University Of Southern California

NIH Research Projects · FY 2025 · 2019-04

This K24 renewal proposes resources, training, and protected time to mentor in addiction regulatory science (ARS) patient-oriented research designed to impact regulation of cannabis, tobacco, and other addictive commercially-marketed products. The K24 also will support efforts to expand capacity for addiction science training. There are three objectives. Objective 1. Training to enhance skills in: (a) translating legal epidemiology to ARS, (b) understanding the cannabis/tobacco industry and retail setting, (c) research methods that can be applied to the Monitoring the Future program or other national surveys to advance ARS, and (d) mentoring and leadership. Objective 2. Execute three trainee-led synergistic ARS research programs that will each leverage a unique resource for mentee-led research that informs state/local regulation of cannabis and tobacco: Research Program 1) new clinical trials testing the effects of simulated regulations on young adult purchasing of cannabis and other products in retail settings, leveraging a life-size replica cannabis dispensary/vape shop space; Research Program 2) new experiments testing the effects of exposure to images of cannabis/nicotine products experimentally manipulated to comply vs. not comply with regulations on youth cannabis/nicotine use perceptions and intentions, leveraging ongoing teen cohort studies; Research Program 3) expanding collaborations with Monitoring the Future study by recommending new measures and analyzing prevalence and policy exposure data to address timely cannabis ARS questions. Objective 3. Expand mentoring activities by: (i) empowering my own mentees to lead ARS through involvement in the three research programs and ARS-focused formal mentoring, and (ii) enhancing USC’s capacity to support development of the addiction science workforce by championing formal mentoring and training programs (e.g., master of addiction science).

NIH Research Projects · FY 2026 · 2019-01

Project Summary The long-term goal of this research program is to understand how genetic interaction among loci (or ‘epistasis’) contributes to phenotypic variation. To achieve this objective, we will pursue two parallel research trajectories. First, we will continue our ongoing work to characterize the genetic and molecular mechanisms that cause spontaneous and induced mutations to show different effects across genetically distinct individuals. These ‘background effects’ are important to human health because they complicate efforts to predict, prevent, and treat disease based on personalized genomic data. We recently used combinatorial DNA barcoding and CRISPR interference (‘CRISPRi’) to screen thousands of protein-coding genes in yeast for background effects in 170 progeny from a cross. With these data, we identified 815 background effects, quantified how background effects shape the phenotypic variance in populations, and mapped a subset of loci causing these background effects. Here, we will extend our work by comprehensively dissecting the genetic bases of hundreds of these already identified background effects, examining the environmental contextuality of these background effects, and determining how certain ‘hotspot’ loci shape the effects of many different genetic perturbations. Second, we have developed an approach for cloning segments of natural chromosomes and assembling them into synthetic chromosomes that can replace the native chromosomes in cells. This method opens new opportunities for characterizing epistasis without a need for mating or meiosis. As proof-of-principle, we showed that a single chromosome could explain nearly the entire difference in the abilities of two yeast species to grow at high temperature. Half of this effect was due to epistasis between different chromosomal segments. Here, we will improve the scalability, versatility, and portability of our technique, and will use it to determine how epistasis shapes trait differences and isolation between yeast species and genera. Our two research directions will produce detailed insights into epistasis that advance efforts to understand and predict the relationship between genotype and phenotype.

NIH Research Projects · FY 2025 · 2018-09

PROJECT SUMMARY: OVERALL CENTER CORE The overarching goal of the Center Core Grant for Vision Research is to support, strengthen and broaden basic and translational vision science research at the University of Southern California. The Center Core will provide shared resources accessible to a group of 28 outstanding investigators, dedicated to elucidating mechanisms, diagnosis, and treatment of ocular diseases. Currently, these participating investigators cumulatively hold 28 NIH-funded research grants, consisting of 21 grants from NEI (13 R01s, 1 R21, 7 K- awards) and 7 grants from other institutes (4 R01s, 1 R21, 1 RF1, 1 K08). The Center Core will support 3 highly integrated Resource Cores: 1) Ophthalmic Therapeutics Engineering Core, 2) Cell & Tissue Imaging and Data Science Core, 3) Animal Models and In Vivo Imaging Core. These Cores will offer exceptional facilities, instrumentation and expertise that are essential resources to enhance and expand the research programs of participating investigators, aid established investigators in pursuing research in new emerging fields, and assist new investigators in developing vision research projects. The Center Core will also coordinate and integrate Core activities, promote utilization of innovative emerging technologies, and facilitate collaborative inter-disciplinary vision research. The Center Core will serve as a cornerstone for conduct of impactful basic and translational vision research focused on advancing knowledge of the biology and pathophysiology of the visual system and development of novel diagnostic and therapeutic approaches for vision impairment.

NIH Research Projects · FY 2024 · 2018-09

PROJECT SUMMARY This is a multi-PI application for an R01 award under PAR-18-513. The proposed project titled “Combination Anti-Amyloid Therapy in Preclinical Alzheimer's Disease” is a multicenter randomized placebo-controlled two arm clinical trial of a combination anti-amyloid therapy: an anti-fibrillar amyloid antibody for the initial 18 months combined with BACE inhibition therapy for 4 years, in preclinical AD, defined as asymptomatic individuals with elevated brain amyloid as determined by florbetapir PET scanning. The primary outcome will be a cognitive composite (a modified version of the Preclinical Alzheimer's Cognitive Composite, PACC5), with functional and clinical assessments along with volumetric MR and tau PET as secondary outcomes (and, in a subset, CSF biomarkers). The specific Aims of the proposed study are; 1. to evaluate the impact of a combination anti-amyloid regimen on fibrillar amyloid in brain as indicated by amyloid PET SUVr, 2. to evaluate the efficacy and safety of a combination anti-amyloid regimen in individuals with preclinical AD, and 3. to evaluate the impact of the combination anti-amyloid regimen on AD biomarkers. Drs. Sperling and Aisen will share responsibility for scientific oversight of the clinical design and execution of the study and Imaging oversight will be provided by Dr. Johnson. The ACTC will provide the administrative and operational support, data capture and data management, clinical monitoring and site management, safety oversight, biostatistical support, and biomarker sample processing storage and support. Final selection of therapeutic agents for this trial will be made by a compound selection committee composed of field experts. Committee membership will include external experts in AD drug development and AD neurobiology, appointed in concert with NIA. The study team will work collaboratively with the pharmaceutical company researchers who have clinical experience with these therapeutics in development. This will be the first study of its kind: a potentially synergistic combination approach to dramatically reducing amyloid from asymptomatic individuals on the AD spectrum. Combination therapy trials are increasingly proposed by investigators and regulators to improve the likelihood of success in trials aiming for disease-modification. This approach could ultimately prevent the onset of AD symptoms

