University Of California, San Diego

NSF Awards · FY 2024 · 2024-07

Minority languages spoken by small communities preserve a wealth of linguistic and cultural knowledge, which is often threatened by larger regional and global languages. This doctoral dissertation project focuses on the production of a grammar, dictionary, and texts that describe one such under-documented minority language. The language has many properties that are of interest, including a complex tone system and a typologically rare vowel inventory – understanding these features contributes to an understanding of linguistic diversity and language more broadly. Linguistic documentation is valuable outside the field of linguistics, as minority languages, through their vocabularies and oral literature, contain ecological and cultural knowledge about local flora and fauna, history, and anthropological practices. For the community who speaks the language, documentation provides data to support resources on language planning and the development of educational materials. This project also benefits society by providing training in language documentation and by depositing data into a publicly accessible archive. This doctoral dissertation project creates a reference grammar that comprehensively details the properties of this language, including its sound system (phonology), the structure of its words (morphology), and the way that the words are organized (syntax). This project includes two directed studies: (1) an analysis of the phonetic properties of a series of pharyngealized vowels and (2) a sociolinguistic survey of variation in pronoun use. Most of the data comes from audio and video recordings of the language. A selection of the recordings, made in naturalistic settings, are edited into short documentary videos, capturing language use during cultural practices like the planting and harvesting of crops, and oral literature like stories, histories, and narratives. In doing so, this project provides insights into the structure of the language. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2024-07

PROJECT SUMMARY Drug craving during prolonged periods of abstinence is a major factor driving repeated cycles of drug abuse. Given the escalating prevalence of substance abuse, it is imperative to have a thorough understanding of the brain circuit plasticity and associated molecular mechanisms that specifically underlie drug seeking. Nonetheless, despite several decades of research, the neural circuit mechanisms underlying strong cravings for drugs after abstinence are not fully elucidated. The medial prefrontal cortex (mPFC) is associated with various complex behaviors including working memory, impulsivity, goal-directed action, and decision-making. Given the diverse roles of the PFC and its efferent and afferent connections to limbic reward circuitry, the PFC is capable of integrating and transmitting drug-relevant signals throughout the brain as the addiction progresses. In particular, several reports show that ventral PFC subregions modulate drug-seeking and extinction behavior and are a viable target for deep brain stimulation to reduce addictive behaviors. However, it is largely unknown how PFC sub-circuitries contribute to drug addiction differentially and whether specific cell types, especially distinct types of interneurons, within the PFC are differentially responsible for drug-seeking after withdrawal and extinction. In this proposed research, we will investigate the role of different interneurons in the infralimbic (ventral) cortex for the seeking and the extinction of cocaine after withdrawal in our newly developed head-fixed drug self-administration paradigm. First, we will directly monitor the activity of different types of interneurons, parvalbumin (PV)-, somatostatin (SST)-, and vasoactive intestinal polypeptide (VIP)- expressing neurons, in infralimbic cortex (IL) during cocaine self-administration at single-neuron resolution using multiphoton photon microscopy. Second, we will directly manipulate the activity of distinct interneurons at the specific timing of drug self-administration to examine the causal roles of these neurons in drug self- administration. Third, we will examine how cortical outputs are regulated by distinct interneurons during drug self-administration. Excitingly, we already acquired preliminary results showing the differential roles of distinct interneurons in cocaine self-administration. Overall, we believe that the successful completion of this project will yield significant benefits by establishing a framework for the research of drug addiction in a circuit-specific manner, as well as by facilitating the development of a treatment approach for drug addiction.

NIH Research Projects · FY 2025 · 2024-07

Project Summary Major depressive disorder (MDD) is a common and burdensome psychiatric disorder. Unfortunately, current depression treatments suffer from numerous weaknesses, including treatment-resistance in a large proportion of patients. Several factors likely contribute to the limitations of current MDD pharmacotherapies, including the heterogeneous nature of depression symptoms and the fact that most conventional treatments were discovered serendipitously rather than by targeting the underlying mechanisms of the disorder. One reason why targeted treatments have not been developed for MDD is the lack of translation between the depression- relevant behaviors quantifiable in humans relative to those used to model MDD. Unfortunately, many behavioral models used to test new medications for MDD are often based on phenomena will limited relevance to those seen in humans, meaning that treatments targeting those behaviors often have limited clinical efficacy. As an alternative to those existing models, specific tests quantify impairments exhibited by people with depression that are also available for testing in rodents. Here, we propose an approach that leverages the clinical sensitivities of behavioral and electroencephalographic (EEG) assessments to better evaluate the putative impact of depression-relevant manipulations. Given the heterogeneous origins of MDD, Aim 1 will test whether three distinct manipulations known to induce depression-relevant behaviors (chronic corticosterone treatment, a short-active winter-like photoperiod, and acute treatment with the acetylcholinesterase inhibitor physostigmine) are capable of inducing depression-relevant states in mice, using cross-species behavioral readouts affected in people with MDD, the probabilistic reversal learning and progressive ratio breakpoint tasks. Because depression can also alter neurological processes independent of its behavioral impacts, Aim 2 will test whether the same three manipulations have effects on specific behavioral-associated neural processes that are known to be impacted in MDD that can be directly tested in rodents (Reward Positivity and parietal alpha power). Finally, to test the ability of these models to detect novel treatment efficacy, Aim 3 will determine the impact on these models of classical psychedelic drugs such as psilocybin (currently undergoing human trials for MDD) that produce long-lasting symptom reductions after acute administration. To disentangle the potential therapeutic-like effects of psychedelics from their intoxicating properties, the psychedelics will be tested at doses equivalent to high and low (micro)doses in humans. Overall, we will develop translational depression-relevant models that target specific domains of performance impacted in people and assessable in mice, potentially enabling the discovery and development of new, mechanistically-targeted treatments for MDD. Given our use of psychedelics in current clinical trials and use of these EEG-linked tasks in clinical populations, these data will enable targeted assessment in patient populations in future studies.

NSF Awards · FY 2024 · 2024-07

The broader impact of this I-Corps project is based on the development of innovative fused filament fabrication (FFF) systems that can print high-performance thermoplastics with superior interlayer adhesion at high rates. A thermoplastic any plastic that becomes pliable or moldable at elevated temperatures and solidifies upon cooling. This technology has the potential to improve the additive manufacturing industry, valued at approximately $20 billion, by addressing critical market gaps and setting new standards for manufacturing robust and reliable components. The innovation will particularly benefit industries such as aerospace, automotive, and medical devices, which require stringent performance requirements. This I-Corps project utilizes experiential learning coupled with a first-hand investigation of the industry ecosystem to assess the translation potential of the technology. The solution is based on the development of new filament materials and heating methods that addresses the limitations of existing fused filament fabrication (FFF) technologies that can print high-performance thermoplastics with superior interlayer adhesion at high rates. The project aims to validate the market need for improved FFF systems through extensive customer discovery and analysis. The project's outcomes will guide subsequent stages of product development and inform a go-to-market strategy, ultimately driving broader adoption of FFF systems and capturing a larger share of the additive manufacturing market. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-07

