University Of California-Irvine

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY The Human Immunodeficiency Virus (HIV), when left untreated, can result in the destruction of the host’s adaptive and innate immune responses, leading to negative pathologies by opportunistic pathogens (AIDS). Some of the greatest barriers in finding an HIV cure is the ability of the virus to establish latency within CD4+ cells, evade human immune clearance mechanisms, as well as induce immune cell exhaustion as a result of chronic infection. An investigatory approach for eliminating latently infected cells, is to use latency reversing agents (LRAs) to force the virus to enter a transcriptionally active state, allowing for host immune mechanisms to identify and kill infected cells. The “Kick-and-Kill” approach has its inherent problems, as it does not address the aforementioned barriers to finding an HIV cure. Additionally, some of the best LRAs, Protein Kinase C (PKC) modulators, are highly toxic in vivo by mechanisms that are not well understood but have been speculated to be toxic due to generalized immune cell activation, or excessive platelet activation/aggregation. The overall objective of this proposal is to augment the “Kick-and-Kill” approach so that the barriers to finding an HIV cure are surmounted, and effective viral clearance in an infection model can be achieved. Current literature has demonstrated that the limitations of the “Kick-and-Kill” approach/HIV cure may be addressed by pairing latency reversal, HIV-specific chimeric antigen receptor (CAR) expressing T cells, and autophagy induction. My preliminary data thus far has shown that PKC modulators are not toxic via an immune cell activation mediated mechanism, and that the immunosuppressive functionality of rapamycin does not prevent HIV latency reversal in our “Kick-and-Kill” approach. The combined effect of the current literature, as well as my preliminary data has allowed us to hypothesize that tolerable PKC modulator-mediated latency reversal, paired with HIV-specific CAR T cells and autophagy induction via rapamycin will effectively deplete the viral reservoir within an HIV-infected humanized mouse model. Aim 1 of this proposal will investigate the role of platelet activation/aggregation in bryostatin-1-mediated toxicity in vivo, by measuring mouse survival and platelet activation/aggregation in byrostatin-1 and platelet aggregation inhibitor treated C57BL/6 mice. Aim 2 will evaluate the effects of bryostatin- 1 and the autophagy inducer rapamycin on T cell exhaustion markers, HIV latency reversal, viral load and time to viral rebound in HIV-infected, ART-suppressed, humanized mice after ART cessation. Finally, Aim 3 will utilize a CAR T cell-expressing (D1D2CAR 4-1BB CAR T cell), ART-suppressed, humanized mouse HIV infection model to test for T cell exhaustion markers, viral load, and HIV latency reversal in tissues and blood upon bryostatin-1 and rapamycin treatment, as well as time to viral rebound after ART cessation. Together, these data will elucidate the curative potential of autophagy induction and HIV-specific CAR T cells in a “Kick-and-Kill” oriented HIV cure approach. At the same time, this work will also shed light on the role of platelet activation/aggregation in PKC modulator-induced toxicity, providing insight into future drug development.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Over 600,000 patients with end-stage kidney disease (ESKD) are on dialysis in the United States, with nearly 100,000 awaiting kidney transplantation. In California, the wait times for deceased donors can extend to 10 years. Living donor kidney transplantation reduces the wait and offers superior survival compared to deceased donation. However, living kidney donors have declined over the last two decades. While donors receive comprehensive pre-donation and perioperative care, post-donation follow-up is often compromised. Despite a U.S. mandated donor follow-up policy, over 40% of donors are lost to follow-up within 2 years. Donors face increased risks of post-donation complications, with inadequate access to post-donation follow-up care. Barriers such as limited access to care, financial strain, and distance from transplant centers exacerbate post-donation follow-up care. Non-clinical donor factors, including education, income, insurance status, and residence status, further compound these challenges. These real-life factors shape targeted interventions, emphasizing the need for person-centered approaches. Effective programs and strategies are urgently needed to address challenges to post-donation follow-up and improve care for all donors. We are tailoring a telemedicine care coordination model to assist donor candidates in completing predonation evaluations. By extension, we envision telemedicine as a potential solution to reduce barriers to post-donation follow-up care. A knowledge gap exists regarding the interplay of non-clinical donor factors in post-donation follow-up and the role of telemedicine as a potential solution to mitigate the modifiable factors. We will conduct mixed-methods research to combine quantitative national data with qualitative donor interviews for a comprehensive understanding of this interplay. Our scientific goal is to understand how non-clinical donor factors influence variations in post-donation follow-up and help mitigate modifiable factors. Our findings will identify high-risk groups and provide insights for tailoring a future telemedicine intervention in post-donation follow-up. This award will support Dr. Al Ammary in completing this proposed research and generating preliminary data for an R01 application to establish and test telemedicine intervention to improve post-donation care for all donors and foster public trust.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY This proposal aims to develop a high-speed, multimodal deep tissue imaging system that integrates reflection matrix optical coherence tomography (RM-OCT) with wavefront shaping to overcome the fundamental limitations of light scattering in biological tissues. By leveraging high-speed lock-in cameras, high-speed spatial light modulators (SLMs), and Tikhonov-regularized matrix inversion, the system will achieve real-time, non-invasive imaging with cellular resolution at unprecedented depths, enabling in vivo applications. This technology will synergize RM-OCT with multiphoton microscopy (MPM) and photoacoustic microscopy (PAM), providing a unified platform for comprehensive structural, metabolic, and hemodynamic imaging. The specific aims are: (1) Develop reflection matrix-based wavefront shaping and demonstrate the enhanced imaging depth ex vivo; (2) Optimize system performance for deep tissue imaging and integrate RM-OCT with MPM and PAM; (3) Achieve, validate, and characterize in vivo multimodal deep tissue imaging in animal models. This project proposes a transformative solution with three key advantages: (1) It uses a model energy matrix to visualize light distribution inside scattering samples, effectively acting as an internal "camera" to assess focusing quality; (2) It achieves guide-star-free focusing deep within scattering media; and (3) It designs optimal wavefronts to focus light across entire target planes, rather than single spots. By overcoming the speed-depth trade-off, this technology will enable researchers to study dynamic biological processes in vivo with unprecedented spatiotemporal precision. The proposed system has broad applications in neuroscience, cancer research, and cardiovascular diseases, enabling researchers to study dynamic biological processes in vivo with unprecedented precision. By breaking the scattering barrier, this technology will transform biomedical research and accelerate the development of new therapies.

