University Of Southern California

NSF Awards · FY 2025 · 2025-09

This project tests whether simple, novel social activities like storytelling, improvisation, or light-hearted conversations can help the brain stay sharp and boost thinking skills in older adults. Early findings show that these moments improve memory, attention, and mood. This project examines brain activity, body responses, and thinking ability before and after such interactions to understand effects on the aging brain. The goal is to turn scientific discoveries into easy-to-use tools that caregivers and community programs can use to support healthy aging. The project advances translational science by applying cutting-edge brain research to real-life challenges and training caregivers in how to incorporate these activities into their work. This research project investigates how brief social interactions affect brain function and cognitive performance in older adults. Using advanced brain imaging techniques (3T and 7T functional MRI), the researchers study how such interactions influence the brain’s salience network, which helps people notice and respond to important information. It also explores how interactions affect the way this network connects with other brain systems related to attention, language, and movement—connections that tend to weaken with age. Physiological responses, such as pupil size, skin conductance, and heart rate, are measured to understand how alertness and emotional engagement may contribute to cognitive benefits. In addition, the project examines how these interactions activate brainstem regions involved in releasing noradrenaline (locus coeruleus) and dopamine (substantia nigra and ventral tegmental area), which are key neurochemicals for motivation and attention. By linking changes in brain activity and physiology to improvements in attention, memory, and verbal fluency, the project aims to uncover how social interactions promote cognitive flexibility in later life. These findings guide the development of simple, low-cost interventions for use in caregiving and community settings, making the project a strong example of translational science that turns neuroscience into real-world solutions for healthy aging. 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 Our lab aims to deepen the understanding of the molecules and mechanisms that drive protein aggregation. We approach this by studying protein aggregation catalysis and inhibition through biological disaggregases, including macromolecular chaperones, proteasomes, and metabolites. Our recent findings suggest that disaggregase activity operates on a continuum, with protein aggregation catalysis and inhibition at opposite ends of the spectrum. Bimodal effects on protein aggregation are a defining characteristic of disaggregases. The disaggregase mechanism, characteristic of macromolecular chaperones, generates fragmented fibrils, oligomers, and monomeric proteins in varying proportions, which seed protein aggregation. Although seeding is primarily associated with disease, bimodal effects by disaggregases on seeding suggests disaggregases might toggle aggregation, regulating protein activity by switching it on and off depending on concentrations and relevant cofactors. However, the extent to which the same disaggregases can function both as inhibitors and aggregation catalysts under different conditions to regulate protein activity remains unclear. Our lab will explore the biological implications of disaggregases in reversibly regulating protein function. We hypothesize that disaggregases generating intermediate species, such as oligomers and fragmented fibrils, promote aggregation by creating seeding-competent nuclei, which inactivate proteins by sequestering them in aggregates. We anticipate that shifting disaggregase concentrations to favor aggregate elimination will restore the activity of functional proteins. Our future objectives include bioinformatic, biochemical, and cellular studies to uncover the molecular determinants of disaggregase activity and identify new biological disaggregases in the human metabolome. By elucidating the factors involved in both protein aggregation catalysis and disaggregase efficacy, our work will reveal disaggregases that can reversibly control protein aggregation. This foundational research will guide our lab’s ongoing efforts to unravel the etiology of protein misfolding and develop diagnostics and therapeutics for protein aggregation diseases.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT The goal of this K99/R00 Award is to accelerate Dr. Anqi Wang’s transition to an independent investigator in cancer and molecular epidemiology by supporting her research into the role of loss of the Y chromosome (LOY) across the prostate cancer continuum. This impactful project will investigate LOY both in leukocytes and prostate tumors to define its potential as a biomarker for etiology, detection, treatment, and prognosis. Dr. Wang is a postdoctoral fellow at Harvard T.H. Chan School of Public Health (HSPH). She holds a PhD in Genetic Epidemiology from the University of Southern California, where her work shed light on germline genetics of prostate cancer. Her plan will leverage her previous training and focus on new directions in 1) developing expertise in tissue-based and molecular biomarkers, 2) gaining clinical and pathological insights into prostate cancer, and 3) advancing leadership and collaborative networks. This plan involves targeted coursework, workshops, conferences, and mentorship from Drs. Lorelei Mucci, Philip Kantoff, Konrad Stopsack, Mitchell Machiela, and Massimo Loda. Her training will be mainly conducted at HSPH and Dana-Farber/Harvard Cancer Center, which provides robust networking, administrative, and educational support, supplemented with annual visits to Dr. Machiela’s lab at the National Cancer Institute and Dr. Loda’s lab at Weill Cornell Medicine for hands- on training in LOY detection. All mentors and advisors will guide her in faculty job applications and future grant writing to support Dr. Wang’s transition to independence. LOY is a common form of genetic mosaicism among men that is associated with increased all-cause mortality and chronic diseases, including prostate cancer. However, its clinical and etiologic impact on prostate cancer and translation has yet to be fully realized. The research will use large prospective cohorts to elucidate the multifaceted role of LOY across the prostate cancer continuum. During the K99 phase, Aim 1 focuses on LOY in leukocytes among cancer-free men, assessing its potential for early detection of prostate cancer and its etiologic role in molecular subtypes and germline genetic risk. The independent R00 phase investigates LOY in leukocytes and tumors in cancer patients. Aim 2 evaluates the impact of LOY in leukocytes on clinical outcomes, including survival and treatment response. Aim 3 examines the impact of LOY in prostate tumors on patient survival, and its joint effect with men's germline genetic risk and molecular subtypes. In summary, this project will provide novel insights into LOY as a biomarker for early detection, risk stratification, prognosis, and management of prostate cancer. This award will further Dr. Wang’s expertise in integrative molecular biomarker analysis and inform future R01 grant applications to improve prostate cancer risk assessments and treatment strategies, positioning her to become an independent researcher who elucidate the molecular mechanisms of prostate cancer and translate findings into actionable strategies.

