contexts. They have the potential to transform today’s practice of scientific workflow management that is traditionally performed using manual/time-consuming processes for resource provisioning, monitoring, security, and configuration management. NSF-funded infrastructure resources, such as Nautilus and Academic Cloud, and public cloud resources, such as Amazon Web Services will be used to deliver the training. Training materials delivered via an online learning platform feature important Cloud DevOps technologies, such as Kubernetes, KubeEdge, Prometheus, Jenkins, OpenFlow, Ansible, KubeFlow, and methods to provide self-assessment and peer feedback for improving learner experiences. Ultimately, the Mizzou Cloud DevOps' scope is to train researchers and cyberinfrastructure professionals to help shorten the scientific application development life cycle in the short-term, while also ensuring that the highest quality of software and infrastructure are created by scientific application communities in the long-term. 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 project focuses on a group of pollutants known as per- and polyfluoroalkyl substances (PFAS). Through their use in numerous applications, these chemicals have made their way into drinking water, thus posing potential risks to public health. The research team will study how PFAS react with other treatment chemicals during water disinfection. While water disinfection protects public health, transformation of PFAs into other potentially toxic chemicals represents an urgent issue. The project explores the reactions between PFAs and common disinfectants such as chlorine and ozone. The research thus addresses a crucial step in developing more effective water treatment methods and contributing to the overall health of communities nationwide. More broadly, the project will enhance public understanding of water treatment processes and promote STEM education, offering long-term benefits to society. The project goal is to determine the transformation mechanisms of PFAS (and their precursors) during conventional drinking water disinfection processes. Given the widespread presence of PFAS in drinking water sources and the potential health risks associated with these pollutants, understanding the behavior and breakdown of PFAS in response to common water-treatment disinfectants such as chlorine, chloramine, bromine, and ozone is paramount. Specifically, the project involves controlled laboratory experiments investigating the oxidation of polyfluorinated substances to more persistent perfluoroalkyl compounds under varied conditions. Effects of bromide ions, natural organic matter, and various disinfectants will be investigated. By integrating experimental results with computational chemistry analyses, the research will unravel the complex interplay of thermodynamic and kinetic factors influencing PFAS precursor transformations. Additionally, the feasibility of sorptive removal techniques for extracting PFAS precursors from water will be examined, potentially offering a practical remediation strategy. The project is poised to significantly advance our understanding of PFAS chemical stability and reactivity, thereby informing the development of more effective drinking water treatment solutions. Moreover, the project will generate valuable resources, such as an open-access database of disinfection byproducts, and contribute to the scientific community's knowledge base, addressing a critical gap in current PFAS research and regulation efforts. 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 · 2024-08