ABSTRACT Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. This devastating disease affects 196 million individuals and is predicted to increase to 288 million by 2050. Most of these patients suffer from the early and intermediate “dry” AMD and are currently without treatment options due to an incomplete mechanistic understanding of this complex disease. In early and intermediate AMD, large diffuse lipoprotein-rich deposits, named drusen, are deposited in the macula, and impair vision. Although drusen are a hallmark feature of AMD, the mechanism of drusenogenesis is unresolved. Drusen form between the retinal pigmented epithelium basal lamina (RPE BLam) and the inner collagenous layer (ICL) of Bruch’s membrane (BrM). RPE BLam and BrM are composed of glycosaminoglycans (GAG), including heparan sulfate (HS). Modification of GAG side chain residues creates binding sites for numerous growth factors, enzymes, and lipoproteins. This structural variation makes GAGs one of the most complex macromolecules found in nature and has been shown to be altered with aging and disease, including as an initiating event in subendothelial deposition of lipoproteins in atherosclerosis. Our understanding of GAGs in general, their role in BrM health, and how they change with aging and diseases, such as AMD, has lagged far behind other macromolecules despite their central role in biology. Our preliminary data show that HS is increased in AMD BrM compared to age-matched controls. In addition, AMD macula is rich in highly sulfated HS disaccharides (N-, 2-O and 6-O sulfation). Notably, Apolipoprotein E (APOE), a critical component of both lipoproteins and drusen, has binding sites to N-, 2-O and 6-O sulfated HS. In this proposal, we propose to test the hypothesis that an age-related increase in HS sulfation (N-, 2-O and 6-O) induces lipoprotein retention in BrM in early AMD. To address this hypothesis and elucidate the pharmacologic potential of this pathway, we propose the following aims: Aim 1: Determine what AMD risk factors are associated with BrM GAG composition. Aim 2: Determine if BrM HS structure or content promote lipoprotein binding in AMD. Aim 3: Determine if HS sulfation regulates lipoprotein retention in vivo in mice. If successful, the proposed experiments will establish alterations in HS sulfation as an initiating event in drusenogenesis and identify therapeutic targets for HS and lipoprotein binding for AMD. The mentored training program is designed to acquire new skills to support a career as a physician-scientist with expertise in glycobiology and lipoprotein biology. Towards this goal, a team of mentors have been assembled at UC San Diego, with expertise in heparan sulfate and lipoprotein metabolism.

NSF Awards · FY 2024 · 2024-07

The newly available millimeter wave (mmWave) spectrum in emerging 5G/6G wireless systems, coupled with advanced multiuser massive multiple-input multiple-output (MIMO) technology, will enable new wireless extended reality (XR) experience for many users in large groups to freely roam through common areas while jointly experiencing interactive, hyper-realistic, immersive virtual or mixed reality environments. While such wireless XR experience has potentially many applications in training, education, and entertainment, delivering such high-resolution digital XR experience requires tremendous data rates that necessitate aggressive use of multiple antennas so that the required data rates can be achieved by means of parallel data streams, but in turn, the dimension of matrices involved in the MIMO decoding process increases substantially. In particular, linear-detection-based MIMO decoding approaches require the inversion of channel matrices, estimated by the base station, at a timescale fast enough to accurately capture rapidly changing channel conditions. Unfortunately, the matrix inversion problem in this decoding process has cubic complexity in the worst case with the number of users, who need to be served simultaneously, making the performance of conventional digital electronics approaches a key limiting factor to the future scaling of massive MIMO systems. The vision of this project is to raise the creation of new, much faster, and efficient linear-algebra accelerators possessing immediate capabilities to advance massive MIMO systems, enable many more simultaneous users, support much more rapidly changing channel conditions, and benefit numerous existing and evolving applications that are limited by linear-algebra computations, including signal processing, image processing, and machine learning. The execution of this project can directly provide and develop scientific training for students at both graduate and undergraduate levels in the fields of optical communication and computation, while continue expending hands-on classes to students engaged in STEM. The main goal of this project is to formulate a computation-efficient matrix-inversion (MI) algorithm for realizing an energy/area-efficient hybrid photonic-electronic integrated accelerator, which can support the unprecedented computation workload of the massive MIMO channel decoding process. To realize this goal, the following objectives will be carried out: (I) co-design of the MI algorithm and hybrid photonic-electronic architecture; (II) co-design of photonic devices and electronic circuits to implement a system-on-chip (SoC) MI computation accelerator fabricated in a monolithic silicon-photonics (M-SiPh) semiconductor process technology (GlobalFoundries 45SPCLO); (III) the SoC prototyping and tape-out execution of the M-SiPh accelerator containing computation capabilities of high-dimensional matrix-vector multiplications, matrix-matrix multiplications, and MIs for massive MIMO channel decoding process; (IV) testing, characterizations, validations, and demonstrations of the fabricated M-SiPh accelerator; (V) rapid prototyping performed at UC San Diego Nano-3 facility for risk mitigations. Overall, the project scope is transformative in nature as it will significantly expand the speed and energy efficiency of next-generation massive MIMO systems, develop a fundamental understanding of performance metrics for hybrid photonic-electronic SoCs, and broaden the current notions of both photonic and electronic functionalities for future tech-transfers from research laboratories to commercial foundries. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-07

The Pharmacological Sciences Training Program, renamed the Cellular and Molecular Pharmacology (CMP) training program in this new submission, is one of the oldest and largest pharmacology training programs in the nation. The program provides a specific set of skills and a strong identification with the field of Pharmacology to students entering through the umbrella Biomedical Sciences (BMS) Program at UCSD. The training program is associated with one of the premier Departments of Pharmacology, whose faculty are highly funded, dedicated to graduate education, and trained and experienced mentors. Junior faculty and those from other UCSD departments and the Skaggs School of Pharmacy and Pharmaceutical Sciences complement the list of Pharmacology Department training mentors to provide broad interdisciplinary research opportunities. Students join the CMP Training Program at the beginning of their second year of graduate work, having taken the first year of required BMS didactic courses and seminars that cover a broad range of state-of-the-art research areas, and emphasize presentation and communication skills, quantitative skills, and rigor and reproducibility. The entire class of first year BMS students (~30 training grant eligible students) are invited to apply to the CMP training program and many do so because of the excellent reputation of the program and its faculty. At present there are 38 students in the CMP training program, with 7-8 students entering each year and supported for two years, corresponding to the requested 15 training grant slots per year. Once in the program, the students become a highly cohesive group through their interactions in additional CMP-specific classes and interdisciplinary training experiences. These include an introductory workshop in the Fundamentals of Rigor and Reproducibility, two courses in Drugs and Disease, computational and/or quantitative courses, a biannual Careers course, a student organized journal club, attendance and participation in the weekly Research Discussion presentations, and a yearly retreat focused in large part on the trainees. Through these activities, the program seeks to build a pool of rigorously trained scientists, with the skills required for leadership roles in areas of biomedical science where training in the fundamental discipline of pharmacology impacts basic research, drug discovery, public policy and education. Intended and realized outcomes, evidenced by those of our extensive pool of alumni, include positions in the pharmaceutical and biotech industry, in government and regulatory affairs, in public policy and secondary education, in law, and in biomedical and pharmacology education. Critical and independent thinking that pushes the boundaries of pharmacological science is emphasized and recognized through a variety of awards to students and alumni.