NIH Research Projects · FY 2025 · 2025-09

Project Summary In this K23 proposal, I detail a 4-year training plan to launch my independent clinical research career focused on mechanism-based early interventions to prevent PTSD and enhance health in traumatic injury patients and their caregivers. Through the rich training environments at the University of Southern California and National Center for PTSD, and the committed mentorship of my exemplary multidisciplinary team comprised of Dr. Haig Yenikomshian (primary), Dr. Denise Sloan (co-mentor), Dr. Johanna Thompson-Hollands (co-mentor), and Dr. Katherine Ehrlich (advisor), I will achieve training in 1) mechanism-based PTSD clinical trial research for acute care interventions, 2) implementation barriers and facilitators with medical, hospital, patient, and caregiver stakeholders, 3) advanced statistical analysis techniques for longitudinal data, 4) inflammatory biomarkers, and 5) professional competencies essential for independence. PTSD impacts approximately 1 in 3 traumatically injured hospitalized burn patients, a rate 3-4x that of the general population. Burns disproportionately impact marginalized and minoritized individuals/families with social and economic insecurities that lead to barriers in access to outpatient mental healthcare, highlighting the importance of early intervention during acute hospitalization. However, there are no validated interventions for hospitalized injury patients at risk for PTSD. The proposed study will adapt and test a brief patient-caregiver early intervention (PoED) associated with reduction of PTSS in discharged emergency department patients and extend it to hospitalized burn patients at risk for PTSD and their caregivers (PoED-B). PoED-B is a cognitive-behavioral dyadic intervention that targets reduction of dyadic social constraints (e.g., invalidating, negative statements) and avoidant coping by teaching dyads to engage in adaptive natural disclosures, supportive responses, and approach coping after the burn trauma using psychoeducation, motivational interviewing, and skills coaching. After refinement through stakeholder interviews and a case series (n=4, 2 dyads), we will conduct a small randomized clinical trial (n=40; 20 dyads) comparing PoED-B to a minimally enhanced usual care psychoeducation control (mEUC). The primary aim is to take an experimental therapeutics approach to demonstrate that PoED-B is feasible, acceptable, and engages the target of reduced social constraining behaviors in dyads relative to mEUC. A preliminary examination will also be conducted of the estimated effects of PoED-B vs mEUC and variability in patient- caregiver social constraints on PTSS improvement, relationship quality, and later PTSD diagnosis. An exploratory aim is to examine the impact of change in social constraints on PTSS and inflammatory biomarkers as theorized mechanisms of change in PoED-B. This early intervention trial aligns with NIMH Strategies 3 “Strive for Prevention and Cures” and 4 “Advance Mental Health Services to Strengthen Public Health” and has the potential to mitigate early risk for postinjury PTSD, reduce symptom burden, and improve overall health in a historically underserved comorbid mental health and medical population.

NSF Awards · FY 2025 · 2025-09

Much of the Arctic is underlain by perennially frozen ground known as permafrost. Over the last few decades, the Arctic is thawing and destabilizing riverbanks and affecting infrastructure, water quality, and fish habitat. Additionally, a significant portion of the United States' natural resources and national security interests are contained within river corridors in Alaska. Arctic and Subarctic Federal, State, and Tribal governments need advanced knowledge and tools to identify and assess more accurately riverbank erosion vulnerability and risk in order to guide local decision-makers. Phase-1 of this work includes an interdisciplinary team of physical and social scientists, land managers, engineering design firms, stakeholders and land owners at local, tribal and federal levels. This team is well positioned to integrate advanced research techniques with community needs to document and forecast ongoing landscape and river changes, and enable the development of pragmatic solutions to protect investments in infrastructure. This project is poised to make an impact with science that informs public policy; increases partnerships between local community members, academia, industry, non-profit, and government sectors; and develops an American workforce in interdisciplinary applied science. This project will develop new state-of-the-art approaches to critical and immediate environmental threats to communities and infrastructure in Arctic Alaska. Solution strategies include: 1) information-based tools for decision making including river-erosion forecasting tools and watershed monitoring networks; and 2) physical solutions to changing rivers including community scale infrastructure to mitigate erosion and siltation and watershed scale solutions. The project will leverage recent advances in Earth science including satellite imagery and novel sub-pixel and machine-learning techniques for change detection, theoretical advances in permafrost erosion and mud transport prediction, low-cost sensor networks for autonomous monitoring of water quality, high-throughput microbial sequencing-as-sensing techniques, and collaborative cyberinfrastructure for watershed monitoring. Solutions will be used to forecast river erosion to protect important infrastructure, increase the ability to mitigate physical risk once identified, and manage water quality for human health and aquatic life. The modeling tools can be broadcast into the future, aiding in decision making that will minimize long-term damage and 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.

NSF Awards · FY 2025 · 2025-09

This project supports research that looks to advance robot mobility in challenging natural environments where land meets water—such as wetlands, mudflats, and tidal zones. Accessing these areas is important for performing search and rescue after hurricanes, geological survey, and ecological/environmental monitoring, but they are often challenging for humans or traditional robots to traverse, because the soft, unstable wet sandy and muddy ground can suddenly shift from solid to fluid-like, causing wheels and legs to slip, sink, or become stuck. This research seeks to create a bio-inspired robot capable of reliably moving across such environments by learning how to sense and respond to these complex terrain conditions, much like animals such as mudskippers do in nature. The outcomes of this work intend to help robots assist humans with disaster response, environmental monitoring, and scientific exploration in water–land transition zones that are currently inaccessible. The project will also provide interdisciplinary training for students from high school through doctoral levels and contribute to public STEM education through outreach and publicly shared datasets, videos, and simulations. The research team looks to create a new robot inspired by mud-dwelling amphibious fishes that can adapt their movement strategies as they encounter different types of wet sandy and muddy terrain. The approach combines the team’s expertise in robotic locomotion, sensing, control, bio-inspiration, and physics modeling of terrain interaction mechanics. The robot seeks to be equipped with direct-drive actuators that can sense ground reaction forces continuously during locomotion and infer the mechanical properties of the terrain on the go. In addition, the team looks to develop terradynamic models to predict how wet sand and mud with varying levels of wetness and clay content respond to locomotion to produce forces and how robot gait must adapt accordingly to attain effective locomotion. By combining these terradynamic models with terrain mechanics sensing capability, this project aims to enable the robot to adjust its gait -- such as changing body undulation or fin movements -- to achieve robust mobility in various wet sandy and muddy terrains. The knowledge from this project intends to deepen scientific understanding of locomotion mechanics and control in cohesive flowable terrain and inform the development of terrain-aware, terrain-adaptive robotic systems. The new methods from this project look to be validated in real-world field testing. 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

