Lehigh University

NSF Awards · FY 2024 · 2024-08

This award supports the Neotoma Paleoecology Database. Neotoma is one of the most widely used and trusted international data resources for fossil data, growing rapidly in the volume and variety of its data holdings, functionality of its software services, and the size and scope of its user community. This award will allow Neotoma to grow and enhance systems to support higher rates of data additions, more streamlined data curation, and better support solutions for new communities seeking to use Neotoma data. This project provides access to publicly funded data and supports researchers, educators, and the public by providing a high-quality, expert-curated open data resource for paleoecological and paleoenvironmental data. Specific activities for this project include better support for rapid upload of hundreds to thousands of datasets from participating research teams through enhancements to the Data Bulk Uploader System (DataBUS), with newly added ORCID user authentication and support for the popular Linked Paleodata (LiPD) format. Embargo Manager will support early data contributions and better data management practice, in alignment with NSF Division of Earth Sciences (EAR) Data and Sample Policy. The Hierarchical Vocabulary and Taxonomy Manager (HVTM) will improve data quality and interoperability by enabling efficient viewing and curation of controlled vocabularies. Neotoma will freely upload supported data types, with priority for NSF-EAR PI data, and will help on-board major geoscience paleodata communities. Neotoma PIs will develop and provide multiple training support activities for scientists, with focused workshops for early career researchers (ECRs) and scientists from underserved regions, multi-lingual support for workshops and online resources, publicly posted training videos, and model workflows for data handling. Neotoma developers will reduce barriers to access and support artificial intelligence and machine-learning applications by deepening Neotoma’s metadata provisioning to Science-on-Schema and DataCite. Lastly, Neotoma stewards will create custom-tailored training and leadership opportunities for ECRs by designing workshops, videos, and code vignettes to address ECR-identified challenges. 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

With this award, the Environmental Chemical Sciences Program in the Division of Chemistry funds Professor Alexander Laskin at Purdue University and Professor Jonas Baltrusaitis at Lehigh University and their graduate and undergraduate students. Struvite, a common wastewater valorization product, contains essential plant nutrients, phosphorus and nitrogen. Utilized as a fertilizer, its low solubility microcrystals exhibit slow-release properties, providing a gradual nutrient release in line with plant uptake rates. Because of the unique composition of struvite and typically present iron impurities, struvite can catalyze environmental chemistry reactions, facilitating the transformation and remediation of organic pollutants and dissolved organic matter (DOM). This project will advance fundamental environmental chemistry knowledge concerning the under-studied colloidal struvite-organic mixtures, which in turn will be transformative to advance broader research on the complex multi-phase environmental aquatic mixtures. It will lay the foundation for the fundamental understanding of processes underlying practical use of the environmentally friendly slow-release struvite fertilizers. The broader impact of the project extends to providing quantitative predictions of the composition and physical properties of struvite microcrystals, a common wastewater valorization product, and their its environmental impact when used as a fertilizer. Project results will inform decisions regarding engineering, process design, and management controls for practical utilization of environmentally friendly struvite fertilizers, enhancing their performance and value, while aligning with the needs of environmental protection and sustainability. The interdisciplinary nature of this project creates a unique educational opportunity for students, offering hands-on experience with advanced synthesis techniques and state-of-the-art analytical methodologies. This experimental project investigates the chemical composition, physical properties, and catalytic behavior of laboratory-synthesized struvite with varying and tailored iron content. Given struvite's potential to serve as a sustainable alternative to conventional fertilizers and mitigate environmental issues such as water eutrophication and tropospheric pollution, this project fills critical knowledge gaps necessary for a predictive understanding of struvite's environmental implications. The project will investigate the chemical transformations of representative laboratory proxies of DOM catalyzed by synthesized struvite colloids with varying iron content. These experiments will yield fundamental insights into the multiphase reaction chemistry of struvite microcrystals and their impact on DOM in aquatic environments. Ultimately, this research will delineate struvite’s role in the complex multi-phase chemistry of terrestrial and atmospheric water systems. 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