NIH Research Projects · FY 2025 · 2018-09

The Florida-California Cancer Research, Education & Engagement (CaRE2) Health Center is proposed by the Florida A&M University (FAMU, University of Florida (UF), and the University of Southern California-Norris Comprehensive Cancer Center (USC-NCCC) to reduce the cancer burden in Florida, California and nationally. The long-term goals of the CaRE2 Center are to reduce the cancer burden through scientific discoveries and community outreach, train and increase the pool of cancer researchers, increase research capacity at FAMU, and increase cancer research at UF and USC-NCCC. This CaRE2 triad is a bi-coastal partnership that brings together investigators and institutions in the two U.S. states that currently have the highest cancer incidence and mortality. The main scientific focus of the Center is to identify, examine, and understand cancer morbidity and mortality among the people living in Florida and California, particularly individuals who are susceptible to reduced survival following diagnosis and treatment. We propose to coalesce expertise, infrastructure and shared resources in support of 6 innovative translational research projects focused on understanding the biological basis of cancer differences among populations in our catchment areas, capturing the wide heterogeneity within these populations, with two foundational projects focusing on pancreas cancer (one full, one pilot) and one full project focusing on lung cancer (Aim 1). Under the leadership of the Research Education Core, we propose to train a total of 160 investigators, including 120 students and early-stage investigators (ESI) and 40 continuing trainees, in research on cancer morbidity and mortality (Aim 2). Leverage existing community partnerships, the Community Outreach Core will disseminate findings in all communities and provide educate about pancreas and lung cancers to enhance risk reduction and prevention and improve participation in biomedical research (Aim 3). Finally, the Planning and Evaluation Core will implement a systematic planning and evaluation plan to improve Center effectiveness using innovative strategies (Aim 4). All research projects will be facilitated and enriched by resources and approaches provided by the Tissue Modeling & Drug Development Core and Bioinformatics, Statistical and Methodological Core. All CaRE2 Center’s activities will be centralized and overseen by the Administrative Core. The FAMU-UF-USC partnership is ideally suited to achieve these aims. FAMU, UF, and USC have worked closely together addressing cancer morbidity and mortality in Florida and California communities for the last 4.5 years, providing complementary and synergistic expertise in cancer research for research training of all populations and development of sensitive tools to reduce the cancer burden among these populations.

NIH Research Projects · FY 2026 · 2018-09

PROJECT ABSTRACT The proposed study will help substantially advance understanding of the immunology, biology, and detection of syphilis, through the study of newly identified cases in Lima, Peru, where syphilis is hyper-endemic. Syphilis remains a serious disease with significant adverse clinical outcomes. Despite over 100 years of research in the biology of Treponema pallidum sub. pallidum, the bacterial pathogen that causes syphilis, the use of modern methods to study this infection is just beginning, with our team spearheading some of this work. Our study builds on the research infrastructure and capacity created through two previously NIH-funded studies, the “Picasso Study” (NIH/NIAID R01AI09972) and “Picasso 2” (NIH/NIAID R01AI139265) as well as an SBIR grant (R43AI149804). In this proposal, investigators from USC, UPCH, UW, and Antigen Discovery will work together to accomplish the proposed three aims and fill critical gaps in the understanding of syphilis. Aim 1: Clinical cohort and epidemiology — Hypothesizing that those with a first versus repeat syphilis infection will demonstrate different immunological profiles, we will conduct a prospective study of incident syphilis cases, comparing those with and without a history of prior syphilis infection. We will a) recruit, treat, and follow 50 individuals with incident syphilis without prior infection and 100 individuals with repeat syphilis infection. We will compare individuals with de novo versus repeat infection with two outcomes: 1.the proportion with clinical manifestations of syphilis at diagnosis and 2. rates of re-infection during follow-up. Aim 2: Immunological — Hypothesizing that the clinical manifestations and immunologic responses (antibody responses and T cell activation) will differ between individuals with repeat infection versus de novo incident syphilis infection (active versus treated infection), we will investigate antigens associated with reinfection, identify TP proteins that activate a CD4 T cell response, and document the T cell receptor response to infection and treatment. Aim 3: Transcriptomics — we will analyze the host transcriptome to identify diagnostic signatures for syphilis. Assays for syphilis remain limited in their ability to differentiate between active and resolved infection. In this study, RNA- seq data from whole blood collected pre and post treatment will be used to identify transcription pathways involved in functional immunity to syphilis. Building on our years of ongoing collaborative work in syphilis pathogeneses and diagnostics, this proposal will focus on new areas of syphilis immunology to inform vaccine discovery and novel diagnostic test development.

NIH Research Projects · FY 2026 · 2018-07

Project Summary Given that eating frequency is largely determined by societal norms, a deeper understanding of the neural substrates that control meal size is critical for the development of novel and more effective treatments for obesity. The amount of food consumed over the course of a meal is determined by a competing balance between an early-meal positive feedback process called appetition and a late-meal negative feedback process called satiation. We hypothesize that melanin-concentrating hormone (MCH), an orexigenic neuropeptide produced in the lateral hypothalamic area (LHA) and zona incerta (ZI), is critical in mediating the poorly understood process of appetition. While such a role for MCH has not been directly investigated, this notion is supported by findings revealing that MCH neurons are glucose responsive 1,2 and MCH injections augment food intake by increasing meal size 3. A role for MCH signaling in mediating appetition is further supported by our preliminary data showing that chemogenetic activation of MCH neurons (LHA + ZI populations) potentiates flavor preference learning for a nonnutritive flavor paired with intragastric glucose infusion. MCH is produced in both the LHA and the ZI, which are adjacent regions that are differentiated both functionally and neuroanatomically 4-7. Our preliminary results, using fiber photometry to measure MCH neuron calcium activity in awake behaving animals, reveal that LHA and ZI MCH neurons show distinct calcium activity dynamics during a meal, such that LHA MCH neuron activity increases during active eating relative to interbout intervals, and ZI MCH neuron activity shows the opposite pattern (activity elevated during interbout intervals relative to active eating). These findings introduce the possibility that LHA and ZI MCH neurons subserve distinct but complementary functions in the control of feeding. Based on our preliminary data, here we will evaluate our hypothesis that LHA MCH neurons promote orosensory-mediated appetition, and ZI MCH neurons promote post-oral nutritive-mediated appetition. This hypothesis will be evaluated by separately targeting LHA vs. ZI MCH neuron populations in Aim 1 experiments measuring physiological MCH neuron calcium activity in response to orosensory vs. post-oral nutrient sensing in lean and obese rats, and in Aim 2 functional chemogenetic and caspace-mediated ablation experiments determining the precise oral and post-oral mechanisms through which MCH neuron activation promotes flavor-nutrient learning. In addition to exploring the physiological responses (Aim 1) and functional relevance (Aim 2) of the two MCH neuron populations with regards to appetition and food intake, Aim 3 will combine MCH neuron population-specific pathway tracing, metabolic brain mapping, and single-nucleus RNA sequencing approaches to extensively characterize the anatomical, network, and transcriptional profiles of ZI vs. LHA MCH neurons. Overall, these complementary aims will significantly advance understanding of the hypothalamic control of food intake and shed light on the potential of MCH-based obesity pharmacotherapies.