Anna Krylov of the University of Southern California is supported by an award from the Chemical Theory, Models and Computational Methods program in the Division of Chemistry to extend the theoretical spectroscopy modeling toolkit by developing novel electronic structure methods in the core and valence domains with particular emphasis on free-electron states. Using light to interrogate matter is the basis of spectroscopy, which provides the most powerful set of tools for unraveling mechanisms of chemical reactions, structures and intrinsic properties of materials and biological objects. Using high-energy (X-rays) and high-intensity radiation opens new exciting opportunities, which motivate the worldwide development of multi-billion-dollar facilities for advanced light sources. Recent advances in beam quality in these facilities greatly expanded possible applications of X-rays, giving rise to a proliferation of techniques including those operating in time-resolved and non-linear regimes. These novel techniques promise to greatly expand our ability to interrogate molecular structure and dynamics, but their full potential can only be realized when experiment is augmented by accurate theoretical tools for modeling these phenomena. Despite significant efforts, the theory is still lagging behind the experimental capabilities, creating a bottleneck for maximizing the scientific impact of multi-billion advanced light source facilities. One of the challenges is that many techniques involve states in the continuum—autoionizing resonances as well as photoejected, Auger, or scattered electrons— which are not amenable to standard quantum-chemistry techniques. This proposal aims to bridge this gap by developing novel electronic structure methods for modeling spectroscopy in the core and valence domains with particular emphasis on free-electron states. Broader impact of the proposed research includes training and mentoring of graduate students and postdocs for careers in academia and industry as well as contributions to research infrastructure by integrating new computer codes in the widely used ab initio programs Q-CHEM and SPARTAN to make them available to the broad chemistry community. Krylov will (i) develop a novel ab initio framework for treating free-electron states using plane-wave-Gaussian basis sets; (ii) use this new framework to implement calculations of photo- electron circular dichroism (PECD), angular-resolved photoelectron cross sections, and extended x-ray absorption fine structure (EXAFS) and to improve the theoretical treatment of Auger and related phenomena such as intermolecular Coulomb decay (ICD) and electron-transfer mediated decay (ETMD); (iii) include spin–orbit effects in calculating Auger spectra for L and M edges; (iv) extend theory to the modeling of spectroscopy with magnetic fields such as magnetic CD (MCD and X-MCD); (v) extend Cholesky decomposition approach to calculations of core-level states within equation-of-motion coupled-cluster theory. 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 research project looks to introduce a new class of intelligent engineered systems: dynamic built environments that engage in continuous, bidirectional interaction with occupants to monitor, interpret, and respond to their mental states. Modern workplaces frequently influence how individuals feel and react, impacting their cognitive and emotional well-being — manifesting as stress, cognitive overload, and distraction — which can detract from personal well-being, productivity, and long-term health. A key adaptive feature of these environments is movable partitions, allowing for on-demand reconfiguration of physical workspaces to minimize distractions and enhance sustained focus. These interactive, dynamic responses replace the static nature of traditional workplaces, fostering intuitive and responsive settings that alleviate mental strain while promoting cognitive recovery and processing. Over time, the building develops personalized patterns of response through human-environment co-adaptation, creating a feedback loop that encourages long-term improvements in attention, cognitive capacity, and emotional well-being. This initiative contributes to national priorities concerning health and productivity, while also advancing broader educational and public engagement in human-centered design. This project intends to enhance foundational knowledge in adaptive collaboration between humans and intelligent engineered systems by facilitating real-time, bidirectional interaction within dynamic, physics-based environments. Utilizing wearable and environmental sensors, the system looks to detect indicators of mental strain and dynamically adjusts the indoor environment by modifying factors such as lighting, acoustics, and spatial configuration. In the field of building science, the project seeks to contribute to the development of a novel control architecture that integrates physiological and environmental sensing to drive personalized, multi-modal adaptations aimed at improving mental well-being. These adaptations include altering lighting characteristics, such as correlated color temperature and illuminance, delivering targeted acoustic masking via white noise, and reconfiguring spatial layouts with movable partitions. In the realm of computer science, the project looks to propel advancement of embodied artificial intelligence by enabling low-latency, on-device inference of mental states through a cutting-edge wearable platform. The experimental design investigates how occupants perceive, interpret, and react to feedback from adaptive environments, bearing implications for behavioral science and human factors engineering research, as well as practical insights for designing intuitive and reliable systems. Through experimental testbeds and continuous co-adaptation models, this project intends to establish a foundation for intelligent environments that enhance well-being, productivity, and safety in complex, real-world settings. 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

A branch of the regenerative sciences looks to non-mammalian species with hyper-regenerative abilities for clues to improve human wound healing. However, this approach has struggled to (1) select appropriate model species for meaningful translation to humans and (2) identify specific, actionable molecular targets for manipulating regenerative capabilities. Lizards are the only adult amniotes and closest relatives of humans able to suppress fibrosis and regrow multiple tissue types following appendage amputation. This extraordinary process involves formation of specialized regenerative structures known as blastemas, collections of reprogrammed fibroblasts that differentiate into replacement tissues. Interestingly, not all lizard species are capable of appendage regrowth, distinguishing lizards as the only group of tetrapods to contain both regenerative and non-regenerative species. My lab has committed to studying singular lizard species that have evolved to lack tail regeneration capabilities as natural losses-of-function models toward understanding the fundamental requirements for blastema development. We hypothesized that losses of regenerative capabilities during lizard speciation are due to mutation accumulations within genetic regions responsible for regulating critical aspects of fibrosis suppression and/or blastema establishment. Consequently, we conducted inter-species hybridizations, phylogenomic sequencing, and CRISPR screens to successfully identify mutation signatures significantly associated with loss of blastema formation capabilities. These studies identified three candidate wound healing processes dysregulated in non-regenerative lizard species, and each of the independent yet synergistic projects proposed here investigates the roles of these processes in blastema formation. Project 1 focuses on immunomodulations of pro-inflammatory signals that result in fibrosis suppression. Project 2 investigates pro- regenerative programs that support stem cell survival, proliferation, and activation within wound environments. Project 3 focuses on the epigenetic changes that establish wound site proximodistal patterning essential for proper blastema formation. Successful completion of the proposed projects will meet our short-term goals of characterizing and correcting mutations affecting key wound healing processes in non-regenerative lizard species. The invaluable experience gained during the course of these projects will directly propel my lab toward fulfilling our longer-term goals of inducing nature’s first blastemas in naturally non-regenerative lizard species. My envisioned research program views these endeavors as “steppingstones” for bridging specific gaps in wound healing capabilities between lizards and mammals. A blueprint for supporting lizard-like healing capabilities will be applied to established models of non-regenerating mammalian injuries, such as proximal mouse digit amputations. Ultimately, these lines of research will be applied to forming blastemas in human patients, holding promise to limit painful scarring, support organized tissue growth, facilitate prosthesis attachment, and bring much-needed improvements to patient quality of life following amputation injuries.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Microorganisms employ enzymatic assembly lines to produce myriad complex small molecules with medicinal importance (e.g., antibiotics, anticancer agents, and lipid-lowering statins). Each among thousands of naturally occurring assembly lines generates a structurally distinct compound by coordinating multistep biosynthesis across a defined sequence of enzyme active sites. In addition, their modular structures provide a natural framework for product diversification, as assembly lines can recombine into seemingly endless enzyme configurations. While decades of assembly-line research have accurately pinpointed the enzymes involved and their relative timing in the biosynthesis of hundreds of natural products, we cannot yet explain how these pathways are pre-programmed to commit their singular reaction sequences; much less, re-program them to specify new reaction sequences while maintaining catalytic integrity. Understanding how modular biosynthetic pathways are encoded at the level of protein sequence could be harnessed to engineer the biosynthesis of truly unparalleled libraries of user-defined chemical structures (>1050). Such advances have the potential to transform human medicine while simultaneously unlocking sustainable methods for chemical synthesis. To this end, our group has focused on decoding the mechanisms of a highly prevalent and versatile group of enzymatic assembly lines: the polyketide synthases (PKSs). Over the past year, we have made progress towards understanding polyketide antibiotic biosynthesis by a model PKS assembly line, the rifamycin synthase (RIFS). We have expressed and purified as multiple fragments ~40% of the 3.4 MDa RIFS assembly line and reconstituted formation of its natural diketide in vitro. Preliminary structural analysis of RIFS by single-particle cryogenic electron microscopy (cryo-EM) has revealed the architectures of its initial PKS modules, including a defunct dehydrating module, as well as a putative new mode of carrier-protein mediated substrate shuttling. This MIRA proposal presents a 5-year plan to continue structure-function analysis of the RIFS model system while implementing ancillary techniques that can test structural observations both experimentally and computationally. We present applications of site-selective and symmetry-unbiased crosslinking combined with mass spectrometry for (1) conformational probing and (2) cryo-EM sample preparation of PKS modules and bimodules. Building off prior developments, we propose a ‘peripheral non-invasive’ crosslinking method for capturing structures of fleeting substrate- or product-bound module states. In collaboration with Dr. Muyuan Chen, we are using machine-learning approaches to extract information about continuous motion (module dynamics) from cryo-EM data. Finally, we are developing in vitro assays for continuous turnover of truncated assembly lines by exploiting promiscuous thioesterase domains that promote polyketide intermediate off-loading. In summary, the proposed research applies innovative structure-function tools to understand mechanisms of polyketide biosynthesis that can engender the design of artificial biocatalysts for sustainable production of copious medicinal compounds.