Currently there is a critical unmet need for workforce development in research enterprise service and support careers. GRANTED: Pathways for Graduate Students into the Research Enterprise provides graduate students training and development to prepare them for careers in research administration, research development, research integrity and technology transfer. The Pathways program will provide: (a) a pipeline of trained research professionals who will be able to step into specialized or generalist roles in the research enterprise and (b) a model for comparable institutions to develop similar programs. These types of employees are widely sought after by research institutions, government labs, hospitals, colleges and universities. GRANTED: Pathways for Graduate Students into the Research Enterprise is a pilot training model that will provide senior doctoral students with training and professional development to prepare them for research enterprise careers. Many individuals that previously trained for research careers in PhD programs ultimately move into staff roles. Beginning exposure and training relevant to research enterprise careers while they are graduate students provides individuals a path to rewarding, research-related careers. It will augment a pipeline of trained research staff ready to step into primarily undergraduate universities seeking to expand research capacity, as well as complex research institutions. The project team will leverage the size and scope of the lead institution to develop and test a program that provides graduate students a broad overview, while also developing deep skill sets in select areas of the research enterprise. 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

Global changes are causing significant shifts in ecosystems worldwide by increasing environmental stress. Species that can withstand these changes are likely to thrive, while those less adaptable may decline. However, it is challenging to link strategies of individual species to community-level responses to global changes. This project explores the vertical layers of forests to test the role of competition and tolerance in community assembly. Abiotic stressors including temperature (3-6°C higher in the canopy), dryness, and microclimate variability increase from the forest floor to the canopy, all within just 20-30 meters of height. This project evaluates how differences in life history strategies, such as tolerance to stress, interactions with other species, and the capacity to colonize new habitats, play a role in community assembly and responses to environmental change. Additionally, this project will develop a curriculum module for secondary school students that aims to foster student involvement in science including the development of educational materials about the value of microbial diversity in nature. The project will develop a novel molecular tool and database for characterizing microbial taxa and traits across the life history strategies, which will be made widely accessible to scientists and practitioners. Finally, the project will support early career scientists by providing professional development and mentorship opportunities for a doctoral student, a research technician, and three seasonal field research assistants. This research will develop a model system – the vertical dimension of forests – to systematically test community assembly and life history tradeoffs of microbial communities across the vertical gradient in a Panamanian tropical rainforest. This will include (1) a multi-omic characterization of the functional and taxonomic diversity of soil communities along the vertical gradient, (2) an assessment of the communities dispersing via air, water, and detritus across the gradient, (3) a reciprocal transplant experiment to test abiotic and biotic controls of community assembly, and (4) a lab-based incubation to specifically evaluate the roles of heat and water stress in shaping community assembly. Finally, the project will (5) synthesize the results using a causal inference modeling approach to explicitly test the role of the competitiveness-to-tolerance tradeoff in shaping community assembly in response to abiotic stress. This project will make significant advances in our understanding of how abiotic stress influences community assembly. Most importantly, this work will test whether a tradeoff between tolerance and competitiveness determines the outcomes of community assembly across a gradient of abiotic stress. Beyond tolerance and competitiveness, the results from this work will provide the first detailed information about trends in dispersal along the vertical gradient and how they vary among different pathways of dispersal. This study will characterize the vertical dimension of microbial diversity in forest soils for the first time, providing insight into this major understudied dimension of global diversity and establishing a model system for testing principles of community assembly. 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 2024 · 2024-08