NIH Research Projects · FY 2024 · 2018-07

Project Summary In the somatosensory system, the detection of external signals, such as mechanical, thermal, and chemical stimuli, is critical for survival. Cutaneous nerve endings sense these changes in the environment, conveying this information first to the spinal cord via specialized sensory afferents that can discriminate between innocuous and noxious stimuli, the latter by pain-sensing nociceptors. The sensations and the physiological effects of cold are distinct among somatosensory modalities in that cold provides a pleasant, soothing sensation at mild temperatures, but is also agonizing as temperatures decrease. The menthol receptor, TRPM8 is the principal cold sensor in mammalian sensory neurons. This and cells expressing the ion channel are required for the sensations of both innocuous cool and noxious cold, heightened cold sensitivity that results with injury or disease and, paradoxically, the ability of cooling to relieve chronic pain and itch. These findings suggest that TRPM8 can centrally differentiate and propagate the distinct percepts of pleasant and therapeutic cooling from painful and aggravating sensations of cold. But how does this lone channel and the cells expressing it mediate these diverse physiological effects? We found that the glial cell-line derived neurotrophic factor-like ligand artemin (ARTN) and its receptor GFRα3 are required for injury-induced, TRPM8-dependent cold pain, the first evidence of a molecule that directly sensitizes cold in vivo. While the cellular and molecular transduction mechanisms used by this signaling complex to induce cold pain have yet to be defined, these findings point to the cohort of TRPM8+ afferents that express GFRa3 as cold nociceptors. We propose a model whereby injury of any etiology leads to cold allodynia via peripheral release of ARTN that acts on GFRa3 receptors on TRPM8 cells to increase their sensitivity to cold, transmitting this centrally via distinct neurocircuits. We propose to test this first by determining the cellular basis for ARTN and GFRα3 mediated cold sensitization. Second, we have generated a novel mouse genetic strategy to target the GFRa3+ and GFRa3- populations of TRPM8 afferents, allowing the lab to differentially study these two cell types and determine their necessity for acute cold signaling, for pathological cold pain, and for analgesic and anti-pruritic cooling in vivo. Lastly, it is critical to unbiasedly identify cold-tuned spinal cells to determine how the pleasant and painful aspects of cold are processed. We have adapted an innovative genetic approach to study cold-tuned spinal neurons molecularly, functionally, and behaviorally, allowing us to critically interrogate the processing of peripheral cold signals at this first important site for conveying somatosensory and nociceptive information. These studies will define the signal transduction pathways of cold and cold pain, providing not only insights into somatosensory signaling and the mechanisms that bring about pain associated with this modality, but also potential therapeutic interventions that use cold as a stimulus.

NIH Research Projects · FY 2025 · 2018-06

PROJECT SUMMARY / ABSTRACT Brainstorm is a Matlab/Java multi-platform (Linux, MacOS, Windows) software environment for analysis and visualization of electrophysiological (e-phys) data. While originally focused on noninvasive EEG and MEG, Brainstorm now also includes tools for analysis and advanced visualization of a broader range of data modalities: intracranial EEG including ECOG, SEEG macroelectrode recordings, MUA and LFP microelectrode data in humans and in-vitro/in-vivo preparations in animal models, and noninvasive NIRS data. The software is widely used and plays an increasingly important role in clinical and cognitive neuroscience research as reflected in the following statistics over the past decade: 1,700 published articles reporting analyses performed with Brainstorm, 30,000 user accounts, 34,000 posts on the online user forum, and 2,000 students, postdocs and faculty around the globe have attended in-person or online Brainstorm training events. Over the past four years we have built on the extensive capabilities of Brainstorm by defining and implementing a BIDS-compatible database structure and adding tools for cloud/advanced computing over distributed data resources. We have added improved interfaces with other EEG/MEG software, leading spike-sorting e-phys software, and hardware (including the ability to import from multiple commercial file data formats). We have also added interoperability with MRI- analysis software and deployed tools for FEM-based head modeling. Under this renewal we will address the following: Aim 1: Enabling Tools for Naturalistic and Single-Trial Neurophysiology Studies: There is increasing scientific interest in eliciting, recording, and analyzing neural responses to non-repetitive and naturalistic stimuli. Data of this type present particular challenges in terms of documenting rigorously varied, uncontrolled sensory events and behavioral responses with machine and human readable annotations, and relating such complex sensory presentations and behavior to measured brain activity. We will therefore develop a suite of tools for preparing and analyzing multimodal e-phys data in the context of naturalistic neuroscience. Aim2: Tools for Invasive Recordings: We will build on developments in the current project period to provide tools for preprocessing and analysis of invasive recordings and FEM-based modeling of intracranial current fields including labelling, localization and co-registration of complex iEEG electrode montages from X-ray CT to MRI, automated identification and tagging of interictal features in iEEG, and characterization, localization and validation of neuronal sources from iEEG. Aim 3: Software Enhancement, Integration, Maintenance, Training, and Documentation: We will pursue a three-pronged development track: (i) a hub-based framework in which third-party tools can be linked, run and with results visualized entirely from Brainstorm as a hub; (ii) build on our existing provenance tools so that users can save analysis histories to allow full reproducibility; and (iii) provide links and interoperability with statistical packages to promote rigor. We will continue to develop Brainstorm with multiplatform compatibility, web-based documentation, user forums, and hands-on training.