NSF Awards · FY 2025 · 2025-09

Wildfire is happening more often near cities and towns, putting people, homes, and communities at greater risk. Since wildfires are growing larger and more intense it is even more important to take steps to protect these communities. One helpful way to prepare and respond to wildfires is by using computer modeling and simulation. This powerful tool helps predict how fires might spread in areas where forests and natural areas meet cities and towns. These areas are called the wildland-urban interface (WUI). However, creating accurate models is challenging because how a fire spreads in an urban area is affected by many complex processes that occur in both small areas (like a building) and large areas (like a whole neighborhood). This project aims to understand these processes better and build more reliable models that can predict how fires will act in WUI areas, whether at small or large scales. The team also plans to create an easy-to-use computer program that will help emergency planners and local leaders use these tools to make better decisions about evacuations, managing fires, and keeping communities safer. The technical aspects of the proposed research are organized around four primary objectives identified as: (i) to develop a fundamental physical understanding of how fire interacts with individual structures and materials in urban environments at the local scale; (ii) to investigate how these localized interactions influence fire dynamics at intermediate scales—such as neighborhoods and communities—thereby bridging the gap between structure-level physics and community-scale outcomes; (iii) use insights from items (i) and (ii) to construct a computationally efficient, large-scale reduced-order model that accurately predicts fire spread in wildland-urban interface (WUI) scenarios, while capturing the essential underlying physics; (iv) to integrate models developed into a user-friendly, operational platform designed to enable real-time prediction and support decision-making for fire preparedness, response, and mitigation in WUI regions. The project outcome is expected to have a significant societal impact, addressing the increasing wildfire risks driven by shifting hydro-meteorological patterns, drought, and urban sprawl. It will produce predictive tools and decision-support platforms to aid real-time evacuation and firefighting strategies. Additionally, it will inform land-use planning, building codes, and zoning regulations to reduce future risk. Notably, the project promotes broad applicability by guiding policies that ensure all populations receive adequate support during disaster preparedness and recovery 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 2025 · 2025-09

Project Summary RNAs play pivotal roles in diverse cellular processes ranging from memory formation to immune activity. Key questions remain, though, regarding the location, degradation, and dynamic interactions of multiple transcripts. This is due, in part, to a lack of robust methods to track RNAs in real time and in physiological settings. Conventional approaches rely on RNA tags coupled with fluorescent probes. Many of these tags are too large to use in conjunction with small RNAs. Additionally, the readouts require excitation light, which can damage biological samples upon repeated exposure. External light can also induce autofluorescence, precluding sensitive detection of low abundant targets. Capturing a broader set of RNAs—and the complete picture of their biological roles—requires new technologies. Our long-term goal is to develop enabling platforms for visualizing RNAs and their dynamics. The objective of this proposal is to build one foundational technology featuring ultra-small RNA tags that can assemble split luciferases. Signal production will only be observed when target transcripts (bearing the small tags) are present. Guided by strong preliminary data, our work involves (1) generating orthogonal RNA tags and complementary split luciferase binders, such that multiple transcripts can be visualized at once; (2) developing a platform for continuous, multiplexed imaging. This aim will make use of bioluminescent phasor, a method for rapid assignment of overlapping and often complex luciferase emission spectra. The experiments will establish optimized parameters for deploying combinations of the RNA tools in biologically relevant systems, and for continuously tracking their abundance and location. A third aim involves benchmarking the imaging probes and methodology against challenging targets, including endogenous and low-abundant RNAs, and collections of differentially expressed transcripts. Collectively, our work removes technical barriers to imaging RNAs and their dynamic functions, marking a significant advance over existing state-of-the-art approaches.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a common pathological change that significantly contributes to cognitive decline in older adults and plays a critical role in Alzheimer’s-type dementia in older age groups. LATE-NC is prevalent in over one-third of participants and half of dementia decedents in aging cohorts, often mimicking Alzheimer’s disease neuropathologic change (ADNC) with an amnestic presentation. LATE-NC and ADNC frequently coexist, leading to multiple-etiology dementia (MED). Despite recent progress in efforts to establish diagnostic criteria for LATE, significant gaps remain in validation of diagnostic criteria, LATE biomarkers, and recruitment strategies for early-phase clinical trials targeting LATE-NC. This project aims to address these unmet needs by creating a "Discovery and Trial Ready Cohort for LATE (TRC LATE)" through recruiting and characterizing 420 participants aged 85 and older across five Alzheimer’s disease research centers (ADRCs). These participants will undergo comprehensive annual assessments, including neuropsychological testing, annual brain MRI, FDG-PET scan every 2 years, annual blood collections, remote cognitive assessments, and recruitment science experiments. Approximately 200 of the participants who fulfill the current LATE diagnostic criteria will be enrolled in the Trial-Ready Cohort for enrollment in future early phase trials of LATE. The study aims to validate clinical, neuropsychological, and imaging markers for LATE (Aim 1), identify novel biomarkers and develop risk scores for LATE-NC (Aim 2), and conduct trial planning and recruitment science studies, which will focus on identifying barriers to participation in clinical trials and evaluating methods to improve understanding and willingness to engage in LATE and LATE/AD combination trials (Aim 3). By establishing this diverse, well-characterized cohort, we will generate crucial data to accelerate early-phase clinical trials targeting LATE-NC, discover new biomarkers, and develop new strategies for recruiting traditionally underrepresented populations in ADRD research. Ultimately, this study will reduce trial timelines and enhance our understanding of the clinical complexities of aging-related dementias. 1

