Northeastern University

NIH Research Projects · FY 2025 · 2022-09

Project Summary Antiretroviral therapy (ART) adherence among nursing home (NH) residents with HIV is less than optimal; in the literature 21% of people with HIV had no ART from their NH, which is in contrast to the 87.5% adherence among community dwelling older people with HIV. ART maintains viral suppression, prevents worsening of chronic conditions and early mortality, and stopping ART is rarely indicated. Therefore optimal ART adherence in the NH setting can only be achieved by understanding facilitators and barriers both documented in claims and perceived by older people with HIV. This mixed methods study will assess ART adherence during the community-to-long-stay-NH-transition period in three aims: Aim 1 will identify person-level, and NH-level, factors associated with changes in ART adherence in socioeconomically diverse Medicare and Medicaid special needs plan (SNP) claims. Aim 2 will assess perceptions and experiences of long-stay NH residents with HIV through qualitative interviews and Aim 3 will examine concordant and discordant factors associated with ART adherence by triangulation of Aims 1 and 2. Quantitative analyses will use two databases 1) Medicare 5% enhanced sample; 2) claims from a New York City-based Medicaid HIV SNP. Logistic and linear regression with generalized estimating equations will examine the change in ART adherence from the 6 months prior, to the first three months after achieving NH long-stay status (1-year continuous enrollment). Subsequently, qualitative interviews will focus on perspectives and experiences of people living with HIV aged 50+ with regard to facilitators and barriers to ART adherence while they were a long-stay NH residents. Recruited through two organizations, interviews will be semi-structured and analyzed with NVivo software using inductive and deductive theory building through grounded theory analysis and until thematic saturation is met. Triangulation using reconciliation and initiation techniques will address discordance between quantitative and qualitative findings. The results will provide nuance beyond administrative claims data by including social determinants and life course experiences (e.g., housing instability). This work will expand Dr Mui’s skills to include Medicaid SNP data, qualitative and mixed-methods research. She will be supported by four co-mentors with expertise in geriatrics, secondary data and qualitative and mixed-methods research, and health policy, in addition to formal training through Northeastern University and related resources. This career development award will complete Dr. Mui’s skills for researching hard to reach populations thereby helping establish her as an independent researcher and leader in HIV and aging. It will also be foundational to future R01 research to analyze healthcare utilization and health outcomes associated with ART adherence in the NH.

NIH Research Projects · FY 2024 · 2022-09

PROJECT SUMMARY Engineered commensal microbes represent a promising platform for controlling microbial metabolism in the gut microbiota for therapeutic outcomes. While strains have been successfully engineered to either reduce the concentration of a toxic metabolite or produce a therapeutic one, strains capable of controlling the level of a metabolite within a narrow window have not been developed. Such ‘smart probiotics’, able to dynamically respond to the environment and either produce or consume a compound based on the local concentration, would be particularly useful for stabilizing metabolites which play a concentration-dependent role in host health and disease. For example, ulcerative colitis and Crohn’s disease have been linked to microbially produced hydrogen sulfide (H2S), with a growing consensus that low levels of this molecule have anti-inflammatory properties and support a healthy epithelium, whereas high concentrations of H2S are genotoxic, inhibit mitochondrial function and butyrate oxidation, and potentially weaken the mucosal barrier. Given that H2S concentration varies spatially and temporally throughout the mucosa, controlling H2S within a tight range is not possible with current small- molecule sulfide donors, which release sulfide regardless of local concentration. We propose a new synthetic biology-based approach to controlling microbial metabolites in situ, in which the engineered microbe uses a transcription factor responsive to the metabolite of interest to dynamically balance the expression of metabolic pathways for production and consumption of the metabolite. This will produce a stable, titratable concentration in a manner analogous to a thermostat. In this proposal, we will demonstrate this technology by developing engineered strains of E. coli Nissle to dynamically control the level of H2S in situ, incorporating mathematical modeling and a human organ-chip platform into the design-built-test cycle to achieve robust and stable operation in the complex gut environment. If successful, the proposed research will establish the design rules for a novel synthetic biology control strategy applicable to many gut metabolites with concentration-dependent roles in disease, identify and mitigate host factors that impact engineered strain performance, and facilitate greater translatability of synthetic probiotics.

NIH Research Projects · FY 2025 · 2022-09

Project Summary / Abstract Alzheimer’s Disease (AD) is characterized by cognitive deficits such as memory loss, as well as deficits in the motivation that drives daily activities. These cognitive and motivational deficits are linked to widespread neuronal and synaptic atrophy, coupled with aggregated extracellular Aβ-plaque and tau deposits, and atypical neural activity across multiple frequencies. Recent work in mouse models of AD have shown that inducing gamma oscillations with a non-invasive gamma-frequency (40 Hz) light-flickering and auditory tone-stimulation regimes reduced Aβ plaques and improved spatial and recognition memory. In humans, restoring gamma-frequency activity while preserving its phase-amplitude coupling with theta-band activity are shown to recover human memory performance in older adults, and in patients with mild AD, thus offering a promising route towards a novel therapy that can prevent brain atrophy while improving cognition. Despite their recent successes, it is a major challenge to translate gamma-frequency neurostimulation from a laboratory study to a behavioral intervention. Our goal is to promote healthy neurocognitive aging using lifestyle interventions; in particular, interventions that sustainably elevate mood and reward motivated behavior while encouraging social bonding may be most promising in slowing the progression of AD. Music listening engages multiple brain networks involved in sensory processing, movement, language, attention, learning and memory, emotion and reward, and social connectedness. Music-Based Interventions (MBIs) have the potential to manage symptoms, slow disease progression, and improve quality of life. Our lab has recently shown that an eight-week MBI can increase auditory functional connectivity to the reward system. Here we propose to test a novel protocol for music-based brain stimulation, gamma-MBI: gamma-light stimulation that automatically adapts to music-based intervention. Harnessing the fact that music listening is an intrinsically rewarding activity, we propose to use music as a carrier for gamma sensory stimulation. As music contains theta-band acoustic energy, music listening is a form of theta- band noninvasive brain stimulation. We will test and refine a novel brain-stimulation tool using gamma-frequency lights coupled with self-selected music for a gamma-music-based intervention for participants with mild Alzheimer’s Disease. Results will yield a gamma-stimulation protocol that reliably influences brain activity (Aim 1), is adaptive, motivating and rewarding to use (Aim 2), and will generate predictions as to who might benefit the most from gamma-MBI (Aim 3). By bridging the gap between neurostimulation and behavioral intervention by combining music therapy with gamma-band neurostimulation, the present project aims to find a sustainable intervention that delays the progression of AD. Our team is uniquely qualified to address all aspects of this innovative and ambitious project.