NIH Research Projects · FY 2025 · 2018-05

PROJECT SUMMARY/ABSTRACT Recognizing the critical need for a broad range of expertise in biomarker analysis at several levels of analysis, we propose a unique postdoctoral training program titled “Training for the Multiscale and Multimodal Analysis of Biomarkers in Alzheimer’s Disease” (AD). USC is home to leading experts who utilize biomarkers in their work investigating AD through a myriad of methods and analyses. Drawing from USC’s eminent resources and expertise, this proposal will focus on preparing investigators for independent research careers in the multiscale and multimodal analysis of biomarkers in AD, by integrating molecular and cellular methods, imaging tools and informatics, quantitative methods for clinical trials research, and large-scale population analyses. Our proposed training program draws preceptors and faculty from 12 schools, departments, institutes, and centers at USC, fulfilling these methodological areas of expertise: USC Mark and Mary Stevens Neuroimaging and Informatics Institute (INI) in the Keck School of Medicine (KSoM); Zilkha Neurogenetic Institute (ZNI) in the KSoM; Department of Neurology in the KSoM; Department of Neurological Surgery in the KSoM; Department of Radiology in KSoM; Alzheimer's Therapeutic Research Institute in the KSoM; Department of Population and Public Health Sciences at the KSoM; Department of Economics in the Dana and David Dornsife College of Letters, Arts and Sciences; Center for Economic and Social Research in the Dana and David Dornsife College of Letters, Arts and Sciences; Institute for Technology and Medical Systems Innovation (ITEMS), a joint initiative between Keck School of Medicine and Viterbi School of Engineering; Leonard D. Schaeffer Center for Health Policy and Economics, a unique collaboration between the USC Sol Price School of Public Policy and School of Pharmacy; and Leonard Davis School of Gerontology. Trainees will complete coursework, lab rotations, and career development activities, such as seminar series, instruction for problem solving, communication, time management, and leadership skills, and instruction and training in grant writing. Trainees will become conversant in all thematic areas and will be able to effectively collaborate outside of their own particular area of expertise. Specifically, the USC Training for the Multiscale and Multimodal Analysis of Biomarkers in AD will aim to: equip trainees with a combination of skills to conduct multiscale and multimodal analyses of biomarkers in AD by providing tailored, didactic research education opportunities to further the research potential of trainees; facilitate eminent research in the multiscale and multimodal analysis of biomarkers in AD by trainees, including the development of research ideas, execution of research projects, and dissemination of research findings; establish among trainees a collaborative and multidisciplinary team approach to advance research in the multiscale and multimodal analysis of biomarkers in AD; and successfully transition trainees to independent research careers, including securing their own research funding.

NIH Research Projects · FY 2026 · 2018-05

Project Summary G protein-coupled receptors (GPCRs) constitute the largest membrane protein superfamily in the human genome, with over 800 unique sequences. GPCR-mediated signaling pathways play a key role in all physiological systems as well as many pathophysiological conditions and therefore represent important drug targets. GPCRs have a seven-transmembrane-helix (7TM) topology and contain multiple binding sites for orthosteric ligands and allosteric modulators. Upon recognition of their native ligands receptors transmit signal across the cell membrane to intracellular partner proteins, such as G proteins or β-arrestins. Developing a detailed understanding of functional mechanisms of GPCRs and facilitating design of novel drugs with high selectivity and potency require access to high-resolution three-dimensional structures, determination of which, however, remains a challenging task. We propose here a comprehensive research program which combines technology development with integrated structure-function studies focused on GPCR superfamily. The proposed research directions are designed to accelerate high-resolution structure determination of membrane proteins, improve our understanding of GPCR superfamily and answer specific questions on ligand specificity and selectivity as well as molecular mechanisms of action using several specific receptors as targets. Our approach integrate structural information on new receptors and complexes with data obtained from biophysical, biochemical and functional experiments through computer-based analysis and modeling. The long-term goal of our laboratory is to develop a deeper understanding of the molecular mechanisms of action of GPCR using the tools of structural biology and to apply the achieved insights towards the design and development of novel and efficacious therapeutics.

NIH Research Projects · FY 2026 · 2018-03

ABSTRACT Obesity continues to increase in disadvantaged populations. Neighborhood revitalization efforts in low- income communities have sought to reverse these trends. One such effort is currently underway in Watts, Los Angeles, where the Jordan Downs (JD) public housing site, an obsolete project housing low-income Hispanic and Black residents, is being redeveloped. The redevelopment is building replacement housing for all original tenants, doubling housing capacity to allow new mixed-income residents, and overhauling the built environment. The redevelopment avoids resident displacement and has created quasi-experimental variation in the timing and “dose” of residents’ exposure to the redevelopment components. In 2018, the parent grant (R01CA228058) initiated a cohort study to examine the JD redevelopment’s impact on residents’ body mass index and obesity in its early years, explore potential explanations for any observed effects, and assess heterogeneity in effects. We recruited a cohort of 888 adults from JD and two comparison public housing sites in Watts and followed them longitudinally, with two baseline (2018-19, 2019-20) and two follow-up waves (2020-21, 2021-22). During the follow-up years, about 1/3rd of the site was redeveloped. The parent study found – (a) alarmingly high rates of overweight or obesity (80%) in the cohort, (b) substantial heterogeneity in residents’ reported barriers to healthy eating and exercising, despite similar socioeconomic background and neighborhood environment, leading to variability in who benefited from the redevelopment; and (c) a 14% decline in abdominal obesity among JD residents with highest exposure that likely operated via lower added sugar intake. However, these effects may have been dampened by the Covid-19 pandemic that coincided with the followup waves. Also, it is unclear whether these changes are temporary (e.g. due to the novelty) or long-lasting (e.g. due to habit formation). This renewal application proposes to follow the existing cohort through the remaining 2/3rds of the redevelopment with 4 additional rounds of data collection to address the following aims – (1) Examine the redevelopment’s impact on residents’ obesity through the remainder of the redevelopment. As more JD households receive higher “doses” of the redevelopment, we will examine if these effects fade, persist, or become more widespread. (2) Evaluate the continuity of previously observed behavioral pathways and identify emerging ones through the remainder of the redevelopment. And (3) Examine how differences in building design and resident mix influence obesity-related behaviors and risk factors. The redevelopment includes several phases that vary in building design and resident mix, creating an opportunity to test novel hypothesis about their effects on obesity and related behaviors. This study will have a high impact because it builds on a well-established cohort and community partnerships to study a comprehensive community intervention in a high-risk population using rigorous methods, novel hypotheses, and a strong interdisciplinary research team.