NIH Research Projects · FY 2025 · 2025-09

Lewy body dementia (LBD) is the second most common cause of dementia after Alzheimer’s disease. In particular, Parkinson’s Disease (PD) progression has been associated with LBD and cognitive decline in a number of cognitive domains including executive function, attention, processing speed, episodic memory, and visuospatial processing. The predominant clinical motor features of PD are bradykinesia, resting tremor, and muscular rigidity; however, the prevalence and severity of the nonmotor effects of PD have significant detrimental effects on quality of life. While conventional pharmacological and surgical treatments of PD are effective in improving motor symptoms of PD, they do not improve cognitive deficits and may even have long-term deleterious effects on verbal fluency and cognition. Chronic high frequency deep brain stimulation (DBS) in the subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) is efficacious for improving motor symptoms of PD. Current stimulation parameters are optimized for motor benefit, with frequencies in the high gamma (100-180 Hz) range. Interestingly, increased low frequency oscillations (i.e. theta rhythms (4-8 Hz)) have been implicated in a range of cognitive functions, including spatial and episodic learning and memory. There is growing evidence that low (theta) frequency STN stimulation preferentially improves executive function compared to standard-of-care gamma DBS (cDBS). Indeed, we have generated data in PD patients with STN DBS that indicate “on” theta stimulation improves hippocampal-based verbal fluency compared to “off” or “on” gamma stimulation. Unfortunately, low frequency (theta or beta; 5-30 Hz) stimulation is not beneficial for motor symptoms. However, recent advances in stimulation programming allows for theta burst stimulation, which integrates high frequency (gamma 50-200 Hz; trains of 5-25) bursts of stimulation repeated at theta (5-10 Hz) frequency intervals. This theta burst stimulation increases theta oscillation activity. Moreover, there is evidence that STN theta burst stimulation is not only safe, but also has comparable motor outcomes compared to conventional gamma frequency STN DBS. Overall Goal: In light of our recent findings that theta stimulation improves cognitive function in PD patients with STN DBS, we hypothesize that chronic theta burst stimulation will confer a long-term cognitive benefit while concomitantly maintaining the motor benefits of gamma stimulation. The proposed randomized double-blind phase 2 clinical trial will focus on determining if 1) short-term and 2) chronic theta burst STN stimulation will improve both cognitive and motor measures; and 3) determining if theta-burst DBS and cDBS result in differing acute and chronic functional brain connectivity. The interpretation of data from this research will improve understanding of the acute and chronic effects of theta burst DBS on cognition and motor function. If successful, this study has the potential to develop a novel STN stimulation paradigm to treat both motor and cognitive PD symptoms as well as understand the effects of theta burst DBS compared to gamma DBS on fMRI functional connectivity measures. As this study is aimed at modulating cognitive networks, the ultimate goal is to develop novel stimulation parameters to treat chronic cognitive dysfunction in PD dementia and more broadly Lewy body dementia. Moreover, data collected, and collaborations developed will lay the foundation for a definitive Phase 3 clinical trial utilizing theta-burst stimulation for cognition and motor symptom improvement.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Liver disease is a leading cause of morbidity and mortality among people with HIV (PWH) driven by high rates of metabolic dysfunction-associated steatotic liver disease. Recently, food insecurity, or the limited or uncertain availability of nutritionally adequate foods or the inability to acquire acceptable foods in socially acceptable ways, has emerged as a risk factor for liver disease in people with and without HIV. Women with HIV are particularly susceptible to food insecurity due to competing demands as caregivers and lack of control over household resources. We have shown that food insecurity is associated with greater steatohepatitis and liver fibrosis, but not with steatosis, in PWH, suggesting that factors besides steatosis mediate this association. Our central hypothesis is that poor diet quality due to food insecurity leads to immune activation, which in the setting of HIV accelerates steatohepatitis and fibrosis progression. The scientific objective of this proposal is to identify the mechanisms that underlie the associations between food insecurity, diet quality, and liver disease progression in PWH. To address these knowledge gaps, we will leverage a robust longitudinal cohort, the Multicenter AIDS Cohort Study/Women’s Interagency HIV Study Combined Cohort Study (MWCCS), which includes serial food insecurity measures, comprehensive 24-hour diet quality recall surveys, immune activation biomarkers, and vibration controlled transient elastography-measured steatohepatitis and fibrosis. The scientific aims are to (1) examine the association of persistent food insecurity and diet quality with liver disease progression (2) determine the contribution of immune activation to the association of food insecurity with liver disease and (3) identify specific dietary factors that influence the relationship of food insecurity and immune activation in people with or at risk for HIV. This K23 will provide key training in (1) nutrition-specific content expertise and skills in rigorous diet quality measures, (2) complex biostatistical methods for longitudinal data and mediation analyses, (3) expertise in measures of immune activation in liver disease and HIV, and (4) career development at the intersection of hepatology and nutrition, which will be achieved through formal courses, workshops, didactics, hands-on experience, and structured mentorship. These scientific aims and training goals are made possible by a rich scientific environment at the University of Southern California, access to a unique prospective multicenter data set (MWCCS), and a strong multidisciplinary mentorship team consisting of Dr. Terrault (liver disease, clinical and translational studies), Dr. Goran (nutrition), Dr. Price (HIV and liver disease, immunology), and Dr. Mack (advanced biostatistics). This research will set the stage for an R01 proposal to develop a dynamic risk score that incorporates the contribution of diet quality through clinical and immunologic biomarkers to predict changes in liver disease over time. In summary, the proposed multidisciplinary team, scientific aims, and career development goals will foster Dr. Kardashian’s transition to a successful independent investigator and guide in the development of interventions that will halt the progression of liver disease in vulnerable populations.