NIH Research Projects · FY 2025 · 2022-09

ABSTRACT Locally-acting rectal and vaginal semi-solid products have been widely used for the treatment of diseases and disorders in the rectum and vagina (and/or cervix) over the past few decades. Despite their prevalence, the development and approval of generic versions of these drug products have remained difficult due to the complexity of these products as well as the challenges of conducting bioequivalence (BE) studies with clinical pharmacodynamic (or pharmacokinetic) endpoints. The main objectives of the project are to: 1) identify critical quality attributes (CQA’s) of a variety of semi-solid dosage forms (such as suppositories with/without a gelatin coating and creams) that are common for rectal and vaginal administration; 2) develop in vitro performance test methods and method validation strategies that are unique for these rectal and vaginal products; and 3) elucidate drug permeation mechanisms across the rectal and vaginal mucosal membranes. The proposed research builds upon our previous research on the comparative product characterization and method development and validation of in vitro performance tests (such as in vitro release test (IVRT) and in vitro permeation test (IVPT)) for rectal suppositories and vaginal creams. Miconazole nitrate that is commercially available in a variety of vaginal dosage forms (i.e., suppository with/without a gelatin coating, cream) and mesalamine will be used as the model drugs. Comprehensive characterization of relevant physicochemical and structural properties of a variety of semi-solid dosage forms prevalent for rectal and vaginal administration will be conducted. The quality-by-design (QbD) principles will be implemented to identify CQA’s as well as the key material and processing parameters that can affect the CQA’s and in vitro product performance for a variety of topical rectal and vaginal semi-solid dosage forms. In vitro permeation behavior of a variety of topical semi-solid dosage forms and drugs (e.g., hydrophilic vs. hydrophobic) will be investigated using both animal and human tissues to elucidate drug permeation mechanisms across the mucosal membranes. Lastly, a pilot study on expanding physiologically based pharmacokinetic (PBPK) modeling to support BE assessment of locally-acting rectal and vaginal drug products will be conducted. It is expected that a comprehensive understanding of the CQA’s and their relationship to material and processing differences will be provided for a variety of topical semi-solid dosage forms. Moreover, robust and sensitive in vitro performance test methods and method validation strategies that are unique for rectal and vaginal products will be developed. The proposed research will support the establishment of in vitro comparative product characterization-based BE approaches that are suitable for locally-acting rectal and vaginal semi-solid drug products, thus facilitating the development of generic versions of these drug products and helping advance the regulatory review and approval processes for both innovator and generic drug products. This will ultimately increase the public access to high quality and affordable topical rectal and vaginal medication.

NIH Research Projects · FY 2024 · 2022-09

Project Summary Targeted Neural Text Summarization of Electronic Medical Records to Improve Imaging Diagnosis Electronic health records (EHRs) contain a wealth of patient information that might inform diagnostic and therapeutic decision-making. However, much of this information is unstructured (i.e., free-text). This makes it difficult to find the few relevant notes that might inform a given decision amongst lengthy patient records, in turn rendering key information buried within EHR practically inaccessible to domain experts operating under time constraints. Consequently, clinical decisions are often made without the benefit of all available data. We propose to design, train, and deploy novel natural language processing (NLP) models that provide extractive summaries of the free-text data within EHR conditioned on particular queries; the intent is for such models to aid diagnosis and decision-making. We also propose to use these models to try and counteract the cognitive biases that domain experts bring to clinical practice. We focus specifically on the important and illustrative area of radiology, although the approach will generalize to other specialties. Radiologists performing imaging diagnosis do not have adequate time to carefully read through patient histories stored within EHR; they must instead make do with limited background information when interpreting imaging. We will build on our preliminary on models that summarize textual evidence extracted from EHR that might support particular hypothesized diagnoses. We envision an interactive system in which this model is used by the radiologist to surface textual evidence that supports different potential conditions that might be suggested by the imaging. Radiologists (and other domain experts) rely on heuristics — type 1 thinking — when making decisions under time constraints. This results in various cognitive biases influencing diagnoses, and these have been shown to be the source of a significant fraction of diagnostic errors in radiology. We propose a novel secondary use of the NLP models to be developed for this project as a means of counteracting these cognitive biases. Specifically, once the radiologist has indicated an initial potential diagnosis via a natural language query, we will automatically present a few alternative plausible diagnosis and summaries of the extracted evidence supporting these (alongside the summary of evidence relevant to the initial query). These alternative diagnoses will be gleaned from gamuts or published lists of differential diagnoses, and we will re-rank them in order of their predicted probability for the current patient according a trained machine learning model. We will evaluate the proposed models in practice at Brigham and Women's Hospital, and assess the degree to which integrating automatically generated summaries actually affects clinical decision-making at point of care.