NIH Research Projects · FY 2025 · 2017-12

This is a multi-PI application renewing the U24 Cooperative Agreement to sustain and expand the NIA’s state-of-the-art Alzheimer Clinical Trial Consortium (ACTC) responsible for conducting academic clinical trials across the continuum of Alzheimer’s disease (AD). This ACTC will continue to leverage the depth and breadth of AD clinical research teams at USC, Harvard, and the Mayo Clinic, as well as the considerable experience of investigators at 35 expert AD trial sites. We aim to sustain the optimized infrastructure that efficiently develops and conducts high quality NIH supported clinical trials in AD and related dementias.. Building on our first five years of experience, we will utilize streamlined contracting processes, a centralized IRB with a specific focus on neurodegenerative diseases, and incorporate state-of-the-art informatics and statistical analyses. We will effectively manage performance of clinical trial sites, while identifying, mentoring and supporting new trial sites to improve access to clinical trials. We will foster continued innovation in AD trial design, providing expertise on novel cognitive, imaging, and biomarker outcomes to support future ACTC trial applications. We will evaluate promising exploratory measures embedded in our current trials, such as Tau PET imaging and computerized cognitive testing, and work to incorporate these measures into a robust platform for future Proof of Concept (POC) trials to rapidly assess signals of efficacy. Our tightly coordinated, distributed leadership model has achieved a collaborative consortium that takes full advantage of the expertise across multiple institutions. The ACTC Coordinating Center will leverage the highly experienced teams in Clinical Operations, Data Systems and Management, and Biostatistics at USC. The MRI Unit, led by Mayo, and PET Unit, led by Harvard and UC Berkeley, will capitalize on unparalleled experience with multi-site protocols through ADNI, the A4 Study, and multiple ongoing clinical trials. The Clinical Outcome Instrument and Biomarkers Units will leverage world-class expertise from Mayo, Harvard, and USC to incorporate both standard and novel outcome measures in future trial designs. The new ACT E2-A2 Unit will provide training and leadership opportunities to young clinical investigators to facilitate continued innovation in trial design, and catalyze the next generation of AD clinical trials. Innovation in trial interventions, outcomes, design and analysis: the experts comprising this infrastructure provide the highest levels of expertise to design and conduct trials across the full continuum of AD, from primary prevention initiatives to combination trials for advanced symptomatic stages. We will build on our successes with public/private partnerships and continue to strengthen our strategic alliances to conduct large scale trials, while also supporting novel approaches to smaller investigator-initiated POC studies that will better inform Phase 3 decision-making. A program facilitating the longitudinal follow up of clinical trial participants with site assistance for brain donation, centralizing tissue banking and sharing is another key aim of the renewal.

NIH Research Projects · FY 2024 · 2017-09

PROJECT SUMMARY/ABSTRACT In contrast to other resistant bacteria, virtually no antibiotics are in the pipeline to deal with XDR A. baumannii. There is a critical need for new strategies to prevent and treat these infections. We spent the first grant period raising MAbs to A. baumannii capsule, and have now identified 4 anti-capsular MAbs (2 of which were used to generate a bi-specific MAb, leaving us with 3 MAb molecules) that collectively bind to 80-90% of US clinical isolates and protect mice from lethal infection. These 3 lead candidates are all highly potent, achieving 100% protection in bacteremia models at single doses of ≤ 50 µg. They are also protective in pneumonia models of infection, and synergize with antibacterials. Furthermore, the bi-specific MAb has increased potency compared to each of its individual MAbs, and retains binding for all target strains, and efficacy in vivo. This lead three- MAb therapeutic has begun translation into full GMP and toxicity, planning for a future Phase I clinical trial. Our goals for the renewal are to enhance feasibility of clinical development and deployment of the MAbs by closing any coverage gaps against international strains, defining surrogate efficacy markers, and validating key assays to support clinical trials and future clinical deployment. We have obtained a new global strain collection, and entered into key partnerships to further these aims, including experts at multi-valent MAb synthesis, clinical microbiology laboratory operations, and statistics. Our Aims are to: Specific Aim 1: Define and optimize strain coverage and surrogate efficacy markers for international clinical strains of A. baumannii. We have collected 50 strains each from Taiwan, Southeast Asia, China, Europe, and South America. We will survey our 3 MAbs against all acquired strains, assessing flow binding and macrophage uptake, and will assess efficacy in our IV bacteremia model for representative strains. We will raise news MAbs as needed to close international strain coverage gaps. Specific Aim 2: Validate bioassays to enable clinical trials of the MAbs, including potency and human surrogate efficacy markers. We will validate LC-MS/MS for the specific amino acid sequences of our variable regions to quantify our MAbs when spiked into human blood, distinct from background antibodies. We will adapt our well-established HL-60 assays to quantify opsonic activity of MAb in human plasma. Finally, we will use multiplex Luminex assays to quantify cytokine modulation of fresh human leukocytes. Specific Aim 3: Optimize a rapid in vitro binding assay as a “susceptibility testing”-equivalent to support clinical trials and deployment of the MAbs. We will validate rapid, high throughput flow binding assays to correlate with protection in mice as a “susceptibility-test equivalent”. Novel solutions for A. baumannii infections are a critical unmet need. We have developed a promising MAb regimen that improves outcomes during blood and lung infection in mice. We will define global strain coverage, close any identified gaps, and develop bioassays to support clinical testing of the MAbs.

NIH Research Projects · FY 2025 · 2017-09

ABSTRACT - “Chemical Tools for the Investigation and Manipulation of Protein Glycosylation” The broad goal of this proposal is the development of chemical tools that will enable the facile and robust identification and inhibition of glycosylation in specific cells, the mapping of glycosylation-mediated and cell- type specific interactions, and monitoring and manipulation of carbohydrate biosynthetic pathways. The addition of carbohydrates to proteins, or glycosylation, is one of the most common forms of posttranslational modifications and is associated with various processes, including protein stability, macromolecular interactions, and cellular signaling. Unfortunately, the currently available tools for interrogating these functions fall short, which limits the study of glycosylation to expert labs. We plan to tackle this unmet need using carbohydrate chemistry, photo-chemistry, and chemical biology in three specific aims. In Aim 1, we will build on our development of glycosylation probes and inhibitors, with a focus on using chemical genetic approaches to create tools to identify and perturb glycosylation in a cell-specific fashion. In Aim 2, we will leverage the advantages of chemoenzymatic modification of glycosylation to install specific photocrosslinkers onto living cells, with a focus on identifying biological interactions that are mediated by glycans, as well as mapping cell interactions. Finally, in Aim 3, we will create novel activity-based probes for measuring and inhibiting critical enzymes responsible for monosaccharide biosynthesis. At the conclusion of these independent aims, we will have generated new powerful tools that will have an immediate impact on the types of questions scientists can ask about glycosylation in human health and disease.