NIH Research Projects · FY 2025 · 2025-09

Abstract Various human diseases rely on blood vessels to carry oxygen and nutrients to fuel disease initiation and progression. While they are crucial for normal development in humans, blood vessels are also vital for the progression of diseases such as cancer and blinding eye disorders. It is thought that the most important signal to induce blood vessel growth is vascular endothelial growth factor (VEGF), which activates quiescent endothelial cells (ECs) and promotes the formation of new blood vessels. Exuberant VEGF signaling is known to play a foundational role in propelling the progression of cancer and diabetic retinopathy and targeting VEGF results in reduced tumor burden due to regression of tumor vessels and improved drug delivery. However, the development of resistance resulting from the upregulation of other angiogenic factors significantly dampens the clinical benefits of this treatment strategy. Therefore, uncovering new molecular targets that regulate VEGF signaling should considerably advance the field. Here, we propose to determine the novel role of Pcbp1, an RNA-binding protein abundantly expressed in the endothelium but possessing high cell and tissue type specificity in terms of its downstream targets and its splicing target Aars2 in regulating VEGF signaling in physiological and pathological settings. Our team has recently discovered that the Pcbp1-Aars2 axis plays a crucial role in cardiomyopathy. Yet, their importance in the vascular system and their novel function in neovascularization and blood vessel growth remain unknown. To this end, we have created unique mice with inducible endothelial knockouts of Pcbp1 and Aars2 and found VEGF signaling and neovascularization are impaired upon loss of Pcbp1 or Aars2 in ECs, suggesting that these proteins are novel regulators of VEGF signaling. We also found that endothelial Pcbp1 interacts with the 5’UTR of VEGFR2 mRNA, and a lack of Pcbp1 diminishes VEGFR2 protein expression. Loss of endothelial Aars2 reduces mitochondrial membrane potential, leading to decreased acetyl-CoA production and attenuated histone acetylation of the VEGFR2 promoter, resulting in downregulation of VEGFR2 gene expression. We hypothesize that VEGFR2 mRNA stabilization and/or translation is regulated by Pcbp1, and VEGFR2 epigenetic activation is modulated by Aars2 in ECs. We will determine the molecular mechanisms by which Pcbp1 regulates VEGF translation, determine molecular mechanisms by which Aars2 promotes VEGFR epigenetic activation, and identify the therapeutic potential of inhibiting Pcbp1 and Aars2 in pathological angiogenesis. Our proposal addresses an important scientific problem, fills a significant knowledge gap, and initiates paradigm-shifting and innovative translational research.

NIH Research Projects · FY 2025 · 2025-09

Our long-term objective remains consistent: to investigate the organizing principles that establish the complex architectures of skin necessary for its various functions. Based on the findings from the previous funding period, we request an extension of this project to delve deeper into our research. Our general hypothesis aligns with that of the previous funding period, with further refinements. We propose that morphogenetic processes, whether simple or complex, can be understood through a fundamental morphogenetic module comprising a sensor and an actuator. The threshold can be adjusted at the modulator level, resulting in a new tissue state (Fig. A). A complex morphogenetic process can be composed of multiple sequentially connected sensor-actuator circuits, each activated by the completion of the preceding circuit until a stable state is achieved. The sensor can detect biophysical differences (such as adhesion forces and ECM pulling), leading to biochemical changes (like new gene transcriptions and enzyme activations), or vice versa. We would like to build on the three aims from the last funding period and extend our study to focus more on mechanistic and epigenetic controls.

NIH Research Projects · FY 2025 · 2025-09

SUMMARY About 10-30% of human and fly genomes comprises pericentromeric heterochromatin, a poorly characterized component of the genome where defective repair of double-strand breaks (DSB) can trigger widespread aberrant recombination and genome instability. Previous studies identified specialized mechanisms for “safe” homologous recombination (HR) repair of heterochromatin, including a poorly understood role for “silent” chromatin marks. The chromatin state is also deeply reorganized in response to damage in heterochromatin, but little is known about the nature of these changes and their roles in repair. This lack of knowledge is a major barrier to understanding how misregulation of this pathway contributes to cancer initiation and progression, and how epigenetic therapies contribute to cancer recurrence. This proposal will fill this knowledge gap by illuminating the role of chromatin composition and regulation in heterochromatin repair. We will test the hypothesis that specific chromatin modifications and non-coding RNA synthesis coordinate HR progression in space and time to enable faithful repair of heterochromatin. Specifically, this study will: 1) establish the role of ‘silent’ chromatin marks in promoting early steps of heterochromatin repair; 2) identify chromatin changes and chromatin modifiers responsible for repair progression in heterochromatin; and 3) define how damage-induced long non-coding RNAs (dilncRNAs) contribute to heterochromatin repair. We are particularly well-positioned to conduct this research. We pioneered the development of innovative approaches and tools that will be used for this study and we generated robust preliminary results at the foundation of this proposal. A particularly creative and original aspect of this research is the combination of unique strengths of the Drosophila system for the 3D analysis of heterochromatin repair dynamics, with transformative tools for site-specific DSB induction and next-generation sequencing, and with innovative in vitro assays. This unique combination of approaches will enable the first systematic characterization of chromatin responses contributing to heterochromatic repair, significantly advancing the understanding of genome stability mechanisms in multi-cellular eukaryotes. By establishing the role of chromatin composition and regulation in heterochromatin repair, this study will contribute to understanding essential mechanisms preventing cancer formation. This study will also help predict the consequences of epigenetic treatments on genome destabilization and cancer recurrences. Misregulation of heterochromatin repair is likely one of the most underestimated and powerful sources of tumorigenesis, and understanding heterochromatin repair mechanisms is a necessary step for understanding cancer etiology and for developing more effective approaches for cancer prevention, detection, and treatment.