NIH Research Projects · FY 2025 · 2022-09

Abstract We are experiencing an antimicrobial resistance crisis (AMR), a direct result of a decline in antibiotic discovery. The WHO designated a list of priority pathogens, and of these, MDR Gram- negative Enterobacteriaceae (E. coli, S. typhimurium, Klebsiella pneumoniae, Enterobacter), Pseudomonas aeruginosa, and Acinetobacter baumannii) are of “critical priority”. These pathogens are the focus of the present proposal aimed at developing a platform for efficient discovery of novel antimicrobials. The field once enjoyed a golden era of discovery, fueled mainly by screening of soil actinomycetes. All major classes of broad-spectrum antibiotics active against Gram-negative pathogens were discovered by the 1960s. Overmining of actinomycetes resulted in the collapse of the discovery platform. Novel antibiotics discovered since then only act against Gram-positive species. We developed methods to access a broader range of bacteria, with a focus on uncultured species that make up 99% of total biodiversity. A number of novel compounds came from this source, including teixobactin, representing a new class of cell- wall acting compounds without detectable resistance (Ling et al., 2015). Teixobactin is undergoing IND-enabling studies; it is also a narrow-spectrum compound. We propose to develop a platform for efficient discovery of novel antimicrobials. The main problem is the enormous background of toxic, and to a lesser extent, known compounds. We hypothesize that the bottleneck of dereplication can be resolved by differential screening that detects the presence of a promising compound prior to dereplication. Using this approach, we recently discovered darobactins that have a novel scaffold and target the essential outer membrane protein BamA (Imai et al., 2019), and several additional novel compounds. In the proposed project, we will develop an ultra-high throughput screen based on encapsulating producing bacteria together with different fluorescently labeled reporters in microdroplets created in a microfluidics device. Our preliminary data show that sorting droplets can be performed at a rate of 106 a day, and leads to detection of producers of desirable antimicrobials. We will evaluate several modalities of this screen, aimed at discovering selective as well as broad-spectrum compounds acting against Gram-negative bacteria; and anti-persister compounds. The platform is likely to be of use to the field of antibiotic discovery. Leads that come out of this screen will be evaluated in vitro and in animal models of infection. Novel leads that come out of this project will be ready to enter IND-enabling studies.

NIH Research Projects · FY 2025 · 2022-09

This project aims to determine biological and behavioral pathways by which maternal psychosocial stress in pregnancy impacts risk for maternal and infant iron deficiency anemia (IDA). IDA is one of the most common causes of anemia worldwide, and around 20% of women in the US experience a stressful life event throughout their pregnancy. Due to the increased iron demands of pregnancy, pregnancy itself poses a significant risk of IDA. IDA increases the risk of adverse pregnancy outcomes and can negatively impact the iron status of the neonate that may cause irreversible harm to neurodevelopment. There is growing concern that oral vitamin supplementation might not be enough to counteract the risks of IDA in the context of systemic inflammation, including inflammation produced by chronic psychosocial stress and subsequent neuroendocrine dysregulation. Maternal psychosocial stress has been associated with infant iron status previously, but the potential biological mechanisms are not yet characterized despite the

NIH Research Projects · FY 2025 · 2022-08

Project Summary Bacteria employ signaling systems to sense and respond to their environment. This allows them to adjust their cellular physiology and collective behavior in response to environmental cues. One subset of these systems are the Hanks-type serine/threonine kinases and phosphatases. These signaling systems have been shown to be critical, and even often essential, for bacterial physiology, including cell growth and division, antibiotic tolerance and resistance, sporulation and germination, virulence, and biofilm formation. To accomplish this, these systems can regulate cellular function through direct post-translational modification of enzymes, or control transcription by adding an additional layer of regulation to the activity of transcription factors from other pathways. As a result, the activity of Hanks-type Ser/Thr signaling systems remains poorly understood, particularly at the single-cell level, where these systems are known to regulate the appearance of rare cells with extreme phenotypes such as increased antibiotic resistance and bacterial virulence. The long-term goal of my laboratory is to explore how these signaling systems regulate population and single-cell-level phenotypes and thereby to understand their contribution to human health and disease. To do so, we will 1) perform a mechanistic and quantitative study of conserved bacterial Hanks-type Ser/Thr kinase-phosphatase systems, focused on understanding how their regulatory architecture enables the generation of rare cells in bacterial populations with extreme phenotypes, 2) determine the role of these signaling systems in developmental transitions such as competence, biofilm formation, and sporulation. Initially we will focus on these systems in the model organism Bacillus subtilis, with the long-term goal to uncover the conserved features that can be generalized to other, less genetically tractable, and clinically important bacteria.