ABSTRACT A first-line treatment for head and neck cancer is radiation therapy, but ionizing radiation can lead to chronic oral complications such as fibrosis of the salivary glands (SG) and xerostomia. Therapeutic strategies to restore SG function include gene therapy, stem cell transplantation and various bioengineering approaches; however, they are dependent on the presence of residual functional SG tissue, a condition not met with full radiation treatment due to extensive fibrotic coverage of the SG. Although a role for Lysyl Oxidase (LOX) in radiation-induced fibrosis has not been investigated in SG, it is notable that each LOX family member has been implicated in various fibrotic disorders affecting a wide range of organs. This has prompted efforts to develop monoclonal antibodies targeting specific LOX enzymes; however, recent Phase II clinical trials of a monoclonal antibody against Lysyl Oxidase-Like (LOXL2) failed to show efficacy against primary sclerosing cholangitis. These findings underscore the importance of considering functional redundancy when targeting individual LOX and since the catalytic site of all LOX family members possesses a conserved binding site for copper (Cu), focusing on inhibition of Cu delivery to these enzymes is a novel antifibrotic strategy. Preliminary studies have identified a novel compound, MKV3, as a potent inhibitor of the ATP7A copper transporter. Furthermore, ATP7A trafficking to the plasma membrane enhances LOX activity in cancer cells which is blocked by MKV3. Ionizing radiation was found to stimulate Cu-dependent ATP7A trafficking in rat parotid Par-C10 cells and that copper modulators, such as tetrathiomolybdate (TTM) and MKV3, block this process. To extend these findings to in vivo studies, preliminary results indicate that radiation treatment not only triggers Cu-dependent ATP7A trafficking in mouse submandibular glands (SMG) from the perinuclear region to the plasma membrane but also causes collagen deposition of extracellular matrix, with these events being reduced by TTM. Finally, ATP7A localization was found to be altered in the fibrotic SMG of irradiated patients, thus indicating a likelihood for clinical applications of these findings. Based on the above, it is hypothesized that ionizing radiation triggers Cu-stimulated ATP7A trafficking in SG, which facilitates the metalation of LOX enzymes leading to increasing collagen crosslinking and fibrosis. Therefore, the following Aims are proposed: Aim 1 will elucidate the molecular mechanisms of altered Cu homeostasis in irradiated SG. Aim 2 will evaluate the therapeutic potential of SMG-specific Atp7a gene silencing on radiation-induced fibrosis and saliva secretion. Aim 3 will evaluate the therapeutic effects of pharmacological targeting of copper transport on radiation-induced SMG fibrosis. Together, these studies will demonstrate that targeting of Cu metabolism can be used as a novel treatment for radiation-induced SG fibrosis.