NIH Research Projects · FY 2025 · 2025-09

Over the past two decades, publicly available large-scale genome-wide sequence data catalyzed our ability to learn more about the human genome, health, and evolutionary history. Large datasets and computational resources provide the genomics research community with valuable insights about disease and complex traits. Our lab aims to continue this forward trajectory by actively bridging the fields of evolution, genetics, and statistics by developing and distributing novel computational methods. Our work will allow researchers to accurately infer complex admixture and demographic histories across human populations and deepen our understanding of deleterious variation that contributes to complex traits and lethality. To infer the timing and magnitude of admixture within a population’s history, our lab will utilize shared genomic segments inherited identical-by-descent (IBD) within populations from publicly available data from human populations. Previous research shows that IBD can be used to infer the demographic history of a population. Similarly, the lengths of runs of homozygosity (ROH) reflect the underlying demography of populations. Although ROH and IBD contain valuable information about a population's history, no existing methods jointly utilize them to infer demography or admixture. We will develop new mathematical models that incorporate empirical data and simulations to assess how population history influences the distribution of IBD and ROH. Then, we will leverage ancestry switches within IBD segments, which are typically excluded from analyses, to model the timing and magnitude of admixture events. Long ROH are a result of recent consanguinity and often harbor deleterious variants. Due to their recent formation, variants within ROH have not yet been substantially influenced by genetic drift, recombination, or selection. Thus, we will utilize ROH to develop and test new variant weighting schemes aimed at detecting rare recessive variations linked to complex traits and diseases. Then, we will analyze data from human biobanks and breed dogs to identify genomic regions with a deficit of ROH. Inbreeding during breed development has resulted in ROH in most genomic regions that can tolerate high homozygosity without negative effects. By examining the cross-species deficit of ROH, we aim to identify regions associated with recessive lethal mutations critical for population viability across species.

NIH Research Projects · FY 2025 · 2025-09

Project Summary / Abstract The vagus nerve is the main conduit of information between the gastrointestinal (GI) tract and the central nervous system. In addition to communicating meal-related satiation signals from the GI tract to the brain to control meal size1, vagal afferent neurons (VAN) also relay information from the gut to the brain to promote the function of the hippocampus (HPC) – an integral brain structure in the regulation of learning and memory. Emerging evidence indicates that the vagus nerve plays a role in the regulation of cognitive processes such as motivation, anxiety, and memory2. Work from our group has revealed that selective ablation of GI- originating vagal afferents impairs HPC-dependent memory function in rodents3,4. The neurobiological mechanisms by which VAN promote memory function, however, remain unclear. Recently, the primary mentor’s group identified the medial septum (MS) as a region relaying signals between the VAN and the dorsal subregion of the HPC (HPCd)3. The MS extensively innervates the HPCd with acetylcholine (ACh)-producing fibers and is integral in the regulation of HPC-dependent memory function5. Thus, we hypothesize that physiological signals that originate from the gut that engage the VAN to modulate HPCd function via MS ACh signaling. Further, reductions in MS-to-HPCd ACh signaling are considered a pathological hallmark of Alzheimer’s disease (AD)6. AD currently affects ~24 million individuals and is marked by reduced ACh tone in the HPCd6. We hypothesize that potentiation of the VAN-HPCd cholinergic pathway through vagus nerve stimulation (VNS) may yield neuroprotective effects against AD and related dementias. Given the uncovered role of the vagus nerve in the regulation of learning and memory, understanding the neural substrates for how the vagus nerve regulates memory in the HPCd is critical for the development of novel therapeutics to treat and/or prevent AD. Preliminary results from fiber photometry recordings indicate that HPCd ACh is released during food consumption, with robust elevations in HPCd ACh release levels upon satiation. Aim 1 experiments build off these findings by examining HPCd ACh responses during intragastric infusion of different macronutrients, peripheral delivery of known satiation signals, and during the intake of isolated macronutrients to unravel what drives meal-induced HPCd ACh release. Moreover, given that various VAN loss-of-function models (e.g., sub-diaphragmic vagotomy), which have been established to cause HPC dysfunction, yield dysregulation of HPCd ACh signaling, we posit that vagus nerve signaling promotes HPC function. Given that VNS paired to ingestive events is sufficient to rescue diet-induced HPC memory deficits, Aim 2 experiments will use a transgenic rodent model of AD (TgF344-AD)7,8 to assess meal-associated HPCd ACh responses using fiber photometry and explore the therapeutic potential of our novel VNS approach for improving AD-associated cognitive impairments. Overall, the outcomes of the proposed research will improve our understanding of the role of VAN in physiological HPC memory maintenance and AD etiology.

NIH Research Projects · FY 2025 · 2025-08

SUMMARY / ABSTRACT The Los Angeles firestorms in January 2025 burned over 50,000 acres, destroyed over 16,000 homes and other structures, and displaced over 150,000 Los Angeles County residents. Most importantly, the fires have significantly impacted air quality across the Los Angeles Basin. The fires released high levels of fine particulate matter, VOCs, CO, NOx, and ozone precursors, exacerbating respiratory and cardiovascular conditions for those throughout Los Angeles. These findings stress the need to study long-term health impacts of wildland- urban interface (WUI) wildfire smoke. The acute and longer-term health effects of exposures from these catastrophic wildfires have yet to be defined. A better understanding of WUI) fire-related exposures and the health impacts is an urgent public health priority for Los Angeles. We will collect biological samples from affected individuals and analyze home dust, surface contaminants and outdoor soil and ash over time. After a wildfire it is critical to assess exposure levels and characterize the composition of toxins before home clean-up and environmental factors, such as wind and rain, alter its distribution or concentrations. We propose to conduct Project Firestorm, a rapid study to quantify the health effects of the wildfires. We will leverage an existing cohort of over 9,000 USC faculty, staff, and students who participated in a longitudinal COVID-19 study in 2021-2022. These participants, most of whom live in or around Los Angeles, have completed surveys about their physical and mental health and sociodemographics, providing an essential baseline assessment. The participants have signed consent forms giving their permission to be recontacted for future studies, enabling us to launch the study quickly without extensive recruitment time. We will recontact these participants and invite them to complete a survey about the effects of the fires on physical, mental, and financial health over the next year. From those who complete the survey (N=approximately 3000), we will recruit and collect more detailed data from a sample of 200 participants--100 who lived near the fires (fire-adjacent) and 100 who live over 15 miles away from the burn site (fire-distant). These participants will provide health outcome data on respiratory and other key outcomes, hair samples, wear silicone bracelets for VOC measurements, and samples of their house dust, surface wipes and yard soil for analysis, in February-March 2025 and again in February-March 2026. We will analyze (1) differences between fire-adjacent and fire-distant participants at baseline, and (2) change over a one-year period among fire-affected households and more distant households. Findings will guide public health interventions, long-term remediation efforts, and strategies to mitigate the WUI fires’ health impacts.