NIH Research Projects · FY 2025 · 2024-07

Project Summary Astrocytes are glial cells involved in the regulation of neuronal synaptic formation, maturation, and plasticity. The period in development when neural circuits are shaped by experience is termed the critical period. In the visual critical period, the development of normal vision depends on proper visual input. This period is characterized by increased plasticity, whereas in adulthood plasticity is decreased and changes to the circuitry are restricted. Plasticity alterations have been shown to contribute to neurological diseases, such as glioma and schizophrenia. Astrocytes secrete different proteins that induce synapse formation or maturation, in an age-dependent manner. Experience-induced neuronal activity elicits transcriptional changes in astrocytes in the visual cortex, including the expression of immediate early gene c-fos. Fos, the c-fos coded protein, acts as a transcription factor and it has been shown to have cell-type specific targets. In astrocytes, c-fos expression is induced upon visual stimulus in the visual cortex. Further, astrocytes upregulate c-fos mRNA throughout development and into adulthood, and c-fos is downregulated when visual input is decreased. Previous findings have shown age- and experience- dependent astrocyte transcriptional changes; however, the astrocyte upstream regulators of these gene expression changes remain poorly understood. I hypothesize that astrocytes regulate experience-dependent plasticity through the expression of Fos and its subsequent regulation of astrocyte-specific late response genes leading to synapse stabilization. With my dissertation, I will elucidate the regulation of astrocyte experience- dependent transcriptional changes via Fos, and its modulatory effect on plasticity, i.e., synapse stabilization in the adult visual cortex. Preliminary data in Aim 1 suggest Fos is an experience-dependent and upstream transcriptional regulator of astrocytes’ response to neuronal activity. These data demonstrate my expertise on molecular techniques, bioinformatics, and mouse surgery. A functional approach that answers whether Fos deletion in astrocytes results in increased plasticity in the adult visual cortex, will further elucidate its role as an experience-dependent astrocyte transcriptional regulator. For the F99 phase, I propose in vivo imaging to assess the functional effects of Fos deletion in astrocytes. For the K00 phase, I will focus on disease models to assess how astrocyte transcriptional dysregulation results in functional and plasticity alterations that contribute to disease. The carefully designed training plan targets gaps in my scientific training and professional development that will ultimately allow me to advance confidently toward my goal of becoming an independent principal investigator and mentor leading a research team. I will work with my Sponsors to continue acquiring the proposed skills, and to enable me to find the right environment and mentors to further my career and reach my goal.

NIH Research Projects · FY 2026 · 2024-07

Project Summary Alzheimer’s Disease (AD) is the most prevalent cause of dementia and the most common age-related neurodegenerative disorder characterized by the progressive degradation of neurons, inflammation, decline in memory and behavior, and the accumulation of β-amyloid (Aβ) plaque in the brain, particularly in the hippocampus and cortex. The roles of microglia in AD are still a matter of intense debate in this disease. Using the 5xFAD double transgenic mouse model of AD, which expresses mutant human APP and PSEN1, we demonstrated that single systemic WT HSPC transplantation fully rescued AD leading to the preservation of memory and neurocognitive performance, reduction of the β-amyloid (Aβ) plaque burden in hippocampus and cortex, prevention of microgliosis and neuroinflammation, and preservation of the blood brain barrier (BBB) integrity. We also showed that HSPCs differentiated into microglia-like cells in the brain, replacing up to 40% of the endogenous microglia in the brain and with a resting and ramified phenotype. In contrast, transplanting 5xFAD mice with 5xFAD HPSCs had limited to no impact on any complications of AD. This work opens new perspectives for utilizing HSPCs for the treatment of AD. However, the exact mechanism underlying the significant therapeutic impact observed after transplanting WT HPSCs in the 5xFAD mice remains unclear. Indeed, WT HSPC transplant fully prevented microgliosis, neuroinflammation and BBB disruption, despite partial replacement of microglia by HSPC-derived microglia-like cells, suggesting a systemic beneficial impact of WT HSPCs. In contrast, HSPCs isolated from 5xFAD mice exhibit limited to no therapeutic effect, suggesting that 5xFAD HSPCs and/or their progeny carry an inflammatory phenotype. This was supported by our preliminary data showing significant decreases in memory and increases in locomotor activity in WT mice transplanted with 5xFAD HSPCs, resembling the behavioral patterns observed in 5xFAD mice. We will investigate the mechanisms behind the impact of HSPCs, by first assessing the impact of 5xFAD HSPCs on the microgliosis and neuroinflammation in WT mice and by examining the hematopoietic lineage profile in the peripheral blood to verify if any skewing towards a specific lineage exists in the mice receiving the 5xFAD HSPCs. We will also identify the genetic susceptibility that may exist in 5xFAD HSPCs or their hematopoietic progeny using RNAseq and ATACseq. In addition, we will test the potential effects of mutated APP and/or PSEN1 on hematopoietic cell lineages and determine whether they could directly trigger a pro-inflammatory state using CRISPR/Cas9 technology to knockout hmAPP and hmPSEN1 in murine Sca1+ HSPCs. Finally, we will determine the ability of WT HSPCs to reverse neuroinflammation and preexisting complications in AD despite the presence of Aβ aggregates by transplanting older 5xFAD mice (6 months of age) with WT HSPCs. This work should shed light on the underlying mechanisms of AD rescue by HSPCs, advance the understanding the pathogenesis of AD, and evaluate the potential of HSPC-based therapy for the treatment of this disease.

NSF Awards · FY 2024 · 2024-06

Ever since the fundamental recognition of the potential role of the computer in modern statistics, the bootstrap and other computer-intensive statistical methods have been developed extensively for inference with independent data. Such methods are even more important in the context of dependent data where the distribution theory for estimators and test statistics may be difficult or impractical to obtain. Furthermore, the recent information explosion has resulted in datasets of unprecedented size that call for flexible, and by necessity computer-intensive, methods of data analysis. Time series analysis in particular is vital in many diverse scientific disciplines. As a consequence of the development of efficient and robust methods for the statistical analysis of dependent data, more accurate and reliable inferences may be drawn from datasets of practical importance resulting in appreciable benefits to the society. Examples include data from meteorology/atmospheric science (e.g. climate data), economics (e.g. stock market returns), biostatistics (e.g. fMRI data), and bioinformatics (e.g. genetics and microarray data). The project also involves developing curriculum, mentoring undergraduate students' research, supervising graduate students, and developing open-source software, organizing workshops. The project focuses on the development of methods of inference for the analysis of dependent and otherwise complex data without relying on unrealistic and/or unverifiable model assumptions. In particular: (a) Subsampling and resampling for big data will be studied, including the notion of scalable subagging applied to deep learning to improve both speed as well as accuracy of estimation; (b) Central limit theorem for the median of a triangular array of dependent data will be proved with application to median-of-means and robust scalable subagging; (c) Model-free bootstrap will be studied and compared to conformal prediction in nonparametric regression; (d) A novel class of nonstationary dependent errors will be introduced with application to fitting large autoregressive (AR) models to nonstationary time series; (e) Markov resampling and linear process bootstrap will be developed for stationary random fields; (f) Skip-sampling of discrete Fourier transform ordinates will be introduced and compared to the traditional frequency domain bootstrap for stationary time series; (g) Smoothing estimators of time-varying covariance matrices will be constructed for locally stationary multivariate time series; (h) Bootstrap for time series with a seasonal component will be further developed; and (i) Multi-step ahead point and interval predictors will be constructed for nonlinear autoregressions. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-06