NIH Research Projects · FY 2024 · 2024-08

Project Summary/Abstract The long-term goal of this research is to reduce the functional impact of cognitive impairment and improve quality-of-life in women treated for breast cancer with cancer-related cognitive impairment (CRCI). The prevalence of CRCI following breast cancer is high and can persist chronically after treatment has ended. Breast cancer survivors often self-report cognitive deficits, primarily in executive functioning (planning, problem solving, multitasking), memory, and processing speed. These cognitive impairments can have substantial impacts on everyday life including work, community involvement, driving, and financial management. Neuroimaging studies suggest this may be due to altered activity in frontoparietal cognitive circuits. Metacognitive strategy training (MCST), in which participants are taught a general cognitive strategy that can be applied in known and novel contexts to devise task specific strategies to successfully engage in an activity, may provide a solution. Our overall research hypothesis is that MCST (1) will be feasible and (2) will improve behavioral indices of cognitive performance in women with CRCI which are associated with improved neural activation and functional connectivity in frontoparietal neural circuitry. This project aims to examine the feasibility of MCST and its impact in women treated for breast cancer on (1) cognitive performance, (2) frontoparietal resting-state functional connectivity, and (3) task-based BOLD activation and task-state functional connectivity in cognitive control circuitry. Participants (n=50) will be randomized to a MCST group (ten, 45-minute sessions over 10 weeks) or an inactive control group. Outcomes will be assessed at pre- and post-intervention. Feasibility outcomes will be analyzed using descriptive statistics reported with 95% confidence intervals. Treatment outcomes will be analyzed with an analysis of covariance (ANCOVA) to compare post-intervention outcomes between groups controlling for pre-test values. Cohen's d effect size with 95% confidence intervals will be reported. Neural outcomes will be examined as mediators of the treatment group effect on cognitive outcomes with a series of path analyses. Completion of this study is likely to result in a clinically feasible intervention to improve cognition and activity performance in individuals with CRCI that is prepared for efficacy testing. The proposed study is consistent with the research priorities of NCI's Division of Cancer Prevention, the Cancer MoonshotSM program, and PAR-22-216 which are to support research related to (1) chronic symptom management for improved quality of life and reduced cancer burden and (2) fostering greater collaboration between disciplines necessary to improve complex behavioral symptoms.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Secondary lymphedema poses a significant financial and health burden afflicting 1 in 1000 Americans, resulting in a debilitating and incurable swelling and fibrosis in the affected extremity or tissue. The prevailing hypothesis for the pathogenesis of secondary lymphedema posits a role for lymphatic collecting vessel (cLV) pump failure in response to elevated lymphatic pressures observed in LE patients, and points to a deficit in lymphatic muscle cell (LMC) function. The process by which LMCs regulate pressure-dependent pacemaking, contractility, and transcriptional regulation are critically dependent on inositol triphosphate receptor 1 (IP3R1)-dependent Ca2+ oscillations, although the mechanisms that sustain LMC Ca2+ homeostasis remain unexplored. The central goal of this proposal is to address this knowledge gap and determine how LMC Ca2+ dynamics regulate contractile activity and transcriptional adaptation to ensure fluid transport homeostasis. The Ca2+ source that refills the store has been assumed to be only voltage-gated L-type channels, however our preliminary studies identified the novel expression of the SR Ca2+ sensor proteins Stim1 and Stim2 as well as the plasma membrane (PM) Ca2+ channels Orai1 and Orai3 in healthy LMCs, which are the critical components of store operated Ca2+entry (SOCE). Our preliminary findings also show functional SOCE in healthy LMCs in response to store depletion and that LMC Ca2+ oscillations are lost when SOCE is inhibited. Intriguingly, robust SOCE activation by excessive vasocontractile agonist signaling or SR Ca2+ leak drives cLVs into a contractile rigor and thus may contribute to lymphatic dysfunction. This led us to hypothesize that SOCE is a key modulator of lymphatic muscle cell function. We proposed the following aims to determine the role of SOCE in the regulation of lymphatic contractility and transcriptional regulation. Specific Aim1: Assess SR-PM junction formation and SOCE activity in LMCs. Specific Aim2: Determine the contribution of SOCE to pressure-dependent LMC pacemaking and contractility. Specific Aim3: Investigate the mechanisms by which IP3R1- Ca2+ oscillations and SOCE regulate LMC contractile protein expression through Ca2+-dependent transcription factor activation such as nuclear factor of activated T cells (NFATs). This project will provide novel information about the role of SOCE as a fundamental Ca2+ homeostatic mechanism in LMCs and the degree to which SOCE is required for acute and chronic cLV adaptation to pressure. These results will identify novel targets for pharmacological intervention in LE patients and may shed light on cLV contractile dysfunction reported in obesity, diabetes, and hypertension.

NIH Research Projects · FY 2024 · 2024-08

Modified Project Summary/Abstract Section During adolescence, friends meet more of youths’ relationship needs, including needs for support. Importantly, despite hundreds of studies focused on friends, relatively few studies have considered friendships between girls and boys. Learning more about friendships between girls and in adolescence, however, is important as the prevalence of these friendships increases during adolescence. Moreover, better understanding these friendships is especially important for girls because girls seem to be at a disadvantage in these friendships. Specifically, boys perceive the friendships to be more supportive than girls. The gap in the literature is that the’ specific behaviors in these friendships associated with positive perceptions of the friendships are unknown. This gap will be addressed in the proposed research by observing 60 friend dyads consisting of one boy and one girl (120 adolescents). Given the importance of social support to friendship, friends’ interactions will be observed in a context in which the adolescents disclose a problem, and friends can provide support (or not). Friends’ responses to adolescents’ disclosures about personal problems will be coded into response categories. Some of these are engaged and positive (e.g., sharing a related experience) and some are disengaged and negative (e.g., minimizing the problem). In a large previous study of friendships, we found that girls produced more engaged/positive responses than boys and that receiving engaged/positive responses from friends was associated with positive perceptions of the friendship. The following hypotheses will be tested in the proposed research. Findings are expected to replicate previous research indicating that boys perceive their friendships with girls more positively than girls perceive their friendships with boys. In addition, girls are expected to produce more positive/engaged responses than boys. Receiving engaged/positive responses from friends also is hypothesized to be related to perceptions of the friendships as supportive and close (no hypotheses are put forth for disengaged/negative responses). Importantly, a line of research that identifies specific behaviors in cross-gender friendships that are associated with positive perceptions of the friendship could have significant and applied implications for programs aimed at promoting positive interactions. Finally, the proposed research is innovative both in the focus on friendships between girls and boys and the application of a very detailed and nuanced coding system.