NIH Research Projects · FY 2026 · 2022-08

Project Summary Broad agreement exists that future epidemics will occur, better preparedness is needed for managing surges, and much should be learned from the COVID-19 pandemic. The SARS-CoV-2 virus to-date has caused over 46 million infections, 3.25 million hospitalizations, and 745,000 deaths in the U.S. alone, with regional surges of varied timing, magnitude, and duration profoundly straining healthcare capacity and impacting patient, staff, and system safety. As with other epidemics, local outbreaks and surges continuously change, often resulting in crisis management, makeshift rooming, sub-standard personal protection equipment, and rationing of limited resources. Among other needs, better real-time methods are needed to anticipate hospital, equipment, and staff capacities and shortages to allow earlier preemptive mitigation (gap). While analytic models are increasingly used, most are at the more macro policy level rather than facility-spe- cific operational level (gap), in the latter case with little known about their use in practice, accuracy, decision- making workflow, adoption, utility, and impact on operations, outcomes, and safety. In our own work, we devel- oped and widely deployed integrated models that predict facility-specific and unit-specific demand, adapt to real-time changes in these, and estimate 4-week ahead daily capacity, demand, and shortages (rooms, equip- ment, staff) within any given facility, downloaded by systems in all 50 states and 91 countries. While use of systems engineering models is well-accepted in other settings, their use, utility, and impact is significantly un- der-studied in this important context and healthcare more generally, with potentially important lessons for the future (gap). This project thus will take a multi-methods approach to (Aim 1) conduct modeling research to further refine re- sults to-date, optimize accuracy, and address identified technical needs, (Aim 2) evaluate impacts and accu- racy of the developed models on improved hospital capacity and safety under a wide range of simulated future and past surge scenarios, and (Aim 3) maximize future utility by studying how our models were used in prac- tice during COVID-19, the model adoption process, types of resulting actions, barriers to use, and user percep- tions of utility, accuracy, and model-based decision-making. The project will be led by an experienced interdis- ciplinary healthcare modeling team, working closely with varied hospital data sites and an advisory committee with expertise in patient safety, epidemic response, hospital surges, and modeling. Anticipated results include (1) validated robust models for preemptively anticipating and responding to care surges, (2) reduced unsafe hospital crisis management conditions during future epidemics, and (3) improved understanding of how to best use systems engineering models to address epidemic surges and other important public health and care deliv- ery problems.

NIH Research Projects · FY 2025 · 2022-07

PROJECT SUMMARY Functional magnetic resonance imaging (fMRI) research has transformed our understanding of human brain function and disease and is flourishing under unprecedented international funding, including dedicated support from the BRAIN Initiative. However, recent work has exposed an endemic lack of statistical power (i.e., ability to detect effects of interest) in typical fMRI studies, leading to findings that do not replicate or uncover only a small tip of the iceberg of true effects. This arises in large part because performing proper power analyses to guide fMRI study design is not straightforward. First, it is difficult to estimate expected effects based on the literature, and study sample sizes are already so small that even smaller pilot data may not yield helpful estimates. Furthermore, fMRI data and inferential algorithms are complex, yet existing fMRI power analysis tools rely on relatively limited simulations, parametric estimates, and omit the most popular inferential procedures. As a result, fMRI researchers often perform misleading power analyses or avoid power analyses altogether, missing a critical opportunity to optimally design studies to detect desired effects. To address this gap, we will create a power analysis algorithm and tool tailored for standard fMRI studies that leverages: 1) large existing datasets to define typical study effects, and 2) recently developed methods for benchmarking power of complex inferential procedures. Finally, it will be designed to provide tailored recommendations and be easy to use, thus promoting its utility to everyday researchers. In Aim 1 (K99), we will create database of effect size maps for typical study designs using large, publicly available datasets and build a web app for exploring these maps. We will use this database in Aim 2 (R00) to design a post hoc power calculator algorithm to estimate power for typical study designs. Aim 3 (R00) will refine this algorithm by creating a meta-regression model that incorporates additional study and participant factors to provide a more tailored estimate of power for an individual researcher. Finally, in Aim 4 (R00) we will create and disseminate an easy-to use web-based tool for performing the “tailored” power analysis, notably only requiring the user to specify information readily available to them. This proposal will result in the first algorithm and tool to perform an empirical power analysis for fMRI study planning, with a potential user base that includes all researchers planning an fMRI study using typical designs. This will enable researchers to more easily and accurately plan well-powered studies, thus promoting more robust and reproducible findings in the field. Furthermore, this proposal will provide training in production-ready web development, study aggregation methods, and independence-oriented professional competencies, which will facilitate my transition to an independent research career leading statistical methodology development in fMRI.

NIH Research Projects · FY 2025 · 2022-07

This T32 application, the Center for Drug Discovery “Training Program on Medications Development for Substance Use Disorder (SUD)”, is to provide broad training to PhD students and postdoctoral scientists on drug development for SUD. The Training Program rationale is driven by the socioeconomic burden and medical need associated with the lack of safe and effective medicines to treat SUD in the US and globally. The Training Program blends mentorship, coursework, and research activities in a setting with state-of-the-art facilities. The goal of training is to equip trainees to develop as productive biomedical research scientists, with consummate expertise in SUD pharmacotherapies research. The main locus of this training program is the Center for Drug Discovery (CDD) at Northeastern University that has unique technologies housed in one cohesive unit, including, high-throughput synthetic chemistry and pharmacological activity screening; mass spectrometry-based genomics, proteomics and metabolomics, as well as, bioanalytical analysis; high-resolution NMR technologies; and in vivo MRI imaging. Notably, CDD Training Program faculty includes SUD researchers at Harvard Medical School and McLean Psychiatric Hospital, as well as, at Tufts University and Medical Center. Moreover, CDD Training Program consultants include drug development scientists from the pharmaceutical and biotechnology industrial community in Boston. All participating institutions are within an 8-mile radius of each other in the metropolitan Boston area. The Training Program presents a premiere discovery and translational node to address the appalling morbidity and mortality associated with apparent lack of effective medications for opioid use disorder and complete absence of approved medications for SUD associated with cannabinoids and psychostimulants—it appears that repurposing of old drugs has not worked and the lack of novel medicines from pharmaceutical industry and federal laboratories provides strong rationale for our academic-based training program on novel medication development for SUD, with its unique multi-disciplinary, multi-institutional approach. A unique feature of the Training Program is engagement of junior faculty, including, from the Medications Development Branch of the NIDA Intramural Program, to provide for the next generation of SUD medication development scientists. Training Program faculty assist pre- and postdoctoral trainees to develop scientific integrity, collaboration, grantsmanship, and presentation skills, as well as, expertise in methodologies, including, synthetic chemistry, molecular and behavioral pharmacology, drug pharmacokinetics and metabolism, “omics” (pharmacogenomics, proteomics, metabolomics), and neuroimaging. In addition to core research ethics training, there will be ethics roundtable discussions. Some other features of the Training Program include postdoctoral–predoctoral trainee collaboration, a trainees’ seminar series, and trainee engagement with SUD scientists at the annual CDD/NIDA-sponsored symposium, Chemistry and Pharmacology of Drug Abuse.