Summary Cilia are surface-exposed organelles found on most eukaryotic cells, needed to sense and transduce varied sensory stimuli. Not surprisingly, mutations in genes that disrupt cilia growth or function result in 'Ciliopathies' that comprise a wide range of developmental syndromes and multi-system disorders. Cohesins represent a second and independent pathway that is critical for development. Cohesins are required inside the nucleus for high-fidelity chromosome segregation, gene transcription, and chromatin organization. Mutations in genes that disrupt cohesin function result in ‘Cohesinopathies,’ which are also multi-syndrome and multi-system disorders. Both ciliopathies and cohesinopathies are characterized by phenotypes including hearing loss, skeletal abnormalities, and cardiac defects. Remarkably, prior and emerging research implicates cohesins in cilia structure and/or function. For example, the cohesin protein Smc3 localizes to kinocilia in hair cells in the zebrafish embryonic otic vesicle (OV) (i.e. kinocilia are specialized cilia specific to hair cells). Further, Smc3- knockdown leads to otolith defects in the OV, and to reduced kinocilia length in the hair cells of the lateral line (LL). These knockdown results are the first functional evidence connecting cohesins with cilia. Thus, the long- term goal of this research is to provide mechanistic insights into how cohesins and cilia functionally interact. The central hypothesis is that overlapping phenotypes in cohesinopathies and ciliopathies are the result of unknown shared functions between cohesins and cilia. The overall goal of this proposal is to collect preliminary data supporting the model that cohesin proteins contribute to cilia structure and function. The rationale for the proposed research is that revealing such connections would lay the foundation for new insights and therapies that will impact future clinical applications. The hypothesis will be tested using two specific aims: 1) determine how cohesin contributes to cilia function, and 2) determine how cohesin associates with cilia. In the first aim, null mutations in cohesin genes will be generated. Mutants will be monitored for established cilia phenotypes and for defects in kinocilia length. In the second aim, an mCherry-Smc3 transgenic line will be generated to monitor Smc3 localization in kinocilia. Additionally, proximity labeling will be completed to identify putative binding partners in cilia. This approach is innovative because this research has the potential to fundamentally alter our understanding of underlying causes of cohesinopathies and ciliopathies, which would in turn influence the future development of therapeutic approaches. The proposed research is significant because connections between cohesins and cilia are largely unknown, yet are fundamental to our understanding of disease phenotypes that underly a broad group of developmental syndromes.

NSF Awards · FY 2024 · 2024-07

Non-Technical Abstract The ability to produce functional ceramics having tailored geometries has been elusive given the complexity of the underlying processes. The proposed work investigates a novel approach to fabricate such ceramics via solid-state synthesis, a process that involves a chemical reaction of mobile atoms to create a desired product phase. The focus of these studies is two-phase systems that react to form a novel product-phase, namely a so-called entropy-stabilized ceramic (ESC) that is stable at high temperatures. Two new prototypes of substantial technological relevance are of particular interest here. First, the CuO-CuAl2O4-CuAlO2 system provides an opportunity for the design of new functional electronic devices such as transparent transistors and junction diodes, and CuAlO2 also has potential as a sensor material and for oxygen storage material applications. Second, the In-Sn-O system may be exploited to fabricate single-crystal thermoelectrics (e.g., In4Sn3O12), which are devices that turn temperature differences into voltages. This combined experimental and modeling program seeks to describe quantitatively the creation and propagation of the desired product phase for each system so that it may be readily fabricated, with the following overarching aims: 1) elucidate the reaction mechanism resulting in the product phase (i.e., how does the reaction occur?); 2) understand the importance of elastic fields on the reaction (i.e., how does the material deform during a reaction?); 3) characterize the diffusion kinetics along internal interfaces (i.e., how do atoms migrate near phase boundaries?); and 4) design patterned single-crystal phases with unique microstructures (i.e., geometries) for specific applications. In short, the intellectual merit of the proposed work is that it will identify the critical processes and reaction parameters in the solid-state reaction to form an ESC. Some broader impacts of this program include the education of the next generation of computational materials scientists using tools developed here and the use of interactive demonstrations developed here to encourage under-represented minorities in existing programs (e.g., CHOICES for middle-school girls) to pursue STEM opportunities. Technical Abstract The ability to exploit solid-state reactions to produce functional ceramics having tailored microstructures has been elusive given the complex interplay among various kinetic processes and the resulting pattern of an evolving product phase. While stochastic reaction-diffusion simulations provide important insight on the kinetics and microstructural evolution, the details of the underlying reaction mechanisms and transport pathways are not well understood. The proposed work, supported by the Ceramics program in the Division of Materials Research, seeks to elucidate these mechanisms by considering several prototypical systems including Co-Ti-O, CuO-CuAl2O4-CuAlO2 and Sn-In-O. These systems were chosen given their technological importance; for example, as a sensor and an oxygen storage material (e.g., CuAlO2) and as a single-crystal thermoelectric (e.g., In4Sn3O12). While for the first system it is known that it proceeds from a duplex two-phase structure to a single crystal of CoTi2O5, a so-called entropy stabilized ceramic (ESC), the important role of misfit strain in dictating transformation kinetics and morphological development remains unclear and will be examined here. The proposed program will also investigate the mechanisms and kinetics of transport along interphase boundaries (IBs) – processes that have received very little attention in the ceramics community. In particular, advanced electron microscope techniques will be employed to characterize both the composition and orientation of phases at the reaction front, and the detailed structure of the IBs. In tandem, numerical simulations will be used to assess the impact of induced transformation stresses as well as boundaries with different degrees of free volume. Finally, to develop greater intuition about underlying kinetic processes, a Whipple-like solution will also be formulated to study reaction and diffusion at a prototypical IB. In short, the intellectual merit of the proposed work is that it will identify the critical processes and reaction parameters in the solid-state reaction to form an ESC. The broader impacts of this work are designed to foster interest in STEM field subjects, particularly in under-represented groups. This will be accomplished, for example, via the CHOICES (Charting Horizons and Opportunities In Careers in Engineering and Science) program, which is dedicated to encouraging middle school girls to consider careers in science and engineering, and a data science boot camp that will provide students with the basic background skills to apply machine learning techniques in materials science and engineering. 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