NIH Research Projects · FY 2026 · 2024-08

Project summary Disruption of supraspinal regulation causes reduced sympathetic and unopposed parasympathetic activity, leading to cardiac and hemodynamic disorders after high-level spinal cord injury (SCI). We recently reported that renewal of serotonergic regulation over hemodynamics could be achieved with transplantation of embryonic raphe nucleus-derived neural progenitors/stem cells (RN-NPCs) in a rat SCI model. It was previously showed that exercise, a viable therapeutic intervention, heightens neuronal activity, axonal regrowth, and production of neurotrophic factors after SCI. Accordingly, we posit that transplanting serotonergic NPCs in the injured spinal cord will reestablish serotonin regulation to improve cardiac function, and combining RN-NPC grafts with exercise will enhance the recovery of cardiac activity, hemodynamics, and autonomic dysreflexia after SCI. In Aim 1, we will determine whether integration of transplanted serotonergic NPCs with spinal cord circuitry will restore sympathetic regulation to improve cardiac electrical conduction following SCI. In Aim 2, we will test whether combining RN-NPC transplants with exercise will further enhance the reconstitution of sympathetic modulation to restore cardiac activity, hemodynamics, and autonomic dysreflexia. Overall, this project will provide novel insight into therapeutic strategy following SCI.

NIH Research Projects · FY 2025 · 2024-08

ABSTRACT The Tobacco Online Policy Seminar (TOPS) series has established itself as a leading venue for disseminating policy-relevant tobacco research, having hosted over 80 events in its three-year history. TOPS is a free, multidisciplinary, biweekly Zoom-based seminar series for research with tobacco policy implications using experimental or quasi-experimental study designs (i.e., with a well-defined counterfactual). This forum is designed to bring together academics, students, government employees, policy researchers, healthcare professionals, advocates, and funders, with the goal of breaking silos in tobacco policy research and providing a platform for high-quality research to be discussed and disseminated. The ultimate goal of the forum is to facilitate the production and sharing of knowledge to develop an effective tobacco policy framework for improving population health. TOPS strives to be a respectful, inclusive, and diverse forum, with participants and attendees united around the concept of presenting and learning from tobacco research using study designs capable of producing results with a causal interpretation. TOPS is managed by an Executive Board of four tobacco control researchers: Jamie Hartmann-Boyce, Michael Darden, Michael Pesko, and Ce Shang. TOPS is supported by an advisory board of 37 experts in tobacco control research. Since submitting our last R13 application (Oct. 2022), TOPS has averaged 175 participants per seminar. The aims of this conference grant application are to: 1) continue TOPS and ensure that the series continues to showcase high-quality tobacco regulatory and policy-relevant research; and 2) continue existing and introduce new career development opportunities. To meet these aims, the TOPS Executive Board will meet regularly throughout the year to continue planning and hosting TOPS seminars. The conference grant will also support the effort of a part-time administrator to oversee day-to-day activities of TOPS.

NIH Research Projects · FY 2025 · 2024-07

Abstract: No vaccines are currently licensed to prevent human brucellosis and existing vaccines for livestock are not entirely efficacious. In humans and other animals, Brucella can cause a lifelong infection. However, mechanisms underlying the ability of Brucella to subvert adaptive immunity remain unclear. In this proposal we show that vaccine elicited antibodies alter host metabolism to protect the host against Brucella to some degree. Therefore, in Specific Aim #1 of this proposal we will determine how vaccine-elicited IgM and class switched antibodies alter tissue metabolism to restrict Brucella infection. We also found that Brucella encodes virulence factors that mediate evasion of humoral immunity. Therefore, in Specific Aim #2 of this proposal we will identify mechanisms by which Brucella subverts antibody mediated immunity. Collectively, our results will enhance our understanding of how current vaccines protect the host, and how Brucella is able to subvert adaptive immunity, and thus could improve the rational design of highly effective vaccines for Brucella.