NIH Research Projects · FY 2025 · 2022-06

SUMMARY Arteries and veins play different roles in human physiology and vascular diseases. Notably, arterial and venous endothelial cells (ECs) demonstrate distinct molecular profiles. The establishment of such molecular distinction is orchestrated by series of transcriptional programs, which have been well studied in developmental biology. However, how these EC transcriptional programs control adult blood vessel structure and function, and how to translate this knowledge into clinical application such as vein or tissue engineered graft adaptation is under- explored. To address this question, we examined the transcription profile of arterial vs. venous ECs in adult blood vessels and have identified several key transcription factors that are differentially expressed in arterial vs. venous ECs. Among them, Sox13 and Sox17 are highly expressed in adult arterial ECs but not in venous ECs. Our preliminary studies demonstrate that over-expressing Sox17 in venous ECs reconstitutes all the known arterial markers, suggesting Sox17 is a key regulator of adult arterial EC phenotypes. Importantly, Sox17 induces the expression of multiple families of molecules (Notch, Ephrin, Connexins, PDGF) that may confer signals from ECs to smooth muscle cells (SMCs) to regulate SMC phenotypes in blood vessels. EC Sox17 also promoted SMC contractile phenotype in EC-SMC co-culture and graft remodeling model. On the other hand, over-expressing Sox13 in ECs facilitates the recruitment of SMCs toward blood vessels. Based on these encouraging preliminary data, we hypothesize that endothelial Sox13/17 play synergistic roles in the homeostatic regulation of adult artery functions by maintaining adult arterial EC phenotype and engaging EC- SMC crosstalk. To test this hypothesis, we will investigate how the endothelial Sox13/17 regulates EC and SMC phenotypes and their role in blood vessel structures and functions using in vitro bioengineered models as well as in vivo animal models.

NIH Research Projects · FY 2025 · 2022-06

This proposal seeks to understand mechanisms of auditory training (AT) and potential of AT to mitigate hearing issues that promote risk of development of Alzheimer’s disease and related dementias (ADRD). Reports from the Lancet Commission (Livingstone and colleagues, 2020), and others, show midlife hearing loss is one of the greatest predictors of late-life dementia, and hearing aids protect against development of ADRD. While this has promoted a push for greater distribution of hearing aids, research from Gates and colleagues (2011) suggests that central hearing processes may be greater predictors of onset of ADRD than peripheral hearing (as addressed through hearing aids). Central auditory processing abilities are fundamental to understand speech, appreciate music, and separate competing environmental sound sources. Hearing challenges experienced with increasing age, especially understanding speech in noisy ambient environments, cause frustration with interpersonal verbal communication and detrimental long-term effects on functional independence, cognitive abilities, and overall quality of life, including increased risk for ADRD. Nevertheless, despite extensive research conducted across multiple fields, clinicians and researchers still disagree about the best ways to address the diversity of hearing difficulties individuals face throughout their lives. The guiding premise of the current proposal is the need for robust and reliable data sets to clarify the underlying mechanisms of AT and to identify the mediators and moderators that impact training outcomes. The overarching goal of this proposal is that better understanding of mechanisms of AT, with focus on speech in competition, can address the most prevalent hearing complaints reported by people as they age, and in turn mitigate transition to ADRD. To address this, we will recruit a large and diverse sample of older adults, including those with prodromal ADRD, and a comparison group of younger adults (1260 participants across training conditions, including separate samples of young and older adults). We will research how baseline cognitive and hearing measures predict training outcomes (moderators) and how these interact with training methods (mediators). To enhance rigor and reproducibility, we will release data sets and training/assessment tools to enable other researchers to conduct analyses, replicate our studies, and test their own training methods using common outcome measures. The proposed research will address four Specific Aims. Aim 1 – Determine the relationship of stimulus complexity and AT outcomes. Aim 2 – Determine the relationship of AT training structures and AT outcomes. Aim 3 – Determine relationships between participant characteristics (moderators) and AT approaches (mediators) on training outcomes. Aim 4 – Create an AT platform that facilitates faithful replication and modelling. Through the collection and dissemination of a large, unique, and comprehensive dataset, this proposal has potential for transformative impact by clarifying moderators and mediators of AT, and will afford translational opportunities to contribute to the mitigation of hearing and cognitive decline in individuals who may be at risk for the development of ADRD.

NIH Research Projects · FY 2026 · 2022-05

Project Summary/Abstract An animal’s brain consists of interconnected neurons that are responsible for processing sensory information over many timescales to guide behavior. The function of that brain is determined partially by the animal’s connectome – the topology, strength, and valence of every connection in its brain. While a draft of the whole connectome for an animal (the worm Caenorhabditis elegans) has been available for decades, recent work has found that this connectome varies dramatically through development and between individuals. It is not stereotyped as expected. We do not know how this large variability in connectivity manifests itself in brain activity through development or between individuals. Nonetheless, the single connectome an animal has must somehow be able to support every behavior that the animal may perform in a given instant. Each of these behaviors may engage overlapping portions of the brain. This project aims to leverage calcium imaging to study how whole-brain activity in C. elegans varies through development and between individuals. Our goal is to clarify precisely how large-scale structure and function are related in a simple system. To do this, we will perform whole-brain imaging with cellular resolution in a collection of behaving individual animals as they progress from newly-hatched larvae through a series of molts and turn into adults. These long-term calcium recordings will be complemented by microfluidic measurements of whole-brain responses to chemosensory cues at multiple developmental stages. Throughout this process, we will focus on the following big questions: (1) How does the activity of every neuron in a worm change through development? (2) How does brain activity vary between genetically identical individuals? (3) How are each of the above questions affected by changes in environmental context? (4) How does the relationship between brain activity and connectivity change over development, and how does it vary between individuals? If successful, this work could provide unprecedented insight into how brain function changes as an animal adds neurons, connections, and synapses. It will show how inter-individual and intra-individual variation are related to the brain’s connectome. This will have immediate value in guiding expectations about how brain activity and brain wiring are related in other model systems and humans, where direct information about wiring is less readily available.