NIH Research Projects · FY 2025 · 2025-09

Project Summary / Abstract Alzheimer disease (AD) is the most prevalent type of age-progressive dementia, significantly affecting many individuals aged 65 and older. Recent studies have uncovered disease relevant cell types and neural circuits in the AD brains including humans and animal models and have identified molecular and functional alterations in specific neuronal and non-neuronal cell types in aging and AD. New investigations that target and manipulate specific brain cell types that are selectively affected by aging and AD progression could lead to major breakthroughs in understanding the cellular and neural mechanisms underlying aging and AD/ADRD. Genetically engineered viral vectors, including adeno-associated viruses (AAVs), are increasingly important neurobiological tools for cell-type-specific neural circuit mapping and genetic payload delivery. AAV vectors that incorporate gene regulatory elements in the viral genomes (enhancer AAVs) have been developed recently to target specific types of neurons and other brain cell types for neural circuit analysis in the mouse and non-human primate models. Of note, almost all of this work has been done in young adult animals, thus their performance and feasibility needs to be established before they can be properly used in aging and AD neuroscience research. In response to RFA-AG-25-024, we propose to leverage our recent technological advances to optimize and develop cell-type-selective enhancer AAVs for genetic access to diverse cell types and their related neural circuit analysis in multiple AD mouse models. Our guiding hypothesis is that brain cell-type-specific enhancers can be further optimized and developed to study disease relevant cell types and neural circuits in the brain environments of aging and AD animals. We will test our hypothesis that both vulnerable neuronal cell types and non-neuronal cell types including oligodendrocytes and vascular cells are critically implicated in AD pathogenesis and progression. In the R61 phase, we propose to screen newly developed enhancer AAV tools initially characterized in healthy young adults and determine their effectiveness in targeting AD-relevant specific brain cell types in vivo in older and degenerating brains. We will test and examine selected enhancer AAVs using different delivery methods and different titers, and we will establish an optimized standard operating protocol for enhancer AAV applications. In the R33 phase, we will use the optimized AAV-enhancer tools to monitor and manipulate brain cell types to understand how they contribute to the aging and disease processes and address their mechanistic implications, including an explicit test that Aβ triggers tauopathy in hippocampal cell types. The enhancer AAVs will express genetic payloads including fluorescent reporters, optogenetic and chemogenetic tools, calcium indicators designed to map and manipulate brain cell subtypes including neuronal and non-neuronal cell types. We will conduct neural circuit manipulation and mapping experiments including cell-type-specific viral tracing, in vivo structural and functional imaging and behavioral experiments to validate our proposed hypothesis.

NSF Awards · FY 2025 · 2025-09

This project addresses the turbulent combustion commonly encountered in gas-turbine engines, rocket engines, and industrial furnaces. Critical physical behavior occurs on sub-millimeter length scales, i.e., over length scales much smaller than the engine size. A study of the full range of design parameters to optimize performance requires large and computationally costly models. The project will uncover new relations between the large-scale combustor behavior and small-scale physics, and results will be applied to develop next generation combustion models. Detailed computations with artificial intelligence modeling will be leveraged to create highly efficient and accurate combustion models that can be used in designing new combustion devices. This project will guide sub-grid combustion modeling from direct numerical simulations of turbulent non-premixed combustion in a three-dimensional shear layer between an oxidizer stream and a fuel stream. The simulations will address a high-Reynolds-number shear layer with a planar mean flow. In the post-processing of results, statistical data will be collected concerning relative vector alignments and magnitudes of vorticity, normal strain rates, scalar gradients, and joint-probability density functions of these rates and gradients. Scaling rules for these magnitudes over the turbulent length-scale spectrum will be sought, to provide inputs for Reynolds-averaged Navier-Stokes computations and large-eddy simulations. The results will be filtered by length scale to understand better the turbulence cascade of scalar and vector gradients. Improvements will be made to existing rotational flamelet models with account for vorticity, variable density, and three-dimensional, multi-branched flamelet structure. Missing physics in current sub-grid modelling for turbulent combustion will be emphasized: (i) shear strain (with vorticity) and its major effect on flammability limits; (ii) realistic three-dimensional flame structures (rather than current 2D and axisymmetric structures); (iii) variable density; (iv) self-determination within the analysis of flame structure (i.e., premixed, multi-branched, or diffusion flames) based on local flow configuration; and (v) the strain rates and vorticity applied at the sub-grid level are determined from the resolved-scale strain rates and vorticity without use of a contrived progress variable. . 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 · 2025-09