NIH Research Projects · FY 2026 · 2024-07

Project Abstract Infertility and pregnancy loss are common health disorders affecting women. Our long-term research goal is to define critical physiological and genetic pathways that regulate uterine development, function, and regeneration to diagnose, treat, and prevent infertility and associated uterine disorders and disease. This application is specifically focused on the glands of the uterus that are characteristic features of all uteri and critical for pregnancy. Pregnancy loss is the most common complication of human gestation, and recurrent pregnancy loss and infertility are observed in uterine gland knockout animal models. The pioneer transcription factor forkhead box A2 (FOXA2), exclusively expressed in the glands of the mouse and human uterus, plays a pivotal role in uterine gland development and function, and is implicated in a variety of uterine pathologies (infertility, adenomyosis, endometriosis, adenocarcinoma). However, our understanding of uterine epithelial development, FOXA2 biology, and gland morphogenesis is very incomplete. Central hypotheses of this application are that: (1) intrinsic genetic and epigenetic mechanisms govern epithelial specification, bifurcation, differentiation, and morphogenesis in the neonatal mouse uterus; (2) glandular epithelium lineage bifurcation requires Foxa2 gene activation via chromatin remodeling; and (3) FOXA2 activates gene regulatory networks and cellular pathways critical for adenogenesis in the uterus. A team of exceptional investigators with complementary and substantial expertise in developmental biology, functional genomics, and bioinformatics will address that hypothesis by conducting a collaborative research project. Guided by strong published and preliminary data, two specific aims are proposed: (1) understanding molecular mechanisms regulating epithelial specification and Foxa2 expression in the developing uterus; and (2) FOXA2 regulation of adenogenesis in the developing uterus. The proposed systems biology approach will integrate in vivo and in vitro studies utilizing mouse genetic models, single- cell profiling of chromatin accessibility and gene expression (multiome), advanced bioinformatics and deep learning techniques, as well as mechanistic studies of mouse and human endometrial organoids. This approach will decipher essential conserved factors, gene regulatory networks, and cellular pathways governing epithelial development and Foxa2 regulation and biological function. The proposed aims are conceptually and technically innovative and together will have a broad impact on the field by filling a substantial gap in our fundamental knowledge of uterine development and biology. This application specifically addresses early pregnancy loss and the genetic basis of idiopathic female infertility, which aligns with the research priorities of the Fertility and Infertility Branch of the NICHD. Ultimately, an increased understanding of uterine gland biology will facilitate diagnosis, prevention, and treatment of fertility and pregnancy problems, as well as benefit the development of regenerative medicine therapies aimed at organ replacement and treatments for infertility and disease in women.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY The primary objective of this proposal is to assess a novel agonist of 4-1BB costimulatory pathway, SA-4-1BBL, as a single agent for cancer immunoprevention in preclinical models that closely represent high-risk populations susceptible to lung cancer resulting from environmental exposures. Advances in immunology led to the development of immunotherapies with remarkable clinical efficacy against various tumors and put the immune system at the forefront of the battle to prevent, intercept, and treat cancer. The perceived modalities for cancer immunoprevention are vaccines, which are well-suited for virally-derived tumors because of the known nature of target antigens. In marked contrast, the design of preventive vaccines against non-viral tumors for high-risk populations faces a significant challenge due to the unknown nature of target antigens. Thus, a cancer immunoprevention approach that does not require antigens and serves as a platform to prevent a wide range of tumor types will be transformative. The 4-1BB costimulatory pathway has been targeted for cancer immunotherapy because of the critical role signaling through this receptor plays in the expansion of CD8+ T cells, acquisition of effector function, and long-term survival. The natural ligand, 4-1BBL, is a cell surface protein and lacks costimulatory activity as a soluble molecule. As an alternative, agonistic antibodies (Abs) to 4-1BB have been pursued for cancer immunotherapy and shown significant toxicity with limited clinical efficacy. We hypothesized that a natural ligand would lack these attributes of Abs and generated an oligomeric form of mouse ligand, mSA-4-1BBL. This molecule has robust costimulatory activity in soluble form and showed therapeutic efficacy as the immune adjuvant component of tumor-associated antigens-based vaccines in various preclinical cancer models without detectable toxicity. mSA-4-1BBL as a single agent also protects mice against various tumor types, a highly significant and unexpected finding. Cancer immunoprevention efficacy is a bona fide feature of mSA-4-1BBL, as agonistic Abs to 4-1BB receptor are ineffective. mSA-4-1BBL exhibits unexpected efficacy in preventing cancer in mice lacking the 4-1BB receptor, suggesting the involvement of additional immune pathway(s). A series of studies under 4 Specific Aims will be conducted to; i) identify additional pathways targeted by SA-4-1BBL for cancer immunoprevention, ii) assess the efficacy of SA-4-1BBL in a tobacco carcinogen- induced preclinical lung cancer model, iii) generate the human version of SA-4-1BBL and assess its efficacy against lung cancer in a mouse model expressing human 4-1BB receptor, and iv) assess the cancer immunoprevention efficacy of human SA-4-1BBL in a mouse model humanized with hematopoietic stem cells and transplanted with patient-derived lung cancer. Various studies will be conducted to elucidate the mechanistic underlying of success or failure of SA-4-1BBL-based cancer immunoprevention. Validation of SA-4-1BBL as an effective cancer immunoprevention agent will be transformative and substantially change clinical practice for cancer treatment with significant health and financial benefits worldwide.