NIH Research Projects · FY 2026 · 2022-03

Project Summary Hematogenous metastasis is responsible for a large majority of cancer-related deaths, where circulating tumor cells (CTCs) shed from the primary tumor into the peripheral blood (PB). A small number of CTCs may form secondary sites, which are extremely difficult to control clinically. Most methods for studying CTCs rely on drawing and analyzing fractionally small PB blood samples (“liquid biopsy”). Although CTCs and multicellular CTC clusters (CTCCs) have been studied for decades, little is known about their “dynamics” in vivo (transient changes in their numbers in PB), and how these may affect metastasis development and response to anti-cancer treatment. For example, it is know that radiation therapy may encourage metastatic dissemination of cancer, yet the mechanisms for this are still poorly understood. Our team recently developed a new method for in vivo enumeration of CTCs in small animals called “diffuse in vivo flow cytometry” (DiFC). DiFC uses diffuse light to detect fluorescent-protein expressing CTCs in large, deeply-seated blood vessels. DiFC can sample approximately 100 microliters of blood per minute, permitting detection of fewer than 1 CTC per mL of PB, and sampling of the entire peripheral blood volume in minutes. We previously used DiFC to study rare CTC and CTCC dissemination in mouse xenograft models. DiFC revealed that CTC numbers are highly dynamic and may change by an order-of-magnitude or more over 24 hour periods. These changes are largely missed by CTC enumeration methods that involve infrequent blood draws. The goal of this project is to build a “wearable” tethered w-DiFC instrument that will allow continuous, non- invasive monitoring of CTC numbers over extended periods in mice. The w-DiFC optical probe and signal processing design will permit data collection in freely-moving mice in ambient lighting conditions. We will first use w-DiFC to study CTC dynamics during disease development in an orthotopic xenograft and transgenic mouse model of metastasis. We will use also w-DiFC to measure continuous CTC dynamics after radiation therapy in a medulloblastoma (MB) mouse model. MB is a common form of childhood brain cancer that aggressively metastasizes to the leptomeningeal surfaces of the brain and spine via the PB. There is significant evidence that radiation may exacerbate metastasis by triggering mobilization of CTCs into the blood. We expect that the ability of w-DiFC to measure CTCs over short-, medium-, and long-term timescales will provide unique insights into this process. We will also use w-DiFC to study the use of anti-inflammatory drugs to block the pro-metastatic effect. Hence, the studies proposed here could ultimately lead to better understanding of metastasis and improved treatment protocols for childhood MB. We anticipate that the unique technologies that will be developed here will have broad application to other cancers and anti-cancer therapies in the future.

NIH Research Projects · FY 2026 · 2022-02

PROJECT SUMMARY Acute and chronic wildland fire smoke inhalation have been linked to increased mortality as well as respiratory and cardiovascular morbidity, though the extent to which the frequency and duration of exposure or the chemical and particle profiles of the smoke contribute to the observed health effects remains unknown. As the occurrences of wildland fires and number of people living at the wildland urban interface (WUI) continue to increase, prolonged inhalation of wildland fire smoke poses a serious threat to public health. Due to this, there is an urgent need to better understand the adverse cardiopulmonary outcomes associated with the exposure to wildland urban smoke. The smoke that arises from wildland fires at the WUI is a complex mixture of gases, trace metals, and fine and ultrafine particles. The latter are particularly dangerous for human health, since they deposit in the deep regions of the lungs and may translocate into the blood stream, increasing the oxidative and inflammatory burden, both locally and systemically. Prolonged inflammation can lead to the development of obstructive lung disease and atherosclerosis. To investigate the link between exposure to WUI smoke and development of cardiopulmonary dysfunction, our interdisciplinary team brings together expertise in fire generation and characterization, rodent aerosol exposures, respiratory mechanics, lung biology, and cardiovascular physiology. To fulfill our goals, we will create lab-scale smoke using materials representative of WUI regions in Southern California and we will deliver it to mice. In Aim 1, we will investigate the role of frequency and duration of the exposure, as well as particulate concentration of the wildland fire smoke. In Aim 2, we will focus on the relative contribution of different fuel sources characteristic of the WUI. Furthermore, as part of this ONES early-stage-investigator project, the PI and co-Is will generate an external advisory panel consisting of inhalation toxicology researchers, public health advocates, and fire protection experts. Dissemination of new knowledge gained from this proposal to the community will be a vital part of this endeavor.