PROJECT SUMMARY As humans age, their immune systems become dysfunctional. Specifically, aging impacts adaptive immunity leading to a decline in vaccine induced secretion of high-affinity antibodies. We know a lot about cellular responses to vaccines in aged individuals from investigating their blood. However, antibody responses evolve in germinal centers (GCs) of secondary lymphoid organs, where T follicular helper cells (Tfh) facilitate the selection of plasma cells that produce high-affinity antibodies. Limited access to human tissues has prevented us from fully understanding how aging and age-associated frailty influences Tfh function in tissue and how they contribute to a concomitant decline in antibody responses. The overarching hypothesis of this proposal is that age- related changes in Tfh frequencies, positioning, and function in human lymphoid tissues contributes to reduced vaccine efficacy in older adults. To address this, I have developed a research plan, spanning both my training during the mentored K99 and independent R00 phase. Using a systems immunology approach, integrating orthogonal transcriptomic, epigenomic, and phenotypic readouts, I will quantify age-associated changes in Tfh heterogeneity in secondary lymphoid organs. I hypothesize that Tfh in secondary lymphoid organs accumulate epigenetic changes with age, resulting in a transcriptional state of reduced metabolic plasticity and muted cytokine responses, which is reminiscent of immune senescence. Next, using a novel in vitro human tonsil organoid model and with the help of training proposed in this application, I will identify features of Tfh that correlate with declining quality of antibodies following influenza vaccination in older adults. I hypothesize that vaccination in older adults will result in poor Tfh differentiation, limited clonal expansion, diminished phenotypic plasticity in GCs and consequently poor B cell help. Furthermore, I anticipate that Tfh- focused immune modulation will improve quality of the antibody response in older adults. To test this mechanistically, in the R00 phase, I will determine how Tfh frequencies and function contribute to poorly cross- reactive antibody responses in older adults. Finally, I will test strategies to rejuvenate the aging GC, by using immune modulatory agents targeting Tfh to overcome suboptimal influenza vaccine responses in older adults. Gaining insight into the factors influencing diminished Tfh responses as individuals age will lay the groundwork for enhancing vaccine effectiveness in older populations. The diverse scope of research outlined in this proposal and an assembled team of mentors, co-mentors, and collaborators will provide me with training in aging biology, microscopy, and antibody assays, which will complement my existing background in systems immunology. Collectively, this training will facilitate my progression towards establishing an independent research program at the nexus of immunology and aging.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Multiple Sclerosis (MS) is a debilitating autoimmune disease wherein activated immune cells mistakenly attack the protective myelin coating on neurons. This results in scarring and the formation of lesions in the brain and/or spinal cord that contribute to a host of symptoms that vary dependent on the location of the injury. The precise etiology of MS remains unknown, though recent studies have pointed towards a combination of genetic and environmental factors. Intriguingly, a strong correlation exists between previous exposure to Ebstein-Barr virus, which increases the risk of developing MS by 30-fold. As this highlights a potentially important role that viral infection may play in the initiation of MS, our lab utilizes a murine neurotropic JHM strain of mouse hepatitis virus (JHMV) that results in an acute encephalomyelitis that is accompanied by gray matter involvement with infection of oligodendrocytes, astrocytes, and microglia. JHMV persists in the white matter tracts of the spinal cord, inducing demyelination resulting in hind-limb paralysis in mice. We and others have demonstrated previously that microglia, a resident innate immune cell population that resides in the central nervous system (CNS), are critical in constraining the immune response in demyelinating models of MS. Intriguingly, in areas of demyelination undergoing remyelination, there is a significant upregulation of cystatin F (Cst7), a protease inhibitor. While Cst7 is expressed on many immune cells, we’ve shown that microglia are the predominant source of Cst7 in the brain. Thus, this proposal seeks to define the role of microglia-derived Cst7 in the context of a viral infection with JHMV. We propose to infect novel transgenic conditional knockout mice for Cst7 on microglia and wild-type animals with JHMV to determine the impact of Cst7 on the immune response. A combination of flow cytometry and imaging modalities will be utilized to characterize differences in brain immune cell infiltration and activation. The impact of the conditional ablation of Cst7 on demyelination and subsequent remyelination will be assessed as well, using state-of-the-art techniques like spatial transcriptomics (Aim 1). Based on our preliminary and published findings, we hypothesize that Cst7 expressed on microglia is host protective. Therefore, we also propose to evaluate Cst7 as a potential therapeutic for demyelinating diseases by employing an overexpression model. Cst7 will be overexpressed in microglia in mice infected with JHMV and the subsequent immune response and myelination status will be evaluated using similar techniques as described above (Aim 2). Together, these aims seek to evaluate the role of microglia-derived Cst7 in an effort to further delineate mechanisms of demyelination and remyelination. As it is extremely rare for damaged neurons to undergo remyelination in MS, defining these mechanisms further will provide invaluable insight for the advancement of new therapeutics.

NIH Research Projects · FY 2025 · 2025-09

Project Summary The progressive cognitive decline observed in Alzheimer's Disease (AD) is linked to synaptic dysfunction and the degradation of perineuronal nets (PNNs), which are critical for neuronal protection, synaptic stability, and plasticity. Interestingly, the role of microglia, the central nervous system's resident immune cells, extends beyond their well-known involvement in neuroinflammation to include the maintenance of PNN integrity. Recent findings from our lab have revealed that β-hexosaminidase, a crucial lysosomal enzyme, is exclusively expressed in and secreted by microglia. β-hexosaminidase is critical in maintaining normal neuronal function and may also be involved in the regulation of PNNs. This research proposal aims to dissect the functional implications of microglial β-hexosaminidase on PNN regulation under normal and AD-associated conditions. In the first aim, we will explore the role of β-hexosaminidase in homeostatic PNN regulation by modulating its levels in the mouse brain. Through a combination of enzyme inhibition, microglial cell replacement, and recombinant protein infusion strategies, we aim to delineate the contribution of β-hexosaminidase to normal PNN architecture. The second aim is designed to investigate whether β-hexosaminidase is implicated in the early-stage loss of PNNs and gene expression changes in parvalbumin-positive neurons preceding their loss, both hallmarks of AD pathology. By employing a mouse model of Alzheimer's disease (5xFAD) and replacing native microglia with β-hexosaminidase-deficient myeloid cells, we will assess the impact of diminished β- hexosaminidase activity on PNN preservation and neuronal health during disease progression. Given its unique position at the nexus of microglial function and neuronal health, β-hexosaminidase represents a novel therapeutic target whose manipulation could offer significant benefits in AD. This project will advance our understanding of neurodegenerative disease research by highlighting the therapeutic potential of targeting microglial enzymes for the preservation of critical neuronal structures. Through innovative methodological approaches and a focus on the complex role of microglia in neurodegeneration, this proposal aims to bridge significant knowledge gaps and offer novel insights into the mechanisms of AD pathology. Ultimately, the findings from this study could broaden our understanding of the complex interplay between microglia, neurons, and the extracellular matrix in the brain, paving the way for the development of new glia-targeted therapies and expanding our repertoire of potential interventions in AD.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY The human genome project was expected to define all protein-coding genes, but many blind spots still persist. Microproteins are a recently uncovered class of proteins composed of less than 100-150 amino acids encoded by small open reading frames (smORFs). Previous studies from our group discovered thousands of unannotated microproteins encoded on transcript regions previously assumed to be non-coding, including on annotated long non-coding RNAs and 5’- and 3’-untranslated regions (UTRs). While the majority of microproteins have yet to be functionally characterized, many have been found to regulate fundamental processes, including DNA repair, RNA metabolism, ER stress, and translation, underscoring their significance and diverse biological roles. Our long-term vision is to develop strategies for identifying functions for the remaining thousands of microproteins, which will ultimately expand our understanding of many areas of biology and potentially reveal new therapeutic approaches for different diseases. In this proposal, our goal is to leverage the unique biochemical properties of microproteins to rationally screen for which pathways and processes they participate in. First, microproteins frequently function by interacting with and regulating the activity of larger proteins and protein complexes. In addition, most microproteins are highly disordered and enriched for short linear motifs (SLiMs) and other binding motifs that would allow for interactions between their intrinsically disordered regions (IDRs) and other biomolecules. Based on decades of research on larger annotated proteins, we know that IDRs are essential to many cellular processes, including cell signaling, RNA metabolism, and subcellular organization. We also know that many microproteins harbor the same motifs as annotated proteins involved in these specific processes. We will therefore use a combination of high- throughput screens and chemical tools to identify protein interaction partners for curated sets of disordered microproteins that are likely to function in these processes. Then for each validated microprotein interaction uncovered, we will characterize the microprotein’s role in regulating the activity of the interacting protein(s) and the particular cellular process it acts on. Altogether, these studies will uncover new functional microproteins that will expand our understanding of basic biology and provide new insights into health and disease.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT This proposed project is responsive to the continued need for improved early detection of postpartum hemorrhage (PPH). PPH is the leading causes of death in pregnant women. Data from multiple published studies strongly suggest that vital signs alone are not actionable during the early stages of PPH. Blood volume loss as great as 30% can occur with current standard vital signs remaining clinically normal. In these stages, compensatory mechanisms for volume loss result in delayed changes in vital signs. Changes in vital signs such as blood pressure often occur only when cardiovascular collapse is imminent, which is often too late to provide a life-saving intervention as the victim enters a state of circulatory shock. The objective of the proposed grant is to develop a robust wearable system, which we call Maternal Obstetrics Monitoring System (MOMS), that can measure high-quality physiological waveforms, from multiple sensors integrated into one easy to wear device, for hospital as well as ambulatory monitoring. We will test the hypothesis that continuous monitoring and analysis of vital sign waveforms with MOMS is a more accurate, precise, and robust early indicator of PPH than current, commercially available technologies. The R61 Specific Aims are 1) to complete and validate the alpha prototype sensor integrating the MEMS-based blood pressure sensor and the CSI sensor and 2) to determine design requirements of the R33 beta prototype from design inputs obtained from shadowing, interviews, and focus groups. The R33 Specific Aims are 1) to design and develop the beta prototype per design specifications of R61 Aim 2, 2) to test this beta prototype with a validated lower-body negative pressure protocol of hypovolemia, and 3) to build multimodal machine learning (MMML) algorithms integrating the multimodal data streams for predictive capabilities and perform explainability analysis. To achieve these aims, we have assembled a multidisciplinary research team with expertise in biomedical device design, biophotonics, clinical obstetrics and gynecology, and machine learning. With the successful completion of the proposed research, we will possess a validated MOMS sensor technology that is ready for use during delivery and postpartum care, which in turn will lead to increased maternal survivability.