NIH Research Projects · FY 2026 · 2024-07

Project Summary/Abstract Human monocytic ehrlichiosis caused by Ehrlichia chaffeensis and human granulocytic anaplasmosis resulting from Anaplasma phagocytophilum are responsible for significant morbidity and are also responsible for mortalities in a subset of high-risk populations. Despite vertebrates and ticks having sophisticated systems of defense, rickettsial pathogens have evolved strategies to evade host immunity and cause persistent infections. Mutational studies to be performed with ease in all members of the rickettsiales, including for Anaplasmataceae and Rickettsiaceae family pathogens, remain a major limiting factor. Similarly, the inability to grow the organisms in the absence of host cell support (axenic media growth) is another major hurdle in research progress on all important rickettsial pathogens. The ability to grow obligate intracellular bacteria under axenic conditions can be a major advancement enabling new paths of investigation, such as manipulating the pathogenic organisms with ease, allowing rapid clonal purification of bacterial mutants, permitting detailed biochemical characterization and genetic studies. Our published research progress on mutagenesis studies and axenic media development forms the basis for the current proposed research goals. We propose to address these gaps through the following three focused specific aims: 1) optimize Himar1 mutagenesis supporting the development of a mutational library spanning a greater portion of E. chaffeensis genome; 2) expand the targeted mutation capability in E. chaffeensis and A. phagocytophilum valuable in diverse research applications, and 3) optimize axenic media conditions aiding the continued replication of E. chaffeensis and A. phagocytophilum. Our prior research progress in creating mutations and similarly the preliminary research advances on the axenic media development in Ehrlichia and Anaplasma species highlights the importance of the planned research and substantiates our expertise that the proposed research goals will be accomplished in a timely manner. At the conclusion of this research, we anticipate filling in major research gaps that will aid in extending investigations on several important tick-borne rickettsial pathogens.