Project Summary/Abstract HIV infection directly impacts both Mycobacterium tuberculosis pathogenesis and disease severity. Timely and accurate diagnosis of active tuberculosis (TB) disease is critical for people living with HIV (PLWH) as TB disease accounts for one third of all HIV-related deaths. Yet, currently there are no diagnostic solutions for active TB disease that are rapid, inexpensive, and highly sensitive; and solutions that are available are designed primarily as sputum-based solutions and optimized to detect pulmonary disease. This exacerbates the diagnostic gap for PLWH, as PLWH are more likely to present with paucibacillary and extrapulmonary forms of the disease. Novel point-of-care, rapid and accurate diagnostic solutions that have been optimized and tested among PLWH are critically needed to reduce treatment delays and improve treatment outcomes. Our central hypothesis is that the identification of the M. tuberculosis specific antigen, 10-kDa culture filtrate protein or CFP-10, in circulating body fluids, specifically blood, is indicative of actively replicating bacteria, and the detection of CFP-10 could potentially be used to diagnose both pulmonary and extrapulmonary disease. Historically direct detection of M. tuberculosis specific antigens has been hampered by the expense and complexity of detecting ultra-low concentrations of circulating antigens in biofluids. However, recent technological advancements in chip-based electrochemical immunosensors have resulted in increased sensitivity, options for miniaturization, and improved operational simplicity allowing for the detection of ultra-low concentrations of target antigens in micro-volume clinical specimens. Using seed funding from SD-CFAR our team developed a prototype Mycobacteria tuberculosis antigen detection assay that successfully detected the M. tuberculosis specific antigen CFP-10 in a limited number of clinical samples from patients with culture confirmed TB. While the initial success of this prototype assay was very promising, more data is needed prior to any further clinical validation studies. In this proposed study we aim to 1) determine the analytical performance of the prototype assay by conducting a series of laboratory- based experiments using contrived samples to standardize the assay, assess its sensitivity and performance parameters (dynamic range, precision, and repeatability), determine the specificity of the assay in the presence of non-tuberculosis mycobacterium, and evaluate its storage stability: and 2) we will conduct a limited clinical performance study of the prototype assay using 144 previously collected (72 from PLWH) and well characterized clinical samples from the R2D2 network (with a pre-selected TB positivity of 50%). The low cost and relatively simple approach of the prototype assay make it ideal for use at the clinic level as a low-tech, point-of-care diagnostic. If ultimately successful, this assay has the potential to fundamentally change global TB diagnostics.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY (ABSTRACT) Alzheimer’s disease (AD) and related dementias like frontotemporal dementia (FTD) disproportionately affect Latinos and socioeconomically disadvantaged groups. Nevertheless, the bulk of the research exploring the multifaceted biology of dementia, which includes both genetic and epigenetic aspects, has predominantly been focused on Caucasian populations and higher-income countries (HICs). To address these disparities and expand dementia research in Latin America countries (LAC) and low-income countries, our group has established the NIH-NIA/Tau Consortium/Alzheimer Association funded Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat) cohort study of Latinos with AD, FTD, and healthy controls. ReDLat represents a first-in-class dataset of Latinos with AD, FTD, and demographically matched healthy controls consisting of biospecimen collection, standardized clinical, neuropsychological, genomic, neuroimaging, and SDH data, which our research group has utilized to identify unique combinations of environmental and genetic factors of dementia in Latin American Countries (LAC). Our preliminary epigenetic data reveals shared and distinct epigenetic DNA methylation differences related to AD and FTD, including a "Hispanic Paradox" with epigenetic biomarkers underestimating biological aging in Latinos despite AD and FTD diagnoses. Moreover, our preliminary data harnessing matched SDH data from ReDLat suggests a link between altered DNAm states of inflammatory, stress, and cardiometabolic genes and socioeconomic status. Our overall hypothesis is that a social adversity-epigenetic signature in immune cells at regulatory regions of proinflammatory, stress, and cardiometabolic genes associates with dementia presentation and heterogeneity in Latinos. In this proposal, we test this overall hypothesis and add epigenetic DNAm data to the ReDLat cohort by (1) leveraging existing blood biospecimens from 1,600 participants (n=400 AD, n=400 FTD, n=800 controls) with different social determinants of health (SDH) levels, including a low-middle income country (Colombia), an upper middle-income country (Argentina), and HICs countries (Chile and the US) and (2) leverage existing ongoing rolling ReDLat recruitment to add an out-of-sample validation epigenetic dataset of 400 additional participants (n=100 AD, n=100 FTD, and n=200 controls) to generate an epigenetic dataset from 2,000 total Latinos in ReDLat. With these rich epigenetic data, we will identify shared and distinguishing epigenetic DNAm features associated with AD and FTD presentation in Latinos. Moreover, we will utilize this extensive epigenetic dataset to better understand the interactions between specific SDH factors and distinct epigenetic changes in the genome. Understanding dementia presentation through the lens of epigenetics and SDH in Latinos across diverse regions of LAC and the US will advance regionally-informed novel strategies to address dementia disparities by paving the way for targeted interventions and prevention strategies that take into account both epigenetic and SDH factors.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY/ABSTRACT Acanthamoeba keratitis (AK) can occur in healthy individuals wearing contact lenses and it is a painful blinding infection of the cornea caused by a free-living ameba Acanthamoeba. Complications include chronic ocular inflammation, corneal melting and scarring. Current treatment for AK relies on a combination of chlorhexidine, propamidine isethionate, and polyhexamethylene biguanide. However, in 10% of cases recurrent infection ensues, because of the difficulty in killing both trophozoites and double-walled cysts. Therefore, development of efficient and safe drugs is a critical unmet need to avert blindness. Because AK is a rare disease, there is a paucity of drug discovery efforts by the pharmaceutical industry and drug discovery for this infection largely relies on academic research centers. To reduce the cost, time and risk associated with the development of new AK therapies, we focused on repurposing of the FDA-approved sterol biosynthesis inhibitors pitavastatin and isavuconazonium for the treatment of AK. Identification of HMG-CoA reductase (HMGR) inhibitors and sterol 14-demethylase (CYP51) inhibitors, which are amebicidal, and combination of novel cysticidal assay with phenotypic trophozoite screen laid the foundation for this proposal. We have generated significant data showing that (1) pitavastatin and isavuconazonium are potent trophocidals against three clinical strains of A. castellanii, (2) isavuconazonium sulfate and its major metabolite isavuconazole exhibit low nanomolar potency against trophozoites, (3) both isavuconazonium and isavuconazole suppress excystment of cysts into trophozoites, (4) combination of pitavastatin and isavuconazole is synergistic on trophozoites, and (5) isavuconazole targets A. castellanii CYP51 and parasite HMGR may be a relevant target for pitavastatin. Based on these results, we propose to 1) evaluate mammalian cytotoxicity and trophocidal and cysticidal activities of combination of pitavastatin and FDA-approved form isavuconazonium and compare that with the effect of pitavastatin and isavuconazonium alone, 2) conduct tolerability and pharmacokinetic- pharmacodynamic studies of topically administered pitavastatin and isavuconazonium, both monotherapy and in combination therapy and 3) test in vivo efficacy of topical pitavastatin and isavuconazonium, alone and in combination with each other, in an animal model of AK caused by Acanthamoeba of two different genotypes. This study is a necessary step toward repurposing of topically administered pitavastatin and isavuconazonium for the treatment of AK. To successfully achieve the proposal goals, we rely on our existing collaboration that combines the unique expertise of Dr. Debnath (PI) in Acanthamoeba parasite biology and Dr. Afshari in ophthalmology. Drs. Debnath and Afshari's expertise and experience in parasitic eye infection has potential to elevate our drug repurposing platform to a translational level.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY / ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD)., the most common genetic kidney disease in the world, is characterized by progressive kidney tubule cyst growth, and after decades of tubule damage, it leads to declining glomerular filtration rate (GFR) and kidney failure. By the time this GFR decline is detected, nearly half the original functional glomeruli and tubules are irreversibly lost. Currently, there is no cure for ADPKD and the vasopressin receptor antagonist tolvaptan is the only drug approved by the FDA to slow progression Tolvaptan slows GFR decline, but is expensive, difficult to take, and has considerable side effects. There is an unmet need to study novel tubular biomarkers in persons with ADPKD with the goal of improving early identification and quantification of risk for progression, targeted treatment for the highest risk individuals, and enrichment methods for future clinical trials. We have worked extensively to expand the paradigm of tubular function in kidney disease. We have demonstrated the utility of a focused kidney tubule health panel (KTHP) consisting of proximal tubule injury, tubulo-interstitial inflammation, repair and fibrosis, and secretion in the general population, and among those with CKD, HIV, and heart failure. However, persons with ADPKD were not included in these studies, and our preliminary data demonstrate that several of these tubule markers are particularly perturbed in APDKD. Our goal is to develop an ADPKD-specific KTHP which will incorporate different dimensions of tubular health and injury, improve kidney failure risk prognostication of persons, and evaluate the potential salient effects of tolvaptan on tubular health. We propose to use a unique repository of biospecimens at multiple timepoints from over 2,700 persons with ADPKD who were enrolled in the Phase 3 TEMPO 3:4 and REPRISE trials – both are placebo-controlled trials of tolvaptan in ADPKD. In Aim 1 we will develop and compare KTHP dimensions and correlate them with ADPKD severity, with the hypothesis that these markers will identifying ADPKD patients at highest risk for rapid kidney disease progression, above and beyond currently available clinical and imaging measures. Leveraging the design of the clinical trials, we will compare the effect of tolvaptan versus placebo on tubule health markers (Aim 2). Finally, we will determine whether short-term changes in kidney tubule health biomarkers can predict long-term progression of ADPKD (Aim 3). This comprehensive approach to phenotypying tubular health will advance the role of tubular biomarkers in risk stratification, patient identification, and monitoring response to treatment in ADPKD.