NSF Awards · FY 2025 · 2025-09

This project addresses how marine phytoplankton — microscopic algae that fuel ocean food webs and contribute to global nutrient cycling — respond to differences in resource availability across the ocean. Nutrient supply in surface waters plays a central role in determining phytoplankton growth and overall ocean productivity. However, the ocean harbors a wide variety of phytoplankton species, and their varied nutritional demands may influence ecosystem responses in complex ways. This research provides a novel technical ability to diagnose the nutritional state of diverse phytoplankton communities using genomic tools while also advancing our understanding of large-scale patterns in marine productivity. The project also contributes to public understanding of marine ecosystems through science outreach and education activities, including hands-on events in collaboration with a state park that welcomes a broad public audience. Additionally, all genomic data and analysis tools are being shared openly, supporting further research and educational use. The research investigates whether different phytoplankton species experience distinct nutrient stress conditions even when living in the same environment. To do so, the team is leveraging a funded GO-SHIP cruise and combining comparative genomics, laboratory experiments, field-based nutrient bioassays, and analyses of existing large-scale DNA and RNA datasets from across the global ocean. A key focus is identifying biomarkers — specific genes or gene expression patterns — that indicate stress from limited nitrogen, phosphorus, or iron. These biomarkers are used to map nutrient stress states across multiple phytoplankton groups and geographic regions. The project compares patterns observed in field samples with predictions from Earth system models to improve scientific understanding of how nutrient conditions shape marine ecosystems. The results provide valuable insight into the relationships between environmental conditions, phytoplankton diversity, and the nutritional balance of ocean ecosystems. 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 2025 · 2025-09

This grant supports research in theoretical particle physics and cosmology at the University of California, Irvine. The Principal Investigators are Professors Jonathan L. Feng, Manoj Kaplinghat, and Tim M.P. Tait, who will carry out the research in collaboration with colleagues and students at UC Irvine and elsewhere. This project serves the national interest by promoting the progress of science in that it will deepen our understanding of the physical Universe at both the smallest and largest length scales, and encompasses a broad research program, including theoretical studies and model building for physics beyond the standard model, collider physics, neutrino and flavor physics, dark matter, and cosmology. The broader impacts of the group’s activities are directed toward increasing public interest in and improving public understanding of the exciting research results in physics and astronomy, in addition to enhancing participation in these and other related STEM fields. The fields of particle physics and cosmology have entered a new data-driven era. A wide variety of particle physics experiments are deepening our understanding of the fundamental interactions and probing the fundamental building blocks of Nature with unprecedented detail. At the same time, outstanding questions stemming from a wealth of data in astrophysics and cosmology also guide theoretical work on physics beyond the standard model, and the interaction of cosmology and particle physics has been very fruitful. The research plan exploits innovative ideas in particle physics, cosmology, and at their interface to address outstanding problems in a wide variety of fields, including searches for new physics at accelerators, neutrino and flavor physics, dark matter particle candidates and their observable signatures, and particle cosmology. The group’s activities include developing and teaching a COSMOS summer course in particle physics and cosmology for high school students, a wide array of public talks and outreach activities through print and web-based media, the training of postdoctoral researchers and graduate students both at UC Irvine and around the world, and significant contributions in the area of professional service. 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 2025 · 2025-09