NIH Research Projects · FY 2025 · 2024-07

Hypospadias is one of the most common birth defects in the world affecting nearly 1% of newborn boys. Hypospadias is the result of disrupted urethral closure where the urethra exits ventrally along the shaft of the penis. The etiology of 70% of urethral closure defects remains unexplained. Androgen signaling in the penis drives cell-to-cell communication between the urethra and the adjacent mesenchyme, which then influences closure of the urethra. Normal penis development requires testosterone. In the absence of testosterone produced by the testis, the urethra fails to close, leading to severe hypospadias. The testis-derived testosterone eventually reaches the presumptive penis, and is metabolized into the more potent dihydrotestosterone by 5-α reductase. Dihydrotestosterone then binds androgen receptor that are localized within the penis, which transcribes a suite of genes that induce penis development. Surprisingly the regulation of 5-α reductase and the diversity of cell populations involved in urethral closure are not well understood. Recently, I discovered a unique cell population in the penis that expresses the steroidogenic enzyme master regulator, Steroidogenic Factor 1 (Sf1). These cells are localized in the ventral-proximal aspect of the penis, express both androgen receptor and 5-α reductase, and appear to be required for urethral closure. My central hypothesis is that these SF1+ cells contribute to proper urethral closure by both producing and responding to androgens. In the two phases of my K99/R00, I will investigate the role of SF1+ cells in penis development and urethral closure. In the K99 phase, I will define the role of SF1+ cells and Sf1 the gene in urethral closure. I will use a combination of the Diptheria toxin, cell ablation mouse model and a penis specific Sf1 gene knockout mouse model. I hypothesize that these cells are essential for urethral closure and are responsible for the penises steroidogenic capacity to convert testosterone to dihydrotestosterone. In the R00 phase, I will reveal how androgen signaling influences SF1+ cell differentiation and urethral closure. Using SF1+ cell conditional androgen receptor knockouts and chromatin binding assays, I will test the hypothesis that androgens are directly involved in SF1+ cell function and differentiation. The results from this study will establish the role of a novel cell population, the function of the gene, Sf1, and androgen responsiveness in penis urethral closure. This new knowledge will provide a better understanding of the mechanisms involved in the occurrence of hypospadias and will further human investigations on the etiology of hypospadias. Ultimately if there is a more comprehensive understanding of penis development, we can begin to develop strategies to prevent this defect that impacts millions of boys. With the technical skills I already have, the data generated in this proposal, and the skills I will acquire during the fellowship, I will be well-poised to become an independent Principal Investigator at an academic institution. Once at my future job, I will be fully equipped to submit an independent R01 grant to further study the androgen responsiveness of SF1+ cell in the penis.