NIH Research Projects · FY 2025 · 2024-06

Project summary Idiopathic pulmonary fibrosis (IPF) is the single most common and lethal type of lung fibrosis of unknown cause, which starts with the build-up of scar tissue from the edges of the lung, and advances toward the inside center over time. This intriguing edge-to-center fibrotic progression suggest the presence of unique biological or physical cues in the lung periphery that initiate the disease, the study of which is still in its infancy. Given the fact that few treatment options are available once interstitial fibrosis develops, early diagnosis and treatment are thus critically important, which is hindered by our poor knowledge on the etiology of fibrotic progression. By using cutting-edge technologies including lineage tracing, mouse modeling and multimodal single cell sequencing, Dr. Xu found that elevated mechanical tension drives the differentiation of a novel population of fibroblasts in the lung periphery, leading to the subpleural fibrosis. These fibroblasts are characterized by expression of Wilms' tumor 1 (WT1), signatures of Epithelial-Mesenchymal Transition (EMT), and secretion of multiple kinds of chemokines and cytokines. Fibrosis progression is achieved through additional lung injury, suggesting that a synergistic effort between these WT1+ subpleural fibroblasts and injured epithelial cells may drive the progression of pulmonary fibrosis. These preliminary data raised the Central Hypothesis that WT1+ subpleural fibroblasts function as a stromal niche that drives the progression of pulmonary fibrosis, which will be rigorously tested here in three Specific Aims: Aim 1. To determine the cellular origins and molecular drivers of WT1+ SPFBs [K99] To address the progenitors of WT1+ SPFBs, and transcription factors that drive their induction. Aim 2. To determine if WT1+ SPFBs act as a stromal niche to promote fibrosis progression [K99/R00] To address the biological roles of WT1+ SPFBs in promoting fibrosis progression. Aim 3. To determine if the recruitment and function of myeloid cells in the subpleural region promote pulmonary fibrosis progression [R00] To address the contribution of subpleural myeloid cells, which are hypothesized to be recruited by WT1+ SPFBs, to fibrosis progression. Dr. Xu is well on track towards his career goal as an independent investigator, evidenced by his multidiscipline training record and academic productivity. To accomplish this, he will receive support from his outstanding and complementary mentor committee, including Dr. Xin Sun (primary mentor), Dr. Zea Borok (co- mentor, lung fibrosis), Dr. Laura Alexander (co-mentor, immunology) and Dr. Kyle Gaulton (co-mentor, epigenomics/single cell technology).

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY Hyperosmotic stress has been linked to several human diseases. Furthermore, drought-linked hyperosmotic stress is of major concern for threatening human nutrition and health. However, these osmotic/drought stress sensors and the early osmotic stress signal transduction mechanisms have remained largely unknown. Hyperosmotic stress triggers rapid intracellular Ca2+ transients in Arabidopsis. Moreover, we have recently discovered rapidly-activated Raf-kinases that are required for early hyperosmotic stress signal transduction in Arabidopsis. These early signal transduction mechanisms are required for resistance mechanisms, including downstream biosynthesis of the stress resistance hormone abscisic acid. Rapid osmotic stress responses in the highly developed Arabidopsis model organism provide an ideal system for dissection of a eukaryotic osmotic stress sensing and signal transduction machinery. The long-term objective of this research program is to achieve a molecular, cellular, mechanistic and quantitative understanding of osmotic stress sensing and signal transduction in the genetically tractable Arabidopsis model system. We will address the question of the unresolved osmotic stress sensor machinery and signal transduction cascade, through an innovative screen and new mutants we have isolated that greatly impair the rapid osmotic stress-induced Ca2+ transients. Moreover, downstream of hyperosmotic stress, we have recently found osmotic stress-triggered genome-wide chromatin remodeling that correlates with osmotic stress-induced transcriptome responses. The question of how osmotic stress signal transduction links to and mediates osmotic stress-induced genome reprogramming will be pursued. Furthermore, the question whether osmotic stress-induced chromatin remodeling primes the genome for future stress resistance will be investigated and underlying mechanisms will be determined. Another question of particular interest is how guard cells rapidly close stomata in response to low humidity (high vapor pressure difference), thereby reducing water loss. This elusive cellular low-humidity sensing and signal transduction pathway has been hypothesized to be related to osmotic stress sensing and signaling. We have recently discovered Raf-kinases, overlapping with the above-mentioned hyperosmotic stress-activated Raf- kinases, and a transmembrane receptor like pseudo kinase that are required for the rapid low humidity response in guard cells, providing a foothold for dissecting the underlying molecular and cellular signal transduction pathway. My laboratory applies diverse cellular signaling, genetic, genomic, biophysical and time-resolved imaging approaches to address fundamental questions in stress sensing and signaling. Results from this research will illuminate the elusive osmotic/drought and humidity sensing and signaling mechanisms and could lead to future strategies for improving food security for human health and nutrition.