Outdoor particulate matter, ozone, and first- or second-hand cigarette smoke collectively afflict over 545 million people globally, with approximately equal distribution between chronic obstructive pulmonary disease (COPD) and asthma cases [1]. As of 2020, Pennsylvania exhibited the highest excess mortality due to air pollution nationwide [2]. Lehigh Valley in eastern Pennsylvania, particularly Allentown, represents one of the most significantly impacted metropolitan regions in the nation, with one of the highest asthma risk profiles in the US [2]. However, there is a notable absence of an early-warning system for environmentally attributable risks for lower respiratory infection, asthma, COPD, and the co- occurrence of asthma and COPD, referred to herein as chronic respiratory syndrome (CRS) for at-risk populations. Furthermore, differentiating between emergent risks (i.e., air pollution-attributable) and baseline risks (i.e., built environment, access, and economic factors) represents a critical advancement in addressing respiratory health needs for vulnerable populations. Our overarching goals focus on developing an intelligent and agile early-warning system for two primary stakeholders: general citizens who can visualize CRS risks through geospatial mapping interfaces, and clinical providers in local healthcare settings who can optimize patient flow management through advanced outbreak prediction algorithms. Our proposed Pennsylvania Asthma- COPD Syndromic Surveillance (PASS) establishes a responsive data analytics infrastructure capable of distinguishing emergent environmental risks (e.g., outdoor air pollution) from underlying health vulnerabilities in geographically susceptible areas, integrating multiple publicly available secondary data streams to enhance public health protection measures. This study represents the first comprehensive analysis of how Pennsylvania and neighboring states' recurrent air pollution episodes and variable weather patterns contribute to outbreaks of CRS-related in-/outpatient visits. Accordingly, we will develop a novel framework for identifying CRS exacerbation-prone regions through data-driven geospatial models (AIM 1). We will quantify the burden of in- /out-patient CRS visits attributable to poor air quality after accounting for other confounding variables. (AIM 2). Finally, we will develop advanced syndromic surveillance systems, capable of detecting the onset of CRS outbreaks across zip code tabulation areas by integrating real-time air quality monitoring data with population susceptibility indicators, thereby enabling more targeted public health prevention, interventions, and resource allocation (AIM 3).