NIH Research Projects · FY 2024 · 2017-09

Birth defects of the head and face are common in the human population. Skull injuries and joint disease, in particular affecting the temporomandibular joint of the jaw, are a major economic and societal burden. This proposal is to support the upward trajectory of a mid-career investigator, Dr. Gage Crump, who works at the interface of craniofacial development and stem cell biology. Specifically, he has developed powerful new zebrafish models of human craniofacial birth defects and disease, which are allowing him to unravel the developmental causes of common craniofacial birth defects and, in a bold new direction, to understand mechanisms of stimulating endogenous repair of the adult skull. Dr. Crump is Director of the PhD Program in Development, Stem Cells, and Regenerative Medicine at the University of Southern California and a founding member of the Eli and Edythe Broad Center for Stem Cell Research, a rapidly growing institute directed by Dr. Andrew McMahon with exceptional core resources and recently recruited junior faculty. He is currently PI on three R01's from NIDCR and has published featured articles in Developmental Cell, eLife, Development, and PLoS Genetics on diverse topics ranging from craniofacial development to jawbone repair and arthritis of the jaw. He has built up an exceptional research team, with several trainees receiving K99 and F31 fellowships from NIDCR, as well as prestigious private fellowships. His previous trainees have gone on to tenure-track faculty and industry positions, and postdocs in HHMI-funded labs. He also participates in local and national efforts to recruit under-represented minority students into stem cell science from high school to graduate levels. These efforts are reflected by a USC Mentoring Award to Dr. Crump in 2017. The research program focuses on the roles of progenitor cells in building the facial skeleton and then maintaining and repairing it in the adult. These studies exploit the unique genetic and imaging strengths of zebrafish, combined with its impressive capabilities of natural regeneration as adults. The first program uses new gene editing technology in zebrafish to analyse requirements for novel craniofacial patterning genes in progenitor regulation, as well as to directly image progenitor lineage commitment using time-lapse microscopy. As exemplified by studies of Jagged-Notch signaling from fish to man, efforts to validate zebrafish findings in mouse will be performed in latter years. The second program investigates the stem cell-based maintenance of two types of joints, the sutures of the skull and the synovial jaw joint. The third program builds on innovative models of bone, cartilage, and joint regeneration in the adult zebrafish jaw, as well as a highly collaborative network of basic researchers and clinicians at USC, to understand how different types of endogenous stem cells are activated to repair craniofacial tissues. Completion of these studies will reveal commonalities and differences between the stem cells that build and then maintain and repair the craniofacial skeleton, with foundational knowledge acquired in zebrafish informing future regenerative approaches towards improving skeletal healing in patients.

NIH Research Projects · FY 2025 · 2017-07

PROJECT SUMMARY Receipt of individual NIH career development awards has been instrumental to the professional trajectories of physician-scientists. However, submitting competitive applications for these awards is difficult without formal mentorship, defined expectations, protected time, and coordinated curricula. The USC R25 Neurosurgery Research Education Program provides the resources, mentorship, and support required to address many of these challenges. The R25 program has advanced a culture of academic research and development of clinician-scientists that has directly benefited the residents and junior faculty members within the USC Department of Neurosurgery. The proposed renewal application seeks to build upon the early successes from the initial funding cycle. This competitive renewal application leverages a similar structure to the first five years of the program but incorporates changes/ improvements based on learning and feedback. Mentors are clinicians and scientists with federal funding and prior track records notable for successful mentorship. Thirty- five faculty members from seventeen different academic departments across the university are included as mentors and advisors. A multi-tiered mentorship system affords each R25 trainee a research supervisor for his/her direct investigative study, guidance from a Neurosurgery Research Mentorship Committee and career development support from a team of clinician-scientists within the candidate’s chosen neurosurgery/ neuroscience subspecialty. A Transition to Academic Faculty Committee provides sustained guidance and oversight to R25 graduates during their final years of residency training and initial junior faculty appointments. The USC Neurosurgery residency program has been restructured to incorporate a dedicated R25 research track that differs from the traditional clinical pathway. An innovative Senior/ Junior mentorship program will allow R25 trainees to receive formal guidance from early career investigators in addition to experienced scientists/ mentors. Dedicated discussions and instruction focusing on ethical and successful scientific practice have been incorporated into the program. The over-arching aim of the proposal is to develop neurosurgeon- scientists capable of securing NIH K-, and ultimately R-, series funding to support independent research.

NIH Research Projects · FY 2024 · 2017-07

ALS, FTD, and Alzheimer’s are complex diseases that each result from many diverse genetic etiologies. Although therapeutic strategies that target specific causal mutations (e.g. SOD1 ASOs) may prove effective against individual forms of ALS and FTD, these approaches cannot address the vast majority of cases that have unknown genetic etiology. Moreover, given the large number of different genes that likely contribute to ALS and FTD and the fact that each genetic form is relatively rare, this strategy may be difficult to implement for all cases. Thus, there is a pressing need for new therapeutic strategies that rescue multiple forms of ALS and FTD, particularly those with unknown genetic etiologies. To identify new therapeutic targets that rescue multiple forms of ALS, we performed unbiased chemical screens to search for targets that can rescue the degeneration of iPSC motor neurons from multiple C9ORF72 and sporadic ALS patients. Inhibitors of PIKFYVE kinase were among the most potent and broadly-efficacious compounds across patient lines. Surprisingly, the data show that PIKFYVE inhibition rescues neurodegeneration by blocking autophagosome- lysosome fusion, which induces secretory autophagy to clear misfolded proteins including C9ORF72 dipeptide repeat proteins and TDP-43 through exosomal secretion. The accumulation of misfolded proteins can induce neuron death and is a common feature of neurodegenerative diseases. Although studies have sought to stimulate known proteostasis pathways including the proteosome and autophagy, these pathways decline during aging and may be difficult to rescue effectively. Intriguingly, recent studies have shown that neurons use exosomal secretion as a third proteostasis pathway. However, it remains unknown if this pathway can be harnessed to treat ALS and related neurodegenerative diseases. The central hypothesis of the proposed study that secretory autophagy is one of the most potent ways to prevent neurodegeneration in ALS, FTD, and Alzheimer’s disease differs from mainstream thinking in the field. Evaluating this hypothesis is crucial because activating the proteasome and autophagy has had mixed results in neurodegeneration models. The proposed study will 1) confirm that secretory autophagy is the therapeutic mechanism of PIKFYVE inhibition, 2) determine the efficacy of secretory autophagy in ALS, FTD, and Alzheimer’s disease patient-derived neurons, and 3) validate the efficacy of PIKFYVE suppression with antisense oligonucleotides in vivo. This application seeks to shift current research by validating the induction of secretory autophagy as a highly effective therapeutic strategy for diverse forms of ALS, FTD, and Alzheimer’s disease. The proposed study will establish PIKFYVE suppression and secretory autophagy as critical therapeutic targets for ALS and related neurodegenerative diseases. More broadly, this therapeutic strategy may be effective for other diseases driven by aberrant protein accumulation.

NIH Research Projects · FY 2026 · 2017-07

SUMMARY The cell bodies of vestibular ganglion neurons express a diverse range of ion channels and neurotransmitter receptors. This diversity provides a rich biophysical substrate for shaping the intrinsic excitability of individual neurons and expands the populations’ repertoire for sensory signaling. In the vestibular nerve, the temporal precision needed to code rapid head movements is determined by neurons firing at irregular intervals, whereas the ability to detect slow head movements sensitively is determined by neurons firing at regular intervals. Here we test whether the ion channels resident in the membranes of vestibular neurons produce this important diversity or whether other specializations of dendritic and synaptic morphology are also needed. The resolution of this question requires joint characterizations of ion channel composition and dendritic morphology in individual neurons. To provide this, we will perform patch-clamp recordings combined with single-cell labeling in semi-intact neuro-epithelium preparations in which neurons are still connected to their hair cells. Definitive relationships between ion channel composition and neuronal function cannot be established without considering the impact of efferent modulation on individual ion channels. Using pharmacology, we will define the impact of cholinergic efferent signals on two ion channels identified as being prominent for controlling the firing patterns and excitability of vestibular ganglion neurons. We will test if some neurons are more receptive to this modulation than others. Identifying such differences may also reveal opportunities for selectively targeting therapeutics to specific neuron groups. We will combine the unique joint characterizations of ion channels and dendritic morphology from our experiments to create computational models to examine the relative importance of ion channel composition and dendritic integration on vestibular afferent responses. Overall, our work integrates powerful computational and experimental approaches to advance our understanding of a fundamental aspect of vestibular function.