NIH Research Projects · FY 2025 · 2024-05

PROJECT SUMMARY The free-living amoeba Naegleria fowleri is responsible for severe primary amoebic meningoencephalitis (PAM), which mostly occurs in healthy children and young adults. N. fowleri is considered as one of the deadliest human pathogens and is a category B biodefence agent. N. fowleri infection is problematic due to the rapid onset and destructive nature of the disease as well as the lack of effective treatments. Currently, there is no single. proven. evidence-based treatment with a high probability of cure. Disruption of sterol biosynthesis in N. fowleri by smallmolecule inhibitors may be an effective intervention strategy against fatal amoebic meningoencephalitis. In the preliminary studies, we pharmacologically validated N. fowleri CYP51 (NfCYP51) as a potential therapeutic target. An intrinsic difficulty in achieving anti-Naegleria effect in vivo is that a drug must cross the blood-brain barrier (BBB) to reach the site of action. Limited brain permeability of drugs targeting CYP51 in pathogenic fungi prevents them from being efficacious in the treatment of PAM. The goal of our proposal is to develop brainpenetrant bona fide CYP51 inhibitors with anti-Naegleria activity and deploy them as the predecessors offuture anti-PAM therapeutics. To achieve this goal, we assembled an interdisciplinary team of investigators with expertise in N. fowleri biology (Debnath, Pl), computational chemistry (Brancale, Co-I), and medicinal chemistry for CNS applications (Ballatore, Co-I). In our preliminary studies, we selected compounds possessing physicochemical parameters compatible with BBB permeability. We identified small-molecule hits that are characterized by the presence of a carboxylate ester moiety which, in vivo, is rapidly hydrolyzed. A follow up study with hydrolytically more stable ether analogs identified two compounds with improved NfCYP51 binding and potency. The in vivo assessment confirmed detection of these two ether analogs in brain tissue. The primary objectives of this application are further evaluation of one BBB permeable ether congener for in vivo efficacy and the design, synthesis, and evaluation of congeners with the carbonyl group isosterically replaced with the 4- membered ring heterocycles, oxetane, thietane or their derivatives, that render compounds more resistant to chemical and enzymatic hydrolysis. Studies in Aim 1A include iterative cycles of design and synthesis of the analogs that, based on our current understanding of the structure-activity and structure-property relationships (SARISPR), are expected to exhibit both anti-N. fowleri activity and favorable ADME-PK. Studies in Aim 1 B will validate the newly synthesized compounds in a cascade of in vitro and in vivo assays for physicochemical properties (pKa, logP, log074), aqueous solubility, hydrolytic stability in buffers and plasma, potency, cytotoxicity, BBB permeability, metabolic stability and brain and plasma PK. Two compounds satisfying all go-no-go criteria will progress to tolerability and proof-of-concept efficacy studies in a mouse model of PAM in Aim 2. We expect to identify a lead compound that significantly extends the lifespan of the infected animals beyond that of the current standard of care, Amphotericin B.

NIH Research Projects · FY 2025 · 2024-05

SUMMARY The pathogen Salmonella enterica serovar Typhimurium (STm) exploits aspects of host immunity to establish a niche in the gut and outcompete the resident microbiota. Despite significant progress in understanding the competitive dynamics between STm and the gut microbiota, there remain gaps in our knowledge regarding the specific mechanisms involved in their interactions. Herein, we propose a combined approach that integrates metagenomic (metaG), metatranscriptomic (metaT), and metatranslatomic (metaRS) profiles to elucidate new mechanistic interactions between STm and the gut microbiota. Specifically, we will use quantitative metaG, metaT, and integrate innovative community-level ribosome footprinting (metaRS) to construct a comprehensive profile of resource allocation and substrate preferences within the gut microbiota. It is our expectation that these combined approaches will lend insight into how metabolic niches are perturbed by STm colonization and associated host immune responses. Through the integration of these multiomics, we have generated testable hypotheses regarding potential mechanisms of competition between STm and the gut microbiota. We intend to test these hypotheses in this research application. Our central hypothesis is that elucidating microbial metabolism in the gut, in conjunction with the analysis of host responses, will unveil new competitors and mechanisms of competition between STm and the gut microbiota. We will test our hypothesis by pursuing two Specific Aims: In Aim 1, we will analyze bacterial metabolism to identify potential Salmonella competitors in mice and test the predictions in vitro and in vivo. We will validate the preliminary finding that STm infection depletes specific members of the microbiota with similar metabolic profiles. We will also test the prediction that metabolic overlap between STm and specific members of the microbiota reflects competition for resources in the gut. In Aim 2, we will investigate whether host antimicrobial responses promote Salmonella competition with selected members of the gut microbiota. Collectively, this study will provide a comprehensive analysis of bacterial metabolism in the gut and how this is perturbed in the context of STm infection. Moreover, the study will test hypotheses stemming from our preliminary data as well as generate and test new hypotheses concerning mechanisms governing microbial competition, also in the context of host responses. Moving forward, the insights garnered from this research hold promise for therapeutic interventions aimed at reducing STm colonization and reinstating intestinal homeostasis.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY Nutrition and fasting have long been known to have major effects on the brain. Previous work linking metabolic energy to brain function has focused on the neural control of feeding, while key mechanisms by which metabolic states control cognitive function remain unknown. Here we investigate how different metabolic pathways support the fast spiking of inhibitory interneurons, which in turn generate gamma oscillations (30-100 Hz) that are linked to cognitive domains such as memory formation, motor behavior, perception, and consciousness. The subset of fast-spiking inhibitory interneurons defined by expression of the calcium-binding protein Parvalbumin (PV) are necessary and sufficient to drive gamma oscillations. These fast-spiking PV interneurons have tremendous energy needs, supported by high metabolism and mitochondria function. While the extraordinary metabolic activity in PV neurons is well-characterized, the mechanisms regulating their activity and the consequences of activity regulation on brain oscillations and cognitive function are not established. We therefore propose to investigate the function of a vertebrate-specific candidate protein (distinctively expressed in these fast-spiking interneurons) involved in energy generation, and to identify new candidate proteins by a genetically targeted mitochondrial proteome screen from PV neurons. The main goal of this screen is to identify proteins that sustain the high energy generation rate as well as proteins that can tune down PV interneuron metabolic activity. Manipulations of these proteins will then be used to identify the consequences of regulating energy metabolism in PV interneurons on neuronal network oscillations, with the long-term goal to understand how metabolic homeostasis and dysregulation in neurons alters brain function in healthy individuals as well as those with brain disorders such as Alzheimer's disease. Our studies are poised to reveal fundamental insights into the mechanisms that orchestrate energy sources for network oscillations and that link metabolism to higher order cognitive functions. These insights will form the basis for a broader understanding of the link between nutrition, brain function and mental health by determining the consequences of dysfunction of the molecular machinery for energy production in interneurons on brain oscillations that are critical for cognitive function.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY Neuroimaging studies show a relationship between accelerated biological aging and accelerated brain atrophy even in healthy populations. Recent machine learning approaches have used neuroimaging variables, such as cortical thickness and subcortical volume, to calculate an estimated “brain age” as a measure of biological aging. Estimated brain age greater than an individual’s chronological age is thought to reflect an accelerated rate of age-related changes to the brain and may predict future impairments in cognitive functioning. Accelerated biological brain aging may occur among people with HIV (PWH), as central nervous system complications from HIV infection may occur even in individuals taking antiretroviral therapy (ART). Methamphetamine (METH) use, which is common among PWH, may also be detrimental to brain health. It is hypothesized that METH’s effects on the central nervous system may have a synergistic effect on the long-term impact of HIV infection. This K01 application will use structural and functional neuroimaging measures to develop a normative model of brain age using data from the Human Connectome Project to leverage hypothesis testing in a locally collected dataset by the UC San Diego Translational Methamphetamine AIDS Research Center (TMARC) that includes adults stratified by HIV infection and methamphetamine use. Specific Aim 1 will estimate brain age in the TMARC cohort using a composite measure of cortical thickness and subcortical volume derived from T1-weighted structural scans and compare it to chronological age and cognitive measures. We hypothesize that HIV infection and METH use will individually accelerate brain age, but that their combined effects will be associated with greater accelerated aging. Specific Aim 2 will integrate T1-weighted and resting-state functional neuroimaging scans to develop a brain-age model based on multi-modal neuroimaging data which is hypothesized to be more sensitive to the effects of METH use and HIV status on brain age and cognitive measures. Specific Aim 3 will investigate whether inflammation indexed by CRP, MCP-1 and NfL from cerebrospinal fluid has an indirect effect on the association between brain age and history of METH use or between brain age and HIV status. Disentangling the biological effects of HIV in older adults and its relation to history of METH use will advance the HIV field through informing our understanding of how biomarkers of neural integrity and inflammation related to cognition, which may inform future health interventions. This K01 application has broad, long-term objectives that include obtaining experience in data-science methodologies using neuroimaging data in order to generate models that will push neuroimaging research towards more clinical applications in substance use and HIV infection. This proposed K01 project will provide the applicant with critical training in data science using neuroimaging data, which will broaden her research skill-set and provide preliminary findings for the preparation of an R-level application.