NIH Research Projects · FY 2026 · 2022-02

PROJECT SUMMARY Poor adherence to continuous positive airway pressure (CPAP) treatment remains the single largest impediment to effective management for obstructive sleep apnea (OSA) leading to increased morbidity, mortality, and higher health care costs. Existing interventions promoting CPAP adherence focus only on the diagnosed individual and are delivered mostly by health professionals, with limited success. As supported by the findings of the PI’s R15 project, the partners of patients play a significant role – either positive or negative – in CPAP adherence, and are part of all of the major facilitative aspects and barriers to CPAP use. A dyadic approach engaging both the patient and partner to promote CPAP adherence remains an untapped opportunity. Our interdisciplinary team has developed a prototype of OurSleepKit, which is an innovative couple-focused mHealth tool to promote CPAP adherence. Guided by the conceptual framework of partner involvement in CPAP adherence, the goal of OurSleepKit is to coach mutual engagement and model positive partner involvement in CPAP treatment, thus motivating greater CPAP adherence. Responding to the PA-18- 722, the goal of this R01 project is to refine and test OurSleepKit to support adherence to CPAP treatment. We will refine and deploy OurSleepKit on an established secure mHealth platform, NUCoach. Getting users to engage with an mHealth intervention is critical to its success, and low user engagement with existing mHealth tools remains a big concern. To address this issue, we will use a participatory approach to refine OurSleepKit and comprehensively evaluate both its effect on CPAP adherence and user engagement. Specifically, we will 1) Refine OurSleepKit using qualitative methods within a standardized iterative participatory approach by working with end users (OSA patients and their partners); 2) Examine the effectiveness of OurSleepKit on CPAP adherence by conducting a 6-month randomized parallel group controlled trial in 180 couples (newly diagnosed OSA patients and their partners); and 3) Evaluate user engagement in the intervention group by tracking objective OurSleepKit usage and understanding the subjective user experience. Results of this project will support the development of an effective and engaging mHealth tool which can be readily adopted by OSA patients and their partners to support adherence to CPAP treatment. Given the frequency and depth of interaction that most patients have with their partner, OurSleepKit is likely to succeed with a sustainable effect on CPAP adherence leading to significant health benefits. If shown to be successful, OurSleepKit can be easily integrated with other interventions and existing technology to better promote CPAP use. This new mHealth intervention facilitates changing the current care of OSA from a reactive disease-focused model to a more proactive self-management model. Going beyond OSA, OurSleepKit can be an exemplar of using mHealth technology to optimize treatment adherence and self-management involving family care partners.

NIH Research Projects · FY 2026 · 2022-02

PROJECT SUMMARY Binocular vision relies on a synergy between sensory and motor fusional mechanisms that jointly construct a single percept of the environment from the differing images formed on the two retinae. A stereoscopic sensory representation of the environment is required for accurate binocular eye movements, which in turn are required for stereoscopic sensory vision. A failure in either component of this system, especially during development, can lead to permanent binocular vision impairment. Sensory impairments can include amblyopia, diplopia and suppression, oculomotor impairments can include strabismus and vergence insufficiency, while socio-economic sequelae include lost education, sport and job opportunities and elevated adverse health risks. The current treatments for amblyopia (occlusion and penalization) are primarily monocular and do not promote binocular perception or eye movement coordination. Similarly, treatments for strabismus do not typically address binocular perception. These limitations are at least partly due to a lack of practical methodologies for the assessment of sensory-motor function and partly due to a lack of coordinated sensory-motor therapies. Recent data show that there is significant plasticity in both sensory systems and motor systems, even in adults. Many groups are now exploring methods to promote sensory plasticity with digitally modified images in dichoptic games and movies, but considerably less attention has been directed to motor plasticity or sensory and motor plasticity together. We hypothesize that additional therapeutic gains and a lower risk of adverse side effects may be achieved with a combined sensory-motor therapeutic approach that is monitored by effective sensory-motor endpoints. We argue i) that the pace of commercialization of virtual reality therapies for anisometropic amblyopia intensifies the need simultaneously to understand sensory and oculomotor deficits in strabismic amblyopia and ii) that the high levels of recidivism following surgical intervention may benefit from combined sensorimotor rehabilitation. In Aim 1, we develop and evaluate efficient methods to measure sensory and motor deficits in people with binocular vision impairment and to provide a quantitative framework for evidence-based assessment of sensory-motor therapy. In Aim 2, we measure the impact across the visual field of strabismus on the three-dimensional representation of virtual and natural environments to understand how the distribution of naturally occurring depth statistics across the visual field may impact the development of binocular sensory and motor deficits and moderate their response to treatment. In Aim 3, we develop and evaluate feedback-based methods that aim to facilitate and maintain ocular alignment and examine the potential benefit of simultaneous sensory and motor interventions for binocular visual function. In each Aim, we employ both laboratory stimuli, because of their high level of control, and natural and virtual 3D scenes, because of their rich structure and relevance to real-world deficits. The overall goal is to demonstrate the theoretical foundation for combined sensory and motor therapeutic approaches to binocular visual dysfunction.