NIH Research Projects · FY 2025 · 2017-05

Project Summary In order to advance the understanding of life processes at the molecular level, we developed multiscale computer simulations that can treat complex biological systems. We intend to apply such strategies to systems which are to important medical problems. Our proposed projects are listed below. A.1 Enzymatic Processes: By exploiting our advances in multiscale modeling, we intend to progress in the following directions: (a) Quantifying computer-aided enzyme design by: (i) reproducing the observed trend in experiments of directed evolution using automatic configuration generator coupled with EVB simulations; (ii) reproducing the catalytic activity of experimentally designed enzymes; (iii) improving the action of promiscuous enzymes; (iv) destroying and rebuilding active sites. Our studies will be done in collaboration with key experimental groups. (b) Continuing to advance the quantitative computational methods, including: (i) using our PD QM(ai)/MM method in for evaluating the ab initio free energy surfaces of enzymatic reactions; (ii) Advancing a maximum entropy approach for fast screening (iii) Quantifying the relationship between folding and catalysis; (c) Conducting studies on important classes of enzymes; (d) Exploring the relations of our findings to medical problems such as the Covid-19 pandemic, drug resistance and other topics like CRISPR. A.2 Multiscale Modeling of the energetics and functions of complex biological systems: Basic functions of living cells are underpinned by proteins that guide the transport of electrons, protons, and ions. Thus, it is crucial to quantitatively explore and exploit the structure-function correlations using computer simulation approaches. We have made a major progress in developing microscopic and coarse grained (CG) approaches for such systems, and we will advance them in the following directions: (a) Simulating the proton transfer (PTR) gating mechanism of cytochrome c oxidase (CcO) and extending our recent studies of FO-ATPase. (b) Exploiting our advances in modeling voltage-gated ion channels for the following purposes: (i) to quantify the interplay between the electrode potential and the protein/membrane energy landscape, (ii) to reproduce the gating voltage and the subsequent ion current and its selectivity using both CG and explicit MC electrolyte models, (iii) to simulating the action of GPCRs and transporters by CG approach, (iv) to explore the relations between our finding and various diseases.

NIH Research Projects · FY 2026 · 2017-04

Project Summary The long-term goal of the proposed research is to identify the mechanisms by which bidirectional communication between the nervous system and the intestine regulates organism-wide responses to oxidative stress through regulated neuropeptide release. Oxidative stress plays a critical role in cognitive dysfunction and neuronal death associated with neurodegenerative diseases, but little is known about the physiological roles that reactive oxygen species play as signaling molecules in the brain. My laboratory uses the model C. elegans to study new signaling pathways that modulate neurotransmitter release. We have identified a role for hydrogen peroxide as a signaling molecule that positively regulates the secretion of specific neuropeptide-like proteins from dense core vesicles through sulfenylation of dense core vesicle (DCV) release factors. We found that the regulated release of these neuropeptides activates the antioxidant transcription factor SKN-1/Nrf2 in the intestine. Here we seek to uncover the molecular mechanisms by which hydrogen peroxide regulates DCV release, and how, in turn, neuropeptide signaling activates the antioxidant response. This study will reveal novel mechanisms underlying ROS regulation of DCV secretion and it will provide fundamental insights into how redox homeostasis is achieved through gut-brain signaling, and may therefore have direct relevance for the development of strategies to treat neurodegenerative diseases whose progression is associated with unregulated ROS signaling.

NIH Research Projects · FY 2026 · 2017-03

Sjögren's syndrome (SS) is an autoimmune disease manifesting with severe inflammation and loss of function of lacrimal (LG) and/or salivary (SG) glands, leading to severe dry eye and dry mouth. SS patients also exhibit extraglandular systemic symptoms including development of autoantibodies, inflammation of visceral organs and increased risk of B-cell lymphoma. Pathogenesis is complex and involves interplay between the activated immune system and exocrine epithelia; thus, SS therapies should ideally achieve both local glandular and systemic immunomodulation to fully treat the disease. Our initial focus is developing an effective treatment regimen for SS-associated dry eye disease (DED) and systemic symptoms, using the male NOD mouse which exhibits these disease manifestations of SS. We later explore efficacy in a model of autoimmune sialoadenitis and systemic symptoms, the female NOR mouse. Topical treatments are currently used clinically to manage symptoms of SS-associated DED, but these approaches are insufficient to suppress LG inflammation. Systemic symptoms are also treated to limited success with general immunomodulatory agents which also lack sufficient bioavailability to treat glandular inflammation. We hypothesize and test that a combined approach of optimized local glandular plus systemic delivery of therapeutics is necessary to effectively treat both glandular and extraglandular symptoms of SS. To achieve this, we use a versatile protein-polymer platform comprised of elastin-like polypeptides (ELPs) that can be genetically fused to peptides/proteins in ways that optimize their pharmacokinetics and bioactivity. Three Aims are proposed. Aim 1. Local LG immunosuppression using Supra-LG Rapa ELP depots and Molecular targeting to ICAM-1. The immunosuppressant, Rapamycin (Rapa), will be complexed to a depot-forming FKBP12-ELP fusion protein that sequesters Rapa; this carrier will be further modified to target intracellular adhesion molecule 1 (ICAM-1) increased in diseased LG in SS. In male NOD mice, efficacy will be assessed when delivered supra-LG towards SS-associated DED and systemic disease. Aim 2. Th17 immunosuppression using systemic delivery of extracellular IL-17 receptor ELPs. Elevated IL-17A is linked to SS pathogenesis. We develop soluble and depot-ELP fusions expressing the extracellular domain of the IL-17 receptor (eIL17R) to form multivalent IL-17A- sequestering nanoparticles for systemic delivery using subcutaneous (SC, flank) administration. In male NOD mice, efficacy will be assessed in SS-associated DED and systemic symptoms. Aim 3: Efficacy of local and systemic combination therapies in glandular and extraglandular symptoms of SS. Efficacy of combination local + systemic treatments will be assessed using formulations delivered by supra-LG (5FV-Rapa) and SC (soluble eIL17R-A192). Efficacy will be assessed both in male NOD mice (autoimmune dacryoadenitis/systemic symptoms) and in female NOR mice (autoimmune sialoadenitis/systemic symptoms).