NIH Research Projects · FY 2026 · 2024-05

One in 10 Americans aged 65 and older (10%) has Alzheimer’s disease (AD), with prevalence increasing with age. AD is a slowly progressive, irreversible neurodegenerative disease with a long preclinical phase. The pathophysiology of AD is not fully understood but is likely to be multifactorial. One postulated contributor is impaired glymphatic clearance. The glymphatic system is conceptualized as a system by which soluble proteins and metabolites are eliminated from the central nervous system via cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange in the perivascular space (PVS). In rodent models, sleep and physical activity have been reported to accelerate glymphatic clearance using invasive methods. During sleep, a nearly 60% increase in clearance of brain waste was observed in rats, caused by expansion and contraction of the extracellular space. Glymphatic clearance was transiently increased in aged mice by physical activity, and physical activity has been reported to improve clearance of brain Aβ in rats. Although animal studies suggest that reduced glymphatic clearance is important for cognitive function in aging, translation of findings from rodents to humans is limited because rodent models do not fully capture the human experience. In humans, use of a gadolinium-based contrast agent (GBCA) via intrathecal injection allows for observation of glymphatic clearance, albeit over a long period. However, this method is limited by its invasiveness, and by the unknown effect of the GBCA tracer on the in vivo time-course of glymphatic clearance. Using a novel, noninvasive, non-contrast 3D MRI technique, we have shown intrinsic glymphatic clearance or CSF outflow metrics decreases with age using a single-tagged method. The intrinsic CSF metrics decrease drastically over 60 years old. Thus, we will develop an advanced double-tagged method from both brain hemispheres. Using the double-tagged method, we propose to study healthy older adults, mild cognitive impairment (MCI), and AD patients on intrinsic CSF outflow metrics by segmenting various regions of interest (ROI) such as upper, middle, and lower parasagittal dura (PSD), superior sagittal sinus (SSS), and entire SSS region. Because CSF outflow is influenced by physical activity, we will monitor their activity level using actigraphy. Our challenges include segmentation of these small ROIs, and measurement of subtle changes in CSF outflow metrics in each ROI. To overcome these challenges, our aims of the project are i) identify the detailed CSF outflow egress pathways; ii) obtain quantitative measures at each ROI from both sides of brain hemispheres; iii) compare quantitative measures of intrinsic CSF outflow in MCI and AD patients to age-, and sex-matched cognitively healthy adults; iv) investigate any preference of intrinsic CSF outflow metrics from the right- and left-brain hemispheres; and compare with their physical activity level. We expect that intrinsic CSF outflow will decrease with cognitive decline; that clearance pathways may be altered in MCI and AD patients from healthy individuals.

NIH Research Projects · FY 2025 · 2024-05

SUMMARY Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting the lives of more than 5 million Americans and their families and is the biggest forthcoming health challenge. AD is a multifactorial disorder manifested clinically by progressive memory loss, decline in cognitive functions and ultimately leading to dementia. Despite being the subject of intense research, there is no cure for AD, therefore, identifying therapies that can reduce disease progression at early stages is critical. Circadian impairment is a major feature of Alzheimer’s disease. Behavioral circadian alterations, known as sundowning, are experienced by more than 80% of patients and represent the leading factor for hospitalization and nursing home placement in AD. New research suggests that circadian disruption occurs early during disease progression and contributes to neurodegeneration. Since circadian rhythms regulate multiple systems in the human body coordinating physiology with the environment, alterations in this system have a profound impact on health, behavior, sleep, and cognition. The proposed work will conduct a preliminary investigation on the beneficial effects of regulating the time of food intake to improve circadian function, on cognition and disease markers in Mild Cognitive Impairment (MCI) or AD patients. One of the most powerful regulators of the circadian system is the daily feed/fast cycle. We recently demonstrated that time-restricted feeding (TRF) improves key disease components including memory, sleep, behavior, disease pathology, and brain transcription in mouse models of AD. Notably, we found that TRF had the remarkable capability of simultaneously reducing amyloid deposition, increasing Aβ42 clearance, improving sleep and hyperactivity, and normalizing transcription of circadian, AD, and neuroinflammation-associated genes in AD mice. Thus, our study unveiled for the first time that circadian modulation through timed feeding has far-reaching effects beyond metabolism and affects the brain as the substrate for neurodegeneration. A similar intervention in human patients may have a profound translational value, addressing the crucial need for accessible approaches to reduce or halt AD progression. We now propose to test the safety, feasibility, and effectiveness of a time-restricted eating (TRE) paradigm in patients with a clinical diagnosis of cognitive impairment due to MCI or AD. We will recruit 40 patients and randomize them into two groups that will follow a TRE model of prolonged fasting during the night (14h without food intake) for 6 or 12 months. We will monitor blood-based markers of health, metabolism, epigenetic aging, and AD pathology; record circadian regulation based on sleep and activity monitoring and evaluate cognitive functions. The data collected will be fundamental to designing a larger clinical trial using TRE to improve circadian function and reduce cognitive and pathology burden in AD. Since this is a safe intervention that does not require drugs or special equipment, this intervention will be immediately available for millions of patients.