This project explores a powerful mathematical process called Ricci flow, which smooths out geometric shapes over time--like heat evening out the temperature on a surface. Ricci flow has led to major breakthroughs, including Perelman's resolution of the century-old Poincaré Conjecture, and continues to transform our understanding of the geometry and topology of space. A major challenge lies in understanding the "singularities" that inevitably form during the flow, where the shape becomes infinitely curved, and hold vital clues about the hidden structure of space. A central idea in Perelman's proof is the use of surgeries to continue Ricci flows through singularities. The PI aims to extend this surgery construction in higher dimensions, with the goal of uncovering new geometric and topological applications. The research will be complemented by mentoring graduate students and organizing workshops and conferences. The research project is split into two parts: The first project focuses on classifying ancient Ricci flows that are asymptotic to cylinders, which serve as potential singularity models. These asymptotically cylindrical flows include the classical rotationally symmetric examples such as the Bryant soliton and Perelman's ovals, as well as new examples recently constructed by the PI, known as flying wings. The flying wings are asymptotic to cylinders with more than one R-factor and break the rotational symmetry. The PI aims to develop a general method to estimate the asymptotic behavior of such flows without relying on rotational symmetry or positive curvature assumptions. These techniques may ultimately enable an extension of Perelman's 3D Ricci flow with surgeries to 4D, providing a broader and more robust topological toolkit. The second project builds on the PI's ongoing work with collaborators to understand 3D open manifolds with positive scalar curvature. The PI has developed a theory of generalized singular Ricci flows that extends the flow to arbitrary 3D manifolds, including those with unbounded geometry. Building on this, the PI will investigate the removal of the bounded geometry assumption and work toward a complete classification of all such manifolds. Please report errors in award information by writing awardsearch@nsf.gov. 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 · 2025-09

Embryonic development is a complex and intricately timed process such that any deviation from the correct sequence of events can elicit unwanted developmental effects. Epigenetic mechanisms, like DNA methylation and microRNAs (miRNAs), have a crucial role in development, impacting gene expression in the cell necessary for tissue-specific gene expression, gene-environment interactions, differentiation, and growth. Human embryonic stem cells (hESCs) have helped our understanding of mechanisms involved in development and disease. Yet, the epigenetic factors involved in early hESC differentiation before specialized cell types need further understanding. My research program seeks to investigate the relationship between DNA methylation and miRNAs during early hESC lineage specification. We will dissect early cell fate changes due to epigenetic regulation using various omics technologies, cell imaging, and transcriptional regulator expression changes. We will explore the interplay between DNA methylation and miRNAs to regulate gene expression during normal and abnormal differentiation. In addition, we will answer questions about the most suitable methods for directed differentiation and cell state identity, such as determining the cell makeup in a pan-mesoderm differentiation approach and using methods that differentiate cells through a specific mesoderm subtype. We are excited about the proposed work and believe our projects will contribute to understanding of embryogenesis, stem cell biology, and identifying epigenetic factors leveraged as biomarkers of aberrant embryonic development.

NIH Research Projects · FY 2026 · 2025-09

Summary The opiate epidemic has led to a surge in overdose deaths and significant societal and economic costs. Opiate withdrawal poses obstacles to recovery by causing emotional, motivational, and cognitive disturbances that disrupt one’s ability to pursue adaptive goals. Understanding the neural mechanisms underlying these withdrawal-induced deficits may facilitate strategies to promote abstinence. Our preliminary research shows that rats experiencing acute morphine withdrawal exhibit reduced motivation and impaired cognitive, goal-directed control over their actions. This project will test the innovative hypothesis that opioid withdrawal-induced motivational deficits are mediated by opposing adaptations in dopamine (DA) and acetylcholine (ACh) release in the nucleus accumbens (NAc) and that withdrawal-induced deficits in goal-directed action selection result from aberrant DA and ACh signaling in the dorsomedial striatum (DMS). We will also investigate whether dysregulated D1- and D2-striatal projection neuron (SPN) activity in the NAc and DMS contributes to withdrawal-induced deficits in motivation and action selection, respectively. Aim 1 will combine sophisticated behavioral analysis, quantitative no-net-flux microdialysis, and fiber photometry to determine the impact of acute and protracted morphine withdrawal on tonic and phasic DA and ACh release and D1/D2 SPN calcium activity in the NAc and DMS, and how these effects relate to deficits in motivation and action selection. Aim 2 will test whether these behavioral deficits can be ameliorated, exacerbated, and mimicked through cell-type and region-specific chemogenetic and optogenetic manipulations of striatal DA and ACh release and D1/D2 SPN activity. The study aims to uncover novel neurochemical and neurocircuit mechanisms contributing to anhedonia-like symptoms in morphine withdrawal, guiding future strategies to combat opioid use disorder.

NSF Awards · FY 2025 · 2025-09

Red-green color vision is found in a variety of animals including primates and insects. Vision involves interactions between pigments and opsins, which are proteins that allow animal eyes to detect light. Yet not all vision systems work the same. The research will advance scientific knowledge of how animals can tell green, yellow, orange, and red apart. It will study how pigment-binding proteins partner with pigments and opsins to filter light in a way that works differently from the system in humans. It will further investigate whether the presence or absence of red-green color vision in insect pollinators is related to the color of flowers that they visit. This study will benefit society by providing new knowledge of how pollinators see and the plants they feed on. This knowledge can be used in the biologically guided design of parks and community gardens to enhance plant reproduction and pollinator and human health. Furthermore, certain pigments and the proteins that bind them have uses in the applied sciences, including manufacture of electronic color-changing devices and design of antioxidant and anticancer molecules. Understanding how new traits evolve is a central goal of evolutionary biology, as these innovations can fundamentally change the ecological interactions that drive biological richness, including interspecific interactions, niche shifts, and mating patterns. This research will investigate the evolutionary processes that drive the gain and loss of red-green color vision across Nymphalid butterflies. Building on previous work that identified a novel gene and molecular pathway underlying this trait, the researchers will examine evidence for parallel molecular evolution, characterize changes in gene regulation, and explore how repeated gain or loss of red-green color vision correlates with ecological variables. The research will combine genetics and gene expression with light microscopy, electrophysiology, immunohistochemistry, and behavioral assays in a phylogenetic framework to address four major questions. (1) Are the same mutations associated with parallel red- or blue-shifts in long wavelength opsin spectral sensitivity? (2) Is long wavelength opsin spectral tuning shaped by filter-pigment expression? (3) Are genetic processes underlying red-green color vision acquisition or loss different between species that have sexually dimorphic vs. monomorphic eyes? (4) Is the loss of red-green color vision associated with shifts in adult food sources, signals, or habitat? 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 · 2025-08