NSF Awards · FY 2024 · 2024-07

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2). A question at the frontier of Earth science is: how do changes in the climate system on our planet's surface interact with magma reservoirs housed within its interior? We will conduct a novel blend of field observations, lab measurements, and numerical model simulations in an integrated study of links between changes in glaciers and topography, and the behavior of several active volcanoes in Chile during the last 50,000 years. These volcanoes were partly covered by the 3,000 foot thick Patagonian ice sheet until it melted rapidly beginning 18,000 years ago. This natural laboratory offers unparalleled means to investigate how the rapid loss of ice impacted the composition and rates of eruptions from these volcanoes. This project will provide career-building experience for several PhD students. A volcano & ice Summer program will engage technical school students from underrepresented groups in the US and Chile in field- and lab-based experiences, including training in drone technology for data collection and geologic mapping. Our collaborations with Chilean scientists and educators aim to: (1) enhance knowledge of the growth rates and eruptive histories of several of the most dangerous volcanoes in South America, thereby improving hazard assessment, (2) generate new climate proxy data critical to calibrating our numerical model of ice sheet retreat, and (3) train students from the communities living near these volcanoes. Utilizing new and existing geochronologic, geochemical, glacial and erosion/deposition observations within the Andean Southern Volcanic Zone, we aim to couple a suite of numerical models to test and refine three hypotheses: (1) Over short timescales (<100,000 year), the composition, volume, and timing of eruptions are strongly influenced by climate-driven changes in surface loading. These short-term responses modulate the long-term (>100,000 year) average eruptive characteristics, which are governed by mantle melt flux, (2) Crustal stress changes associated with the local onset of rapid deglaciation and erosion at 18,000 years ago promoted eruptions by enhancing volatile exsolution that in turn pressurized stored magma and propelled dike propagation to the surface, and (3) Responses to rapid unloading will vary among volcanoes, reflecting contrasts in the composition, volatile contents, and compressibility of stored magma, as well as the rate at which crustal reservoirs are recharged from depth. This variability can be exploited to reveal fundamental controls on the sensitivity of glaciated arcs to the climate system. To investigate these hypotheses, we will pursue four objectives: (1) Generate high-resolution records of cone growth, eruptive behavior, and geochemical evolution of six volcanoes during the last ~50,000 years spanning 250 km along the subduction zone, (2) Build new records of ice retreat, and landscape evolution owing to the erosion, transport, and deposition of sediment adjacent to the six volcanoes, (3) Use the observed chemical and physical patterns in the volcanic, climatic, and topographic records to constrain crustal loading through time, and explore the effects of this forcing in numerical models, and (4) Integrate findings to contextualize processes in continental settings, and provide a framework for examining the sensitivity of arc volcanism to external forcing elsewhere and across a spectrum of climate states throughout Earth history. 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 · 2024-07

The Cnidarian Model Systems Meeting, or "Cnidofest," is a biennial conference that brings together researchers studying cnidarians, a group of animals that includes jellyfish, corals, and sea anemones. These animals have several features of scientific interest, including their importance to ocean health, for example coral reef habitats, and their unique biology, for example their extreme regenerative abilities and diverse forms. Cnidofest 2024 is the third iteration of this meeting and is taking place at Lehigh University. The first Cnidofest was held in 2018 at the University of Florida and the second in 2022 at the University of California, Davis after taking 2020 off due to the pandemic. This growing conference emphasizes the importance of bringing together scientists of all career stages. The conference prioritizes trainee involvement and networking, with trainees giving 75% of the oral presentations. Through the support of trainees, Cnidofest is committed to expanding the community, both in total numbers and in diversity. In particular, expanding opportunities for researchers from diverse backgrounds as well as researchers using diverse model systems is a high priority. Therefore, efforts are made to keep costs low and provide financial support for trainees, ensuring broad participation. Cnidofest also showcases cutting-edge technologies, helping researchers integrate new tools into their research. These talks are given by researchers outside of the community to enable new perspectives. Overall, Cnidofest supports the growth and advancement of the cnidarian research community and is vital component of their success. Cnidarian laboratory models have been used to make fundamental discoveries, including in neurobiology, developmental biology, ecology, evolution, and symbiosis. However, this group of organisms have been historically understudied due to technology limitations. In the past several years, this has changed due to advances in genomics and gene manipulation technologies that can now be easily applied to diverse animals. The advantages of cnidarians for laboratory research include: 1) Simple, well-understood body plans with highly complex and variable life cycles. 2) An informative phylogenetic position as the clade that is sister to bilaterians; discoveries made in cnidarians often uncover deeply conserved processes. 3) Transparency makes them amenable to live imaging. 4) Interesting biology such as self/non-self recognition, the study of algal symbioses, such as found in reef-building corals, and extreme regenerative abilities. The Cnidarian Model Systems Meeting, or "Cnidofest 2024," will bring together researchers studying diverse cnidarians and will emphasize new technological approaches to enhance cnidarian research. Three technology speakers will present seminars on emerging technologies 1) Spatial Transcriptomics, 2) Expansion Microscopy, and 3) Optogenetics. Interactions among participants will be encouraged through a schedule that includes oral presentations, lightning talks, and poster presentations. In addition, time is built into the schedule for informal discussions over breaks and meals, which are all done as one group. The goal is to exchange ideas for advancing research in cnidarians, as well as foster growth in the community by supporting trainee meeting costs. 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 · 2023-07