NIH Research Projects · FY 2026 · 2024-05

Project Summary/Abstract The 2017 Nobel Prize in Physiology and Medicine was awarded for work on circadian rhythm (CR) regulation. Now the challenge is to translate these basic science principles to clinical populations. Significant hormonal changes during the perimenopause (P-M) may disrupt CRs, manifesting as mood, sleep and activity dysfunction, increasing depressive illness risk. In this proposal we aim to test further a hypothesis of CR dysregulation in P-M mood and sleep dysfunction by administering critically-timed sleep + light interventions (SLI) designed to target and correct CR misalignment, and thereby improve mood and sleep. By this approach, ultimately we aim to optimize P-M health and prevent disease and disability. Hypotheses are: 1) SLI which phase-advance (shift earlier) vs phase-delay (shift later) CRs, best measured by melatonin, will ameliorate mood and sleep dysfunction, and 2) A corrective phase-shift in the primary biological target, melatonin timing, will be a significant mediator of improved function. In P-M depressed participants (DP) vs normal controls (NC), we recently reported increased plasma melatonin secretion and delayed morning melatonin offset associated with mood and sleep disturbances; correcting the phase-delayed melatonin CR with critically-timed sleep (wake therapy) + light interventions improved mood and sleep within 1-2 weeks, correlating significantly with melatonin phase-advance. To confirm target engagement and intervention mechanisms, in P-M women we will compare 1) an Active Phase-Advance Intervention (PAI): phase-advanced restricted sleep (sleep 9pm-1am) for 1 night, followed by 2 weeks of phase-advancing morning (AM) bright white light (BWL) for 30 min/day starting within 30 min of wake time, vs 2) a Control Phase-Delay Intervention (PDI): phase-delayed restricted sleep (sleep 3-7am) for 1 night, followed by 2 weeks of phase-delaying evening (PM) BWL for 30 min/day ending 30 min before bedtime. In pilot data, we found relatively inert effects of Control PDI on melatonin and nonsignificant (non-worsening) effects on mood and sleep. Combining SLI hastens, potentiates and maintains their beneficial effects. In a randomized parallel design in 100 P-M women with mood and sleep/activity dysfunction, we will administer either PAI or PDI at home (to enhance ecological validity), assessing effects on psychometric measures, urinary 6-sulfatoxy-melatonin (6-SMT) and actigraphy sleep/activity. This innovative combination of SLI identifies novel targets for health and disease prevention, and addresses an unmet therapeutic need in P-M women. It extends to the P-M our investigations of CR dysregulation and its restoration with SLI in other mood and sleep disorders associated with hormonal change in premenstrual and peripartum depression. This approach potentially offers a safe, efficacious, rapid-acting, well-tolerated, non- pharmacological, sustainable, affordable, home, and thus effective, intervention that can reduce health disparities. This work also forms the basis for future trials, aiming to optimize treatment outcomes by identifying chronobiological targets specific to an individual, the goal of personalized, preventative medicine.

NIH Research Projects · FY 2025 · 2024-05

PROJECT SUMMARY/ABSTRACT Ovarian cancer is the most lethal gynecologic malignancy for women; standard of care surgery and chemotherapy treatment can provide a short period of remission but cannot eradicate the disease and prevent recurrence. Cancer immunotherapy has shown great potential in treating cancers, but no clinical success has been reported for ovarian cancer. One major hurdle for cancer immunotherapy that is needed to overcome is to convert the immunosuppressive tumor microenvironment (TME). The goal of this proposal is to develop effective nanomedicines that are capable of reprogramming and converting the suppressive TME for ovarian cancer treatment. To achieve this goal, I will utilize viral nanoparticles (VNPs) to incorporate various functionalities targeting different aspects of the TME through bioengineering approaches. The two VNPs that will be used in this proposal are cowpea mosaic virus (CPMV) and hepatitis B virus capsid (HBVc), which both have well-characterized and stable structures for in vitro bioengineering. Toll-like receptor (TLR) agonists have been demonstrated to be potent to activate the innate immune system and modulate the TME. CPMV is a triple TLR 2, 4, and 7 agonist and is effective to reprogram the TME of ovarian cancer. In the mentored K99 phase, I will focus on using CPMV as a triple TLR agonist to develop an adjuvant and antigen combination in-situ vaccine for ovarian cancer treatment (Aim 1) and developing multi-TLR agonists to investigate the mechanism of action (MOA) of CPMV and multi-TLRs activation in cancer treatment to design potent TLR agonists combination for downstream applications (Aim 2). During my independent R00 phase, I will use HBVc as a nanotechnology platform to develop multiple functional therapeutic nanomaterials aiming to reprogram the suppressive TME to treat ovarian cancer and investigate the MOA. First, I will develop HBVc-based TLR agonist and pro-inflammatory cytokine combination therapies, which can exert the functions of reprograming the TME and killing cancer cells concurrently (Aim 3). Secondly, I will develop HBVc into a “smart” nanoparticle that functions as a TLR agonist and targets and converts the pro-tumor M2 macrophages into anti-tumor M1 macrophages (Aim 4). During my graduate study, I have been trained in manipulating HBVc in vitro assembly and genetic engineering of HBVc to design novel structures. In the past two and a half years as a postdoc in Dr. Steinmetz’s lab at UCSD, I have been trained systematically in the bioengineering of VNPs and the application of engineered VNPs for cancer treatment. A further two years of training in Dr. Steinmetz’s lab will allow me to enrich my background in cancer immunology, immune-oncology, and tumor modeling. With the help and guidance from my advisory committee, by the end of my mentored phase, I will be able to secure a tenure-track faculty position in a top-tier research institute to establish my independent research program focusing on using HBVc as a nanotechnology platform to develop novel and effective multi-functional nanomedicines for cancer patients.

NIH Research Projects · FY 2025 · 2024-05

PROJECT SUMMARY/ABSTRACT Peripheral insulin administration and impaired insulin clearance lead to hyperinsulinemia and insulin resistance in individuals with type 1 diabetes (T1D). As independent risk factors for cardiovascular disease (CVD), hyperinsulinemia and insulin resistance contribute to the high burden of CVD experienced by this population. The long-term goal is to develop approaches to reduce the excess risk of CVD in T1D. As the next step toward this goal, the overall objective of this proposal is to quantify the ability of combination adjunct-to-insulin therapy to reduce hyperinsulinemia and insulin resistance in T1D. The central hypothesis is that combination adjunctive therapy will (1) mitigate peripheral hyperinsulinemia via decreased insulin dosing and increased insulin clearance and (2) improve insulin resistance in muscle, adipose, and liver tissues. The rationale for this work is that gaining insight into the relationship between hyperinsulinemia and insulin resistance will inform new treatment strategies to mitigate the risk of CVD in T1D. The central hypothesis will be tested in a double-blind, placebo-controlled, crossover study in which participants with T1D will receive combination adjunct-to-insulin therapy and double placebo treatment, in random-order. The following specific aims will be pursued: (1) Quantify the reduction in hyperinsulinemia induced by combination adjunctive therapy and (2) Quantify the effect of reducing hyperinsulinemia on tissue-specific insulin resistance. For the first aim, ambulatory insulin dosing and circulating insulin concentrations will be measured, and the metabolic clearance rate of insulin will be calculated to determine the relative contribution of insulin dosing and insulin clearance in reducing hyperinsulinemia. For the second aim, insulin sensitivity will be measured in adipose, hepatic, and skeletal muscle tissue using hyperinsulinemic-euglycemic clamps with stable isotope tracer. This research is innovative because it leverages a unique therapeutic intervention (combination adjunct-to-insulin therapy) to achieve meaningful improvements in insulin clearance, hyperinsulinemia, and insulin resistance in T1D. This research is significant because it is expected to demonstrate a novel treatment approach and justify the study of adjunctive therapies to mitigate hyperinsulinemia, insulin resistance, and potentially CVD risk in T1D. The proposed studies will also provide a framework for mentored research training. The principal investigator (PI) seeks to gain expertise in advanced human metabolic research techniques to study insulin clearance, insulin resistance, and CVD in T1D. The PI has established a comprehensive training plan and a multidisciplinary mentorship team with diverse but complementary expertise to achieve the research and career development goals and transition to independence. This training will prepare the PI to pursue high impact research using novel therapies to mitigate hormonal and metabolic imbalances in T1D, with the mission of improving the health and wellbeing of people living with the disease.