NIH Research Projects · FY 2026 · 2017-02

Abstract Hepatitis B virus (HBV) is one of the most important human pathogens. There are approximately 300 million chronic HBV carriers in the world, resulting in nearly 1 million deaths every year. Most chronic HBV carriers acquired the virus from their infected mother early in life. HBV has a very narrow host range, which has greatly hampered its research. By crossing female hemizygous HBV transgenic mice that carry the 1.3mer overlength HBV genome to male naïve mice, we had developed a mouse model to study the mechanism of HBV persistence. We found that the persistence of HBV in mice was dependent on the HBV e antigen (HBeAg) and Kupffer cells, the resident macrophages of the liver. The requirement of HBeAg for HBV persistence is consistent with the clinical observation that the HBV persistence in babies is dependent on the HBeAg-positivity of their mothers. Our recent studies revealed an interesting interplay between HBeAg and hepatic macrophages. This interplay can either promote the HBV persistence or HBV clearance. In this application, we will continue to study this interplay between HBeAg and macrophages to understand the mechanism of HBV persistence. We had recently discovered that HBeAg could reprogram the metabolism of macrophages to promote the oxidative phosphorylation (OXPHOS). This metabolic reprogramming by HBeAg appears to be important for the attenuation of pro-inflammatory activities of Kupffer cells. We will therefore continue to study how HBeAg reprograms the metabolism of macrophages and study the implication of this reprogramming in the anti-HBV response. Our preliminary results also indicated that the toll-like receptor 4 (TLR4) mediated the effects of HBeAg on Kupffer cells. Thus, we will also investigate whether TLR4 serves as the receptor of HBeAg and its role in HBV persistence. Finally, we will determine whether HBeAg by itself is sufficient to promote HBV persistence and whether HBeAg can train Kupffer cells in utero to promote HBV persistence. Our proposed studies will provide important information for us to understand the mechanism of HBV persistence and help to improve the treatments for chronic HBV patients.

NIH Research Projects · FY 2026 · 2016-09

OVERALL – PROJECT SUMMARY/ABSTRACT This is a continuing multi-disciplinary program on VASCULAR CONTRIBUTIONS TO DEMENTIA AND GENETIC RISK FACTORS FOR ALZHEIMER’S DISEASE with multiple projects, cores, institutions and 24 investigators from the Zilkha Neurogenetic Institute, Stevens Neuroimaging and Informatics Institute, Alzheimer’s Disease Research Center (ADRC), University of Southern California (USC), LA, CA; Washington University Knight ADRC, Dept. of Neurology, Washington University, St. Louis, MO; Huntington Medical Research Institutes, Pasadena, CA; Banner Alzheimer’s Institute and Mayo Clinic, AZ; Dept. of Psychology, UC Irvine; Dept. of Molecular Medicine, Scripps Research Institute ; and Centre for Clinical Brain Sciences, Univ. of Edinburgh, Scotland. The overall goal of the program is to test the ‘neurovascular hypothesis’ of AD and establish whether the neurovasculature has a major role in the pathogenesis of early cognitive decline, and therefore could be a key new therapeutic target to treat early cognitive impairment, dementia and early AD. The program includes continuing participation by accomplished investigators in all aspects of this research plan. The collective expertise of the investigators, overall environment, preliminary results, and experimental design for each of the projects and supporting cores produced considerable success of this program over the past 4 years. During this period we collected vast amounts of data, analyzed them and wrote an impressive number of high impact papers. Our renewal is concentrated on apolipoprotein E (APOE), the major genetic risk factor for AD. We propose longitudinal studies in APOE4 carriers (ε3/ε4; ε4/ε4) that are at high genetic risk for AD and develop early cerebrovascular changes including breakdown in the blood-brain barrier (BBB) relative to APOE3 homozygotes (ε3/ε3) that are at a lower risk for AD and develop slower cerebrovascular changes. We anticipate following 402 APOE4 carriers and 465 APOE3 homozygotes (ages 45-90) initially enrolled as cognitively unimpaired (CU, 75%) or with mild cognitive impairment (MCI, 25%). This includes 510 participants enrolled in the program during the initial P01 period, and 360 new participants to be recruited during the first 3 years of the renewal. In these APOE4 and APOE3 participants we will apply cutting-edge molecular and imaging methods to study the contribution of BBB/vascular dysfunction to preclinical cognitive decline, loss of brain connectivity, neurodegeneration, and longitudinal clinical progression along the continuum from CU to MCI, and MCI to dementia, in relation to Aβ and tau AD biomarker abnormalities (CSF, PET). Experimentally, we will study how BBB/vascular dysfunction relates to synaptic and neuronal dysfunction and behavior in APOE (knock-in)flox/flox (KIF) mice with and without apoE deletion from astrocytes and pericytes (key sources of BBB-associated apoE), and in these mice crossed with APP/PS1-21 and P301S tau lines, and treated with a cell-signaling activated protein C (APC) analog, 3K3A-APC. The results of this work may lead to new ways of thinking about pathogenesis, treatment and early prevention of cognitive impairment, dementia and AD for which we still do not have effective therapies.

NIH Research Projects · FY 2026 · 2016-09

Abstract The superficial white matter (SWM) lies directly beneath the cortex and contains the short association fibers, or U-fibers, connecting neighboring gyri. The SWM contains around twice as many fiber connections as the deep white matter (DWM) and plays a crucial role in brain development, aging, and various brain disorders. Existing connectome imaging research based on diffusion MRI (dMRI), however, mostly focuses on the connections of long fiber bundles in the DWM even though tremendous advances have been made in human connectome imaging with much improved spatial and angular resolution. In this proposed renewal of our R01 project (NIBIB R01EB022744), we will conduct systematic development of novel computational tools to fill major technical gaps in current SWM research. Our project will provide fundamentally novel solutions to many of the current challenges in SWM connectome research by developing surface-based tools for fiber tracking, atlas construction, and personalized analysis. We will also develop novel personalized dMRI harmonization methods with a particular focus on accounting for the variable cortical anatomy. These developments will for the first time provide dedicated tools for modeling SWM connectome with greatly improved robustness and accuracy. There are three specific aims in our project: 1. Development of novel surface-based fiber tracking and filtering algorithms for the modeling of superficial white matter connectivity. 2. Development of surface-based U-fiber atlases and personalized SWM connectivity analysis. 3. Development of personalized diffusion MRI harmonization tools with improved consistency in cortical anatomy. Rigorous validations of our novel surface-based U-fiber tracking and modeling methods will be performed on high-resolution MRI of post-mortem brains, in vivo intracranial neural recordings from surgically implanted electrodes in patients with epilepsy, and their application in multiple large- scale connectome imaging datasets (n>5000). All software tools and atlases developed in this project will be publicly shared, which will allow brain imaging researchers to augment their current connectome models with U- fibers in SWM and more completely map human brain connectomes for the detection of their alterations in various brain disorders.