PROJECT SUMMARY Temporomandibular joint (TMJ) disc perforations pose devastating morbidities for millions of Americans. Interventions to slow or prevent progression of this disease do not exist. Toward addressing this as-of-yet intractable problem, tissue-engineered neodisc constructs made with allogeneic costal chondrocytes have shown promise in healing TMJ disc thinning, but larger defects remain a major challenge. Due to the exposed allograft area, larger defects elicit a more severe immune response compared to smaller defects, necessitating novel approaches to engineer TMJ neodisc constructs for large defects typically associated with TMJ disc perforation. Novel tissue-engineering strategies, termed “tissue-immunoengineering” in this proposal, are set forth, where TMJ neodisc constructs are cocultured with macrophages to improve construct functional properties (i.e., biochemical and mechanical properties), toward achieving TMJ disc healing in vivo. Pro-healing and anti- inflammatory M2-polarized macrophages will be examined for their effects on enhancing the robustness and resilience of TMJ neodisc constructs. Prior work for enhancing tissue-engineered constructs has used bioactive agents, such as growth factors and chondrogenic conditioned media, but no studies have introduced coculturing constructs with macrophages to improve TMJ neodisc properties. Macrophages have been shown to direct healing through secretions and their reactions to changes in tissue composition and stiffness during healing. A potential mechanism for the coordination of TMJ disc healing is the bidirectional interaction between macrophages and chondrocytes, resulting in continuous adjustments to changes in the healing microenvironment. Despite their potential, the utility of M2 macrophages, including both pro-healing or M2a (i.e., stimulated with IL-4/IL-13) and anti-inflammatory or M2c (i.e., stimulated with IL-10) subtypes, have not yet been examined for enhancing the suitability of engineered tissues for implantation. Collaboration between the Athanasiou and Liu laboratories recently showed that improving construct functional properties not only results in mechanical durability but, also, excitingly, resistance to immune-mediated degradation. Moreover, exciting new scRNA-seq results from this collaboration are providing insights as to how macrophages and chondrocytes communicate to coordinate tissue formation. Encouraged by these novel and significant results, we propose to test the hypothesis that coculturing TMJ neodisc constructs with M2-polarized macrophages in vitro will increase functional properties of the constructs, thus, improving healing outcomes in large perforation TMJ disc defects in vivo. This overall hypothesis will be examined through three aims: 1) To identify the macrophage origin and in vitro activation conditions that maximize functional properties of TMJ neodisc constructs. 2) To tune the mechanical environment of macrophage-construct direct coculture systems to improve construct functional properties through a) direct mechanical stimulation and b) enhancement of M2 macrophage polarization. 3) To improve the healing of large perforation defects of TMJ discs in a minipig model using a tissue- immunoengineered TMJ neodisc construct. It is anticipated that this proposal will establish a novel and robust tissue-immunoengineering strategy to improve healing of the TMJ disc, with the potential to improve the lives of millions living with TMJ disc perforation.

NSF Awards · FY 2025 · 2025-08

In the era of big data, researchers and analysts have unprecedented access to extensive datasets, opening up new opportunities for scientific discovery and predictive modeling. These datasets, often collected from different sources, contain various forms of heterogeneity, such as distribution heterogeneity, observation heterogeneity, and task heterogeneity. Effectively addressing these complexities is critical for maximizing their potential. This project tackles various sources of data integration in supervised learning by introducing a novel framework, the Representation Retrieval (R2) framework, which simultaneously addresses all three types of heterogeneity. The new framework combines advanced representation learning with sparse-induced machine learning algorithms to achieve its objectives. Additionally, the investigator develops a new integrative penalty designed to improve the integration and effectiveness of the learned representations. This project will lead to a new paradigm for extracting and integrating information from heterogeneous data sources, providing fundamental solutions and a rigorous framework to address these challenges. This project will have broad applications across various fields, including medical and health sciences, social sciences, political science, education, finance, marketing, and artificial intelligence. The investigator will integrate education with research by developing a new course on data integration. The new framework extracts a shared representation dictionary from multiple heterogeneous data sources, then selects multiple source-specific retrievers, and estimates source-specific learners. The representation dictionary, accessible to all data sources, contains a set of representers which can represent covariates in a low-dimensional latent space. Each data source employs its own retrievers to select informative representers which project their covariates into an appropriate latent space. Using these retrieved representations, source-specific learners can then be applied to predict responses. The project aims to make significant contributions to the field of data integration through the following advancements: (1) Formulating a General Data Integration Framework: Define a supervised learning problem that incorporates three types of heterogeneity. This formulation generalizes several well-studied problem setups as special cases. (2) Introducing the Representation Retrieval (R2) Framework: Develop a comprehensive framework to address all three types of heterogeneity and overcome common limitations in existing methods. (3) Addressing Distribution Heterogeneity: Leverage a “partially-sharing structure" to model distribution heterogeneity effectively, solve optimization problems with sparsity-induced penalties, and introduce a novel “Selective Integration Penalty" to encourage representers shared across multiple data sources. (4) Handling Observation Heterogeneity: Propose a non-imputation-based approach to manage observation heterogeneity, providing a robust alternative to conventional methods. 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 2025 · 2025-08

A challenge of developing artificial intelligence (AI) that can work with and serve human needs is developing systems that can smoothly communicate with humans. An aspect of human communication that is effortless for humans, but that remains challenging for AI systems, is communication about space – that is, where people and things are and where they are going. Simple words like “this” and “there” help speakers point to objects, give directions, and share information. These words are important in every human language, and they are critical to get right for robotic systems that will inhabit human spaces and interact with human users. But these words are used in different ways across languages, and scientists do not yet fully understand why. This project quantitatively and experimentally measures how people talk about space using computer models and experiments. The researchers work with speakers of a variety of languages, analyze how people choose words to describe space, and build computer models that explain how this communication works. Other benefits to society include providing innovative educational opportunities that support workforce development for AI and other language technology industries. This research investigates how human languages express spatial relationships using deictic words (e.g., “this,” “that,” “here,” “there”). The project integrates cross-linguistic experimental data with information-theoretic computational models – specifically using the Information Bottleneck approach that was developed to explain artificial neural network behavior – to explore how people balance accuracy and simplicity when using spatial language. Using methods such as behavioral experiments, geospatial analysis, and machine learning, the project explores the cognitive and environmental pressures that shape how speakers refer to locations and objects. The models developed in this project also provide insights into how AI systems can more naturally interpret and produce spatial language, supporting improvements in areas such as robotics and AI more generally. This award is made possible through the NSF-UKRI lead agency opportunity. 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 · 2025-08