PROJECT SUMMARY/ABSTRACT The olfactory system is critical to several aspects of behavior and survival in mammals, including humans. The olfactory bulb is the first processing station of the olfactory system and constitutes an exceptional model system for the study of neural coding, capable of encoding a highly complex sensory space within a compact and well- organized structure. Understanding local circuit computation within the olfactory bulb will thus provide key insight into fundamental principles of brain function. Broad perturbation of synaptic inhibition within the olfactory bulb significantly disrupts projection mitral/tufted cell synchronization and olfactory-guided behavior, underscoring a central role of inhibitory interneurons in local circuit computation. In contrast to other regions of the brain such as neocortex and hippocampus, however, fundamental understanding of how the diverse inhibitory interneurons within the olfactory bulb specifically support neural coding has remained elusive, with detailed knowledge of how unitary synaptic interactions contribute to the precise regulation of mitral/tufted cell spike timing in particular lacking. To advance understanding of local circuit computation and neural coding in the olfactory bulb, this project will therefore directly examine unitary synaptic interactions between mitral/tufted cells and a highly-conserved but understudied class of fast-spiking interneurons, using whole-cell pair recordings in acute mouse brain slices together with pharmacology, morphological reconstruction, immunostaining, and simulations. Investigation will specifically address three aims: 1) determine how fast-spiking interneurons regulate mitral/tufted cell spike timing, 2) determine how dendritic computation supports fast-spiking interneuron function, and 3) determine how fast-spiking interneuron signaling adapts with neural activity.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY/ABSTRACT Adaptive evolution is a fundamental process in biology. At its simplest random mutation produces phenotypic variation on which selection acts, enriching for favorable phenotypes and purging the less- favorable ones. This process has produced the diversity of life on Earth. Yet at the same time, adaptive evolution is responsible for some of the most vexing problems in human health, from the growing problem of antibiotic resistance to real-time evolution of viral pathogens to cancers that resist drug treatments and evade the immune system. Despite this, we lack a basic mechanistic understanding of how genomes respond to selection. One major unknown is how adaptive evolution “chooses” one particular path from among a vast number of possible ones. Another major unknown is how genetic variation produces new phenotypes on which selection acts. Experimental Evolution provides a way forward to address both of these significant gaps in our knowledge. With advances in high-throughput biology we can evolve hundreds of initially identical populations in parallel for thousands of generations, with exquisite control over experimental parameters. This versatile technique makes it possible to test evolutionary theory through experiments that are impossible to perform in natural populations. At the same time, experimental evolution is powerful tool for functional genomics. By identifying the genes and pathways that respond to selective pressures, and how these mutations interact to alter phenotype, laboratory evolution experiments identify previously unknown cellular connections. In the past five years my laboratory has advanced a mechanistic understanding of adaptive evolution. Future work will determine how genetic changes give rise to complex phenotypes. We will perform evolution experiments following perturbation of the genetic background and in shifting environments. In addition to advancing our understanding of adaptive evolution, we expect, based on our prior work, to identify previously unknown nuclear-nuclear, nuclear-cytoplasmic, and gene- environment interactions. Finally, we will develop a fast and reliable method for performing multiple rounds of pooled gene editing in yeast, and we will use this method to systematically assay genetic interactions that have been missed by other methods. By connecting genotype to phenotype in an evolutionary context, our work will provide a mechanistic understanding of how complex traits evolve. This work will advance our understanding of adaptive evolution and the genetic basis of complex traits in less tractable systems, including humans and human pathogens.