NIH Research Projects · FY 2025 · 2025-08

Title: Explore a key nucleotide synthesis enzyme to develop a broad-spectrum antiviral therapy Co-PI: Pinghui Feng (contact) and Chao Zhang With highly infectious viruses rapidly emerging and re-emerging (such as SARS-Coronavirus, influenza virus and drug-resistant herpes simplex viruses), the human society is challenged with limited options to treat diseases associated with these human viruses. In fact, antiviral therapies that effectively thwart the infection of a broad spectrum of viral pathogens are long sought in the antiviral community. In studying viral immune evasion, we have discovered that diverse viruses, including SARS- CoV-2, herpes simplex virus 1 (HSV-1) and influenza A virus (IAV), activate a key nucleotide synthesis enzyme not only to fuel nucleotide supply, but also block antiviral inflammatory cytokine production, thus efficiently promoting viral replication. We aim to target the key nucleotide synthesis enzyme for inhibition, which will deplete nucleotide supply and restore antiviral immune response to impede their replication. To achieve this goal, we have engineered conditional knockout and knockin mouse strains that will enable the genetic interrogation of the enzyme- mediated evasion of inflammatory response and metabolic reprogramming during the infection of SARS-CoV-2, IAV and HSV-1. Teaming up with a chemical biologist (Dr. Chao Zhang, University of Southern California), we have synthesized a library of small molecules and characterized specific inhibitors of the nucleotide enzyme. Furthermore, we will collaborate with a structural biologist (Dr. Santiago Ramon-Maiques, Instituto de Biomedicina de Valencia, Spain) to perform structure-activity relationship (SAR) analysis to further improve the lead small-molecule inhibitors. This study will provide a proof-of-concept to target a nucleotide synthesis enzyme in an effort to combat the infection of key human viral pathogens.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY The objective of this K99/R00 proposal is to facilitate Dr. Choi to establish an independent and specialized research program on climate hazards and the risk of Alzheimer’s Disease and Related Dementias (ADRD). The frequency, intensity, and duration of extreme heat events are expected to grow rapidly in the coming decades, affecting over 100 million Americans in 2050. High temperatures may pose significant hazards for cognitive and brain health. Yet, the precise nature and magnitude of extreme heat-induced ADRD risks remain unclear, particularly among a diverse older population. This project aims to fill this gap by providing Dr. Choi with strong content and methodological expertise in the social vulnerability approach to heat and neurobiological underpinnings to determine if high outdoor temperatures increase ADRD risks and to assess how socioeconomic and environmental factors at personal and community levels modify these risks. This project merges longitudinal daily climate records with neighborhood contextual data and the nationally representative and diverse Health and Retirement Study of U.S. adults aged 50, which has collected decades of data on cognitive function, dementia, social factors, and recently, neuropathological biomarkers. In the K99 phase, four training objectives support Dr. Choi’s transition into a leading interdisciplinary investigator who drives substantive questions on how climate hazards affect cognitive health and dementia risk. First, she will develop expertise in heat exposure assessment and the social vulnerability approach. Second, she will acquire knowledge of the biological underpinnings of neurodegeneration and blood-based AD biomarkers. Third, she will cultivate proficiency in advanced longitudinal and mixture analyses to model dynamics across heat and vulnerability factors. Fourth, she will pursue professional development opportunities to establish independence and leadership. This set of training will prepare her to achieve three research aims. Aim 1 determines how outdoor high temperatures contribute to cognitive decline and dementia risk. Aim 2 examines the effect modification by, or joint effects with, neighborhood and individual-level multidimensional vulnerability factors that exacerbate the cognitive risks induced by heat based on advanced epidemiological models. Aim 2 examines the association of extreme heat with blood-based AD neuropathological markers. Dr. Choi proposes to pursue these training goals and begin the proposed research within the Davis School of Gerontology at the University of Southern California, an ideal environment with abundant intellectual and structural resources, training opportunities, and interdisciplinary researchers in ADRD, environmental health, and the biology of aging. This project works towards reducing emerging climate hazards for ADRD risk by elucidating the neurobiological and social pathways leading to individual differences in neurocognitive risks from neighborhood climate environments. It aligns with the NIA’s goal to address the exposome in ADRD and offers new insights into multi-level intervention strategies to mitigate risk among the most vulnerable populations.

NSF Awards · FY 2025 · 2025-08

Knowing a language well and communicating successfully requires a sufficient breadth of vocabulary, including a lot of nouns. However, what exactly a person knows about any given noun varies from language to language and includes not just its dictionary meaning but also grammatical information about how that noun can be used. Understanding the multiple ways that languages encode noun-related information and how humans know and use that information during language communication is critical both for advancing cutting-edge, competitive technological tools such as AI chat and writing generators, and for a deeper understanding of how the brain manages language in everyday circumstances and during communication breakdown. In addition to meaning, various types of linguistic information are relevant to know for nouns, whether a noun is singular or plural or animate or inanimate, as well as other types of grammatical classes found across languages that serve to characterize nouns. One aim of this project is to innovate experimental tools for investigating what speakers know about nouns in languages. Developing such replicable scientific resources gives researchers a competitive edge in developing language technology and in mapping human cognition in the domain of spoken and written language. A second aim of this project is to determine whether certain types of noun structures facilitate noun recognition during language processing. Different languages encode important noun information in the suffixes and/or prefixes of the noun. This information is placed later or earlier relative to the noun’s meaning, respectively, and as such is predicted to have a differential effect on how these words are processed. The processing of suffixes has been well studied, but it is the grammatical information provided by a prefix that is the earliest information about a noun that someone encounters during processing. This project uses experimental tracking of human eye-movements to determine whether listeners access the grammatical information of the prefix early during processing and to investigate how listeners are able to use that information to help recognize the upcoming noun itself, thus facilitating and optimizing language processing. 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