NSF Awards · FY 2024 · 2024-07

The broader impact of this Partnerships for Innovation - Technology Translation (PFI-TT) project is to enhance wearable heart monitors for improved cardiac health management. Heart diseases, the primary causes of deaths in the United States, result in nearly 655,000 fatalities annually and incur about $219 billion in healthcare costs each year. Ambulatory, real-time, long-term electrocardiogram (ECG) monitoring using wearable devices outside of clinical environments is essential for the early detection and timely intervention of heart conditions. The market for wearable heart monitors is expected to grow from $1.95 billion in 2022 to $3.43 billion by 2027. However, current ambulatory wearable heart monitors usually provide single-lead ECG data and suffer from issues like limited long-term biocompatibility and motion-induced artifacts. These problems could lead to discomfort for patients, unreliable disease diagnosis, and increased workload for healthcare professionals due to the need for frequent adjustments or replacements of wearable devices. This project aims to develop six-lead wearable heart monitors using innovative, multifunctional, porous, soft materials to address the current limitations and improve the efficiency and reliability of heart condition monitoring. This solution will benefit patients, healthcare providers, and the medical community by enabling more effective early detection and management of heart conditions. The project focuses on the development of six-lead, wearable heart monitors with multifunctional, porous, soft materials, which combines ultra-softness, high breathability, antibacterial properties, strain-insensitive electrical performance, and thermal-responsive adhesion. Ultra-softness reduces skin irritation, while breathability prevents inflammation caused by sweat accumulation. The antibacterial feature safeguards against infections induced by pathogenic microbes, essential for home-based telemedicine applications. Strain-insensitive electrical performance and thermal-responsive adhesion can minimize motion-induced artifacts, enhancing the device’s reliability. Six-lead ECG recording offers a comprehensive view of cardiac status. The integration of these features can facilitate the development of innovative, wearable heart monitors with long-term biocompatibility and high fidelity for ambulatory and comprehensive assessment of heart health conditions in everyday scenarios. The four research tasks include: (1) the development of multifunctional, porous, soft materials with thermal-responsive adhesion, (2) the printing of six-lead ECG sensing electrodes onto multifunctional porous substrates, (3) the assembly of mobile cardiac monitoring systems, and (4) on-body device assessment on healthy human participants. Moreover, beyond heart monitors, this technique can be harnessed to build a range of customized wearable biomedical devices with long-term biocompatibility and long-lasting fidelity of bio-signal recording to satisfy a variety of home-based, precision healthcare needs. 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 Summary/Abstract Cells are in a constant battle to maintain homeostasis and respond to stress. Autophagy is a conserved eukaryotic pathway that responds to cellular stresses. Autophagy identifies and encapsulates cellular debris in an autophagosome, which is ultimately fused with the lysosome for degradation. Studies have shown that the final step of autophagy, termed autolysosomal fusion, requires several factors. This includes membrane effector proteins, Rabs and Atg8 homologs, multifunctional scaffolding proteins and specialized lipid headgroups (e.g. PI3P). The assembly of proteins ‘hubs’ often promote cellular processes and are required for function. The Homotypic fusion and vacuole Protein Sorting (HOPS) complex, Ectopic P-Granules 5 Autophagy Tethering Factor (EPG-5), and Pleckstrin homology domain-containing family M member 1 (PLEKHM1) are scaffolding proteins present at the final steps of autophagy. Mutations in these multifunctional scaffolds lead to poor cellular health and have been implicated in several human diseases, specifically defects in these proteins lead to neurodegenerative diseases. Despite the importance of the final stages of autophagy, we currently lack fundamental information on how these interaction hubs tether and organize sites of autolysosomal fusion. The overarching goal of this proposal is to resolve the protein interaction network that drive autolysosomal tethering. We are initiating both in vitro and in vivo techniques to discovery the molecular interactions that drive autolysosomal tethering. Single particle cryo-electron microscopy analysis will serve as our main tool to determine how the human HOPS complex engages with autophagy adaptor PLEKHM1 at the membrane surface. These studies have the potential to reveal the molecular interactions which drive the formation of the autolysosomal interface and generate specificity within the autophagy pathway. In tandem, we will utilize cryo- focused ion beam (cryo-FIB) milling along with in situ cryo-electron tomography methods to examine autolysosomal tethering in the native cellular environment. To accomplish this, we will focus on EPG-5, a scaffold that binds to both lysosome and autophagosome directly (via protein-protein interactions with Rab7 and Atg8 homologs, respectively). EPG-5 is an ideal target for in situ studies given its large size (300 kDa) and distinct shape. By using cell biological techniques, we will enrich autolysosomal tethering events and perform cryo-FIB milling. These innovative approaches have the potential to discover the cellular context of autolysosomal fusion at resolutions (<20Å) not possible by traditional techniques. Taken together, our work will provide to a deeper understanding at both an atomic level and contextual level. Long term, we hope our data contributes to novel therapeutic approaches to treat membrane tethering defects to improve human health. Moreover, the principles we discover could lay a foundation for understanding organelle tethering events throughout eukaryotic biology.