NIH Research Projects · FY 2026 · 2022-08

Summary We plan to explore the functional topography of electrical synapses in the thalamic reticular nucleus (TRN), a central brain region that controls cortical attention to the sensory surround by gating thalamocortical interactions. During slow-wave of sleep and absence epilepsy, the brain is unresponsive to sensory input; the TRN is thought to focus this neural “searchlight” of attention, and to generate the rhythms that appear as spindles during sleep and sharp-wave discharges in epilepsy. Neuronal communication in the TRN is dominated by the electrical synapses that are formed by connexin36 gap junctions amongst its GABAergic neurons. Our best understanding of electrical synapses is limited by current techniques to pairs of neurons and a single electrical synapse. Here, we will leverage modern optogenetic and focal photostimulation techniques to map electrically coupled networks in molecularly defined populations of GABAergic neurons of the live TRN. Our central hypothesis is that the electrically coupled networks within the TRN link neurons across molecular identity, sensory modality and higher-order and primary relay channels, and thereby regulate thalamocortical transmission. We will test the hypothesis that activity-dependent electrical synaptic depression, which is induced by bursting patterns that are prominent during slow-wave sleep, is global for all synaptic coupling to a strongly bursting neuron, due to its dependence on pan-neuronal T currents. Finally, we will model and experimentally validate how plastic electrically coupled networks finely control the inhibition that TRN neurons deliver to thalamocortical relay cells, and thereby gate thalamocortical communication. Because these synapses are both widespread and underappreciated for their power throughout the mammalian brain, it is crucial to understand the molecular and functional topography and the dynamics of their networks. The significance of this proposal lies in its potential to, for the first time, identify and characterize electrically coupled networks in vitro, both in the TRN and eventually, throughout the brain. This research will make great strides in our understanding of the physiological function and plasticity of electrical synapses, and provide insight into how the TRN controls thalamocortical information processing.

NIH Research Projects · FY 2026 · 2022-06

PROJECT SUMMARY A remarkable feature of lipid membranes is their fluidity: they can self-heal, bend, and circulate. Individual cells also experience and respond to the flows in their environment. Flow responses regulate diverse processes such as blood pressure, bone density, and neural growth. This is particularly apparent in blood vessels, where a monolayer of endothelial cells forms the interface between flowing blood and stationary tissue. Correlation between regions of low flow and atherosclerotic plaques was observed a century ago, leading to the hypothesis that shear flow impacts endothelial cell function. Understanding how cells accomplish mechanotransduction of shear stress into cellular signals is of wide interest. However, the molecular determinants behind flow mechanotransduction remain unclear. Particularly, we lack information on the lateral movement of extracellular membrane proteins located at the cell-fluid interface. While flow has been observed to transport membrane proteins, how this transport affects protein function and cell responses remains unknown. The goal of the proposed studies is to quantitatively measure the physical interactions specific to lipid membranes that determine how lipids and proteins move in response to flow and test whether flow transport of a membrane protein activates intracellular signaling in endothelial cells. Our central hypothesis is that physiologically significant protein and lipid concentration gradients arise from physical interactions between fluid flow and complex membranes. This hypothesis is based on the premise that extracellular lipid-anchored proteoglycans like glypican-1 can be transported along the plasma membrane by external flow, with the aqueous part of the protein acting as a molecular sail. We will accomplish three specific aims: Our first aim is to identify the fundamental properties and principles that govern flow transport of membrane-linked proteins in model membranes and to build a model to predict protein motion in physiological contexts. In the second aim, we will determine how the flow-mediated lateral transport of a physiologically important membrane protein (glypican-1) initiates the short-term flow response in endothelial cells. In our third aim, we will investigate how lipid sorting by flow contributes to flow signaling in our model system and living cell membranes. Our approach is to conduct parallel experiments in model membranes and living cells, allowing us to directly relate physiological function to molecular biophysics. The experiments rely on the PI's expertise using experimental microfluidics and confocal microscopy to determine fundamental membrane properties. While the model protein studied here is specific to endothelial cells, the principles of fluid mechanics that we will uncover are universal. We, therefore, anticipate that our models will apply to multiple cell lines and flow conditions, and will lay the groundwork for future research directions.