Summary Bladder cancer is one of the most common malignancies in the U.S. Non-muscle invasive bladder cancer (NMIBC) accounts for 80% of all incident cases with a high recurrence rate (up to 70%), for which the initial treatment is transurethral resection of bladder tumor (TURBT). Approximately 20% of patients initially present with muscle invasive bladder cancer (MIBC). For these patients, the gold standard treatment is neoadjuvant chemotherapy (NAC) followed by radical cystectomy, but despite aggressive surgical management, the overall 5-year survival rate in these patients is 50%. Currently there are no non-invasive methods to monitor recurrence and/or drug response during NAC. Thus, there is a critical unmet need for reliable markers that can detect recurrence of NMIBC at an earlier stage and monitor tumor response during treatment of MIBC. Aberrant DNA methylation is one of most common epigenetic changes during tumorigenesis. DNA methylation (DNAm) alterations are chemically stable and can be experimentally quantified, which makes them promising tumor markers for bladder cancer detection and monitoring. Studies, including those from our group, have shown that bladder cancer specific DNAm changes can be detected in urine sediments and can be used as diagnostic or monitoring markers. DNAm changes in urine sediments mirror those found in primary tumor tissues and serve as a non-invasive means to identify cancer-specific alterations. We can detect specific DNAm markers for each stage of disease, not only through direct tumor biopsies, but also non-invasively through analysis of patient urine sediments. When applying DNAm to monitor treatment response, the research efforts thus far have underutilized the strength of DNAm as a continuous, dynamic, longitudinal biomarker, and have treated DNAm as a fixed status (cross-sectional measurement) to predict either binary outcome status or survival status. Without seeing the full trajectory of DNAm data, it will be difficult to reach the ideal predictive performance for treatment response. Thus, a personalized medicine approach for monitoring recurrence of NMIBC and treatment of MIBC patients is urgently needed with a dynamic quantitative monitoring of tumor burden. The final goal of this study is to analyze the pattern of longitudinal trajectory of tumor burden quantified by DNAm for the prediction of treatment outcome of both NMIBC and MIBC. With the support evidence from our pilot data, we hypothesize that bladder cancer DNA methylation marker panels can be used to: 1) check residual tumor cells after transurethral resection of bladder tumor (TURBT) and 2) monitor recurrence of tumors after TURBT in patient urine sediments as active surveillance for NMIBC patients (Aim 1); 3) monitor the trajectory of tumor cells in urine sediments for the association with NAC treatment response in MIBC patients (Aim 2), thus indicating treatment response. We aim to collect 60 patients’ urine sediments during/after TURBT and 70 patients for NAC treatment.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY This grant proposes to investigate three critical areas of human genetics: the role of natural selection in shaping the genetic architecture of complex traits, gene-environment interactions, and demographic history inference. First, we will model recessive selection on complex traits by leveraging X chromosome data to better understand the strength of selection across different traits and diseases. Second, we will explore gene- environment interactions using innovative statistical models, focusing on how genetic risk evolves with age and environmental exposure. Third, we will develop novel methods based on ancestral recombination graphs to refine our understanding of human demographic history, including migration patterns and ancient admixture events. This research will generate new insights into genetic variation, improve the predictive accuracy of polygenic risk scores, and clarify population histories, with broad applications across diverse genetic datasets.

NIH Research Projects · FY 2025 · 2025-08

Project Summary The Keck Genomics Platform (KGP) at the University of Southern California (USC) seeks to acquire, install, and integrate the Hamilton NGS STAR automated liquid handling system to revolutionize our Next Generation Sequencing (NGS) operations. This state-of-the-art system will significantly improve the efficiency and throughput of our NGS library preparation processes, addressing critical bottlenecks in our current workflow. By implementing the Hamilton NGS STAR, we aim to streamline sample preparation, reducing hands-on time and minimizing manual errors, while enhancing reproducibility across diverse NGS applications. The system will increase our capacity to handle larger batch sizes and more complex protocols, optimizing reagent usage and reducing waste through precise liquid handling. The automation provided by the NGS STAR will allow us to reduce overall costs associated with library preparation and decrease turnaround times for sequencing projects. This efficiency gain will enable us to expand our service offerings to include more sophisticated NGS applications at a lower price, attracting a broader customer base and facilitating cutting-edge research across USC and beyond. The system's flexibility, enabled by the Hamilton System Language (HSL) and VENUS software, will allow us to develop and implement custom protocols, further expanding KGP's capabilities. By investing in the Hamilton NGS STAR, KGP will strengthen its position as a leading genomics core facility, supporting innovative research and fostering scientific discoveries at USC. This upgrade aligns with our commitment to providing top-tier sequencing services and will significantly contribute to advancing genomics research in our academic community.

NIH Research Projects · FY 2025 · 2025-08

Abstract Chimeric Antigen Receptor (CAR) T cell therapy is a groundbreaking treatment for cancer, with the potential to elicit long-lasting immune responses. However, its application in solid tumors is significantly limited by off-tumor toxicities, where normal tissues expressing similar antigens are targeted, leading to lethal side effects (on-target off-tumor toxicity, OTOT). Therefore, there is an urgent need for high-precision control of CAR T cells to confine their activation to local tumor regions. We previously demonstrated the feasibility and safety of using MRI-guided focused ultrasound to precisely control CAR-T cell activation through local hyperthermia. Despite its potential, this approach has notable limitations, including restricted accessibility due to the need for specialized MRI equipment. To overcome these barriers, this project proposes the development of a wearable patch controlled, wireless thermo-activator device that enables precise, localized CAR-T cell activation at tumor sites through controlled heat. The system includes injectable, biodegradable receiver micro-coils, a wearable of a flexible Tx coil and a flexible metasurface. This innovative approach offers remote thermal control, activating thermo- activator CAR-T (TA-CAR) cells with high spatiotemporal precision, providing a convenient, portable, patient- friendly alternative to MRIgFUS. Accordingly, three specific aims are proposed: (1) to develop and optimize wireless injectable thermo-activator device, (2) to test wireless thermo-activator on engineered CAR-T cells for tumor cell killing in vitro, and (3) to evaluate the in vivo therapeutic efficacy of the wireless thermo-activator controllable CAR T cells in solid tumor killing. By providing a flexible, accessible, and repeatable method for CAR-T activation, this technology seeks to enhance the safety and efficacy of cancer immunotherapy. We expect that each component of our approach, wearable controlled thermos-activators, thermo-controllable CARs, will allow opportunities for continuous evolution and adaptation, targeting a broad range of solid tumors and precancerous conditions. This wearable patch controlled therapy offers a groundbreaking advancement in remote-controlled immunotherapy against solid tumors, holding promise in translations to clinical applications.