PROJECT SUMMARY The microbes that live in and on our bodies—our microbiota—represent an emerging field for precision medicine and personalized care. Microbiota composition varies significantly between individuals, with over 4,500 different species represented across broad human metagenomic analyses. This variety of species appears to have functional consequences, and correlative studies have associated specific microbes with better outcomes for multiple immune-related diseases, including cardiovascular disease, neurological disorders, and many cancers. However, translating these findings into microbiota-targeted medicines has been largely limited by the significant lack of mechanistic data that underlie these associations. In this New Innovator Award proposal, we will tackle this critical gap in knowledge by discovering precise molecular, cellular, and spatial factors that allow commensal and so-called “probiotic” microbes to modulate host immunity. Here, we will focus on exo- and capsular polysaccharides, which are well-known modulators of both innate and adaptive immunity. Although glycan extracts from multiple microbial isolates have been implicated to alter inflammatory signaling, polysaccharides remain incredibly difficult to characterize compared to other biopolymers due to a lack of high-throughput and generalizable tools. Moreover, microbial polysaccharides pose an incredible challenge for current strategies used to study mammalian glycans due to the sheer diversity of glycan composition, structure, and localization found even across closely related microbial isolates. Our proposal will address this major technical challenge through the development of diversity-oriented approaches that will directly identify the host receptors, glycan motifs, cell types, and gut regions that are involved in microbial glycan signaling to the host. These goals will be achieved through new techniques to (1) screen glycome-receptorome interactions, (2) generate libraries of homogeneous and multipurpose glycan probes, and (3) engineer functionality into the microbial glycocalyx. As validation, we will then use our approaches to (4) illuminate the molecular mechanism(s) by which structurally disparate polysaccharides can act as novel ligands for a well-known pattern recognition receptor. Together, the strategies of our innovative proposal will provide a new molecular roadmap that reveals how microbial glycans mediate pro- and anti-inflammatory signaling in the gut and beyond. The methods generated by this proposal will also be generalizable to other polysaccharides found in pathogenic bacteria and even those from other kingdoms of life, expanding our arsenal of tools in chemical glycobiology to better characterize fundamental principles of glycan signaling.

NSF Awards · FY 2025 · 2025-08

This project will contribute to the national need for well-educated scientists, mathematicians, engineers, and technicians by supporting the retention and graduation of high-achieving students with demonstrated financial need at the University of California, Irvine (UCI). Over its 6-year duration, this Track 2 project funds scholarships for 32 unique full-time students who are pursuing Master of Science (MS) degrees in research-focused Biology and Biotechnology programs. These students receive one or two-year scholarships. Scholars are introduced to new curriculum and cohort-based activities that foster resilience, develop research and professional skills, and prepare them to enter the biotechnology workforce. Scholars are paired with both near peer mentors and established faculty mentors to support academic and research progress. This project ultimately seeks to contribute well-prepared individuals to the biotechnology workforce in the region while simultaneously increasing the earning potential of scholars. The overall goal of this project is to increase STEM degree completion among high-achieving Master of Science (MS) students in Biology and Biotechnology with demonstrated financial need. This goal is achieved by awarding scholarships and enhancing curricular and co-curricular activities to foster resilient student cohorts, implement multi-tiered mentoring programs, and develop a new and sustainable MS program in biotechnology that continues beyond the funding period. The new degree program enables high-achieving undergraduate students engaged in research to complete a research-intensive MS degree in a single year instead of the typical two-year duration. The project employs evidence-based strategies to design curricular and co-curricular activities that strengthen resilience in STEM. All participating students receive support throughout their MS studies and transition into the biotechnology workforce or a STEM-related PhD program. An external evaluator monitors scholar recruitment, scholarship distribution, student outcomes from academic and co-curricular engagement, and the impact of holistic mentorship. Project outcomes are shared through social media, conferences, publications, reports, and alumni engagement. This project is funded by NSF's Scholarships in Science, Technology, Engineering, and Mathematics program, which seeks to increase the number of academically talented low-income students with demonstrated financial need who earn degrees in STEM fields. It also aims to improve the education of future STEM workers, and to generate knowledge about academic success, retention, transfer, graduation, and academic/career pathways of low-income students. 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 2025 · 2025-08

This project explores how certain types of molecules come together to form tiny structures that can be useful in medicine, energy, and the environment. These molecules are special because they have parts that like water and parts that don’t, so they naturally organize themselves when mixed with liquids. This self-organization can lead to the creation of materials like soft particles or thin films, which are useful for carrying medicine, storing energy, or cleaning up pollution. The research will focus on understanding what happens when these molecules first form small liquid droplets and then transform into solid particles. By learning how this process works, scientists can better control the design of new materials for specific uses. For example, it could help create better ways to deliver medicine exactly where it's needed in the body or make materials that capture and store energy more efficiently. Additionally, the project emphasizes education and outreach, and will actively involve students and local schools in engaging activities to inspire future scientists and engineers. The goal of this project is to fundamentally understand the structure, dynamics, and encapsulation behavior of multiphase amphiphilic block copolymers in solution. The research is divided into three aims. First, a comprehensive library of block copolymers will be synthesized, and their phase behaviors will be systematically mapped using advanced characterization techniques, including electron microscopy, optical microscopy, and X-ray scattering. The outcomes of this aim will establish robust relationships between polymer structures, solution conditions, and their phase behaviors. The second aim will explore the internal structure and dynamics of the polymer phases using sophisticated techniques such as in-situ Synchrotron X-ray Scattering, Cryo-Electron Microscopy, and Liquid Phase Electron Microscopy. This integrated approach will provide unprecedented insight into the transformation from liquid droplets into solid particles, significantly advancing the fundamental understanding of amphiphilic polymer assembly. The third aim focuses on studying how these polymer systems encapsulate small molecules, essential for applications like drug delivery. Using model encapsulants and confocal microscopy, the research will elucidate the relationships between polymer properties, phase behaviors, and encapsulation efficiency. Overall, this research will offer transformative insights into polymer self-assembly, enhancing our ability to design advanced, functional materials with broad applications across biotechnology, sustainability, and energy fields. 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.