NIH Research Projects · FY 2026 · 2022-05

Project Summary: A longstanding and fundamental question of neural development in sensory pathways is: What is the role of the organization of the sensory epithelium in establishing central topographic organization? In the auditory system a direct approach to addressing this question has been elusive because it has not been possible to manipulate the input to the brain from the auditory periphery without either complete ablation of the inner ear or induction of hearing dysfunction. The proposed experiments will establish for the first time, a model of repatterned frequency representation in the chick inner ear by utilizing a new genetic manipulation in embryos. This manipulation takes advantage of the known genetic factors that establish the organization of the ear at a very early developmental stage that precedes the auditory nerve innervation of the central nervous system. By overexpressing one of these factors, bone morphogenic protein 7 (BMP7), inner ears develop almost exclusively low frequency hair cell phenotypes. In the first brain structure to receive auditory nerve input, the cochlear nucleus, neurons express a number of well characterized biophysical and morphological specializations for processing sound in specific frequencies. Frequency specific tuning is topographically mapped in both the ear and auditory brain regions, a feature known as 'tonotopy.' Thus, neural specialization occurs along an orderly tonotopic map in the cochlear nucleus. The central hypothesis of this proposal is that tonotopic refinement of specializations in the cochlear nucleus is developmentally determined by patterned input from the inner ear, and is not independently induced by local cues in the developing brain. This hypothesis is now testable using animals with tonotopically altered inner ears. The first aim of this proposal is to examine whether the BMP7 manipulation indeed induces repatterning of hair cell tuning mechanism in the inner ear. The second aim investigates the electrical input response properties of cochlear nucleus neurons in animals that have developed with tonotopically altered inner ears. Finally, the third aim will investigate the dependence of cochlear nucleus structure on normal topographic innervation from the auditory nerve. These research objectives, if successful, will provide new insights into the mechanisms that establish the functional organization of auditory structures. Revelation of these mechanisms may be informative to optimization strategies for therapeutic interventions in early deafness or hearing loss that aim to preserve normal function and capacity in auditory circuitry.

NIH Research Projects · FY 2024 · 2020-08

The overarching goal of my research program is to understand how naturally occurring genetic variation results in evolved differences in behaviors. To examine these relationships, it is imperative to have a model organism that is both genetically and behaviorally variable, as well as genetically accessible. Natural populations have evolved an extraordinary diversity of behaviors. Developing and applying functional genetic tools and genomic resources to organisms from these natural populations provides an opportunity to uncover the mechanisms by which natural selection has produced these behavioral differences. Further, these approaches may provide general insights into the molecular and genetic bases of social behaviors in other species, such as humans. The blind Mexican cavefish has evolved a variety of morphological, physiological and behavioral traits, including reductions in social behaviors like aggression, relative to surface fish of the same species. My laboratory has focused on establishing methods to identify and functionally validate the role of naturally occurring genetic variants in cavefish behavioral evolution. The research program outlined here will leverage this evolutionary system to identify the genetic architecture underlying within-population differences in aggression, and to test the mechanisms by which differences in aggression evolve. Utilizing genetic mapping approaches, we will identify and functionally test candidate genes for aggressive behavior. Further, using integrative approaches, we determine the mechanisms by which naturally occurring genetic variants impact behavior. Together, this research program will provide important insights into the genetic and neural mechanisms underlying variability in complex behaviors.

NIH Research Projects · FY 2026 · 2020-04

Project Summary/Abstract The ability of cells to divide, establish a polarization direction, and move by crawling requires the coordinated interactions of the cytoskeleton with membranes as well as with the signaling system organizing on membranes. A major challenge for the development of predictive mathematical and computational models of these mechanisms of subcellular organization is accounting of how highly specific interactions at the molecular level lead to the emergent collective behavior. We address this complexity by employing computational and mathematical modeling methods linking molecular to cellular scales, in close collaboration with experimentalists working on model systems that reveal important cell biological functions and are amenable to quantitative approaches. We have three areas of current focus. (1) Understanding the molecular mechanisms and biophysical principles governing the nanoscale assembly of fission yeast nodes, which orchestrate cell cycle progression and cytokinesis. A multiscale approach, combining computational modeling techniques with experiments by collaborators will investigate the interactions among node proteins and the membrane, focusing on Cdc15, Mid1, and Cdr2. Key questions regarding node assembly, phosphorylation regulation, and nuclear shuttling will be addressed. (2) Modeling of membrane hydrodynamics and mechanics during fission yeast cytokinesis and its coupling to the spatial distribution of exocytosis and endocytosis. Coarse-grained fluid simulations will be tested against experiments with vesicle traffic mutants. We will investigate flow-induced transport of membrane proteins and its implications for the membrane and cytoskeleton. (3) Understanding force generation by dendritic networks in the presence of myosin I, the significance of severed oligomers in cellular actin transport, and the interaction for the actin cytoskeleton with focal adhesions and the extracellular matrix. Mathematical models will be developed at the level of individual actin filaments, oligomers, and talin linkers. Overall, the research integrates computer simulations, experimental observations, and collaborative expertise to deepen our understanding of actin and membrane dynamics and its implications for cellular behavior.