NIH Research Projects · FY 2026 · 2021-12

PROJECT SUMMARY Pediatric feeding disorders are on the rise and are present in 20-50% of typically developing children (1-8) and in 33-80% of children with developmental delay (9, 10). Furthermore, infants who are born preterm are particularly at-risk for sucking and feeding difficulties (11, 12). Early non-nutritive suck (NNS) – or sucking without nutrients being delivered – and feeding skills have been shown to be reliable indicators of central nervous system (CNS) integrity (18). In fact, delays in sucking and feeding have been reported in approximately 35-48% of infants with different types of neonatal brain injury (18). Sucking, feeding, speech, and language all develop in parallel in the first year of life and rely heavily on sensorimotor integration. However, the link between sucking and feeding skills, CNS function, and development extends beyond the neonatal period. Emerging retrospective research links neonatal sucking and feeding patterns to subsequent speech (13) and language (14-17) development in early childhood. Although these behaviors emerge on a similar timeline and share neural resources and musculature, they are rarely studied together and the links between them remain unknown. We propose a longitudinal study to sample NNS data at 3, 6, 9, and 12 months of age and speech outcomes at 12, 24, and 36 months of age across full-term (n=85) and moderate to late preterm (32-37 weeks’ gestational age; n=85) infants. The specific goals of the proposed research are as follows: (Aim 1) to establish typical patterns of NNS across infants born full-term and preterm in the first year of life and utilize a functional data analysis to examine infants’ NNS burst waveforms, and (Aim 3) to determine the ability of NNS to predict subsequent speech development across preterm and full-term infants until age three. We hypothesize that infant suck will change significantly across the first year of life with infants born premature performing worse on these measures compared to full-term infants. In addition, we hypothesize that neonatal suck will predict speech development across preterm and full-term infants. This study provides an unprecedented level of power in identifying the connection between neonatal sucking and subsequent speech emergence for several reasons: we will use our (1) innovative, custom and quantitative NNS device to sample suck across (2) two groups of infants and will (3) utilize functional data analyses to better understand NNS development and its implications for speech development later in life. (4) We will use standardized and non- standardized approaches to longitudinally study speech development, which will allow for a more robust and nuanced understanding of how NNS and speech are connected in infants and children. Overall, this project captures three years of in-depth oral motor coordination using state-of-the-art methods and collaborators to answer important theoretical questions. Results generated by this clinically relevant and theoretically driven study will create a paradigm shift in how clinicians approach feeding and speech therapies in early childhood.

NIH Research Projects · FY 2026 · 2021-12

Abstract Listeners with hearing impairment can often understand spoken language, but with increased effort, taking cognitive resources away from other processes such as attention and memory. An important challenge is therefore to understand how the brain copes with a degraded speech signal and the cognitive processes that are most critical to successful comprehension. Adult listeners with cochlear implants are a unique group in which to investigate effortful listening: They have typically adapted to auditory deprivation for a period of years of profound hearing loss, followed by some degree of hearing restoration following implantation. Following increased auditory input due to cochlear implantation, the degree to which individual listeners are able to successfully recognize speech, especially in the presence of background noise, is extremely variable. Previous attempts to explain this variability in the context of underlying patterns of brain activity have been unsuccessful, in large part because the technical challenges associated with neuroimaging in the presence of an implanted medical device have prevented adequate localization of neural responses to speech. The goal of our research is to understand the cognitive systems that support speech recognition in listeners with cochlear implants and to use knowledge about these systems to improve behavioral outcomes. We do so using converging evidence from behavioral measures and functional brain imaging. We make use of high-density diffuse optical tomography (HD-DOT), a form of optical brain imaging that produces anatomically-localized indices of regional cortical activity. We will map the brain networks supporting speech comprehension in listeners with cochlear implants, which we expect to differ from those engaged by listeners with good hearing. We will then evaluate the degree to which neural markers of effortful listening can predict individual differences in speech recognition success in the presence of background noise. Together the findings will help ground our understanding of cochlear implant-aided speech recognition in a neuroanatomically-constrained framework and develop more accurate outcome measures.

NIH Research Projects · FY 2024 · 2021-09

Project Abstract Evaluation of the school-based Healthy Relationships Project for primary prevention of child sexual abuse among children pre-K through 5th grade Child sexual abuse (CSA) is a major issue worldwide, with rigorous evidence of its magnitude and impacts on social, emotional and physical health. While interventions for the primary prevention of CSA exist, few have been rigorously evaluated. A review of school-based education programs for CSA prevention (Walsh et al., 2015) found a total of 24 trials representing 5,802 participants in both elementary and high schools across 7 countries. Findings included evidence of improvements in protective behaviors and knowledge, with limited evidence of increased odds of disclosure. None found changes in incidence/prevalence of CSA over time. The Healthy Relationships Project (HRP) created, modified and run by the organization Prevent Child Abuse Vermont, has been delivering CSA primary prevention curricula since 1990 with implementation across 30 U.S. States, including statewide in Vermont. During those decades, substantiated cases per year in Vermont dropped 61% and the number of child perpetrators per year dropped 69%. Addressing Research Priority 1, implementation of the HRP in Pre-K through 5th grade will be rigorously evaluated in a mixed-methods stepped wedge randomized trial design with 16 public charter schools in three high-need wards in Washington, DC. The School Safety Omnibus Amendment Act of 2018 was enacted to obligate DC schools to prevent and address student sexual abuse. Our partner Safe Shores, the Child Advocacy Center (CAC) for DC, has implemented HRP in public charter schools with success; the opportunity remains to conduct this trial in schools where it has not been delivered and increase its feasibility via established trust with the district and schools. Our findings about its efficacy will potentially place the HRP into the echelon of evidence-based programs that many schools seek to use, especially those mandated to deliver CSA prevention programming. Data from Safe Shores, the CAC that receives reports of suspected child abuse from all Washington, DC public schools, will be utilized as the primary outcome including the numbers and types of CSA investigations and other services provided by the CAC involving the participating schools which include forensic services, family advocacy, case management and more. More commonly utilized measures of improvements in protective behaviors, self- efficacy, knowledge and disclosure will be collected from caregivers (n=3,500) and teachers (n= 266). Qualitative research will be included to assess strengths and weaknesses of intervention rollout, fidelity monitoring, lessons learned and sustainability. This innovative and novel mixed methods evaluation study will move the science of child sexual abuse prevention research forward with a community-based participatory research partnership between scientists in family violence prevention research, professionals at community-based organizations and participating public elementary schools in high need urban areas. In summary, a rigorous experimental evaluation will be conducted of an existing universal primary prevention program with a history of 30+ years of implementation across 30 states and robust pilot data.

NIH Research Projects · FY 2022 · 2021-09

PROJECT SUMMARY The overall objective of the proposed work is to test the benefits of a music-based intervention on speech-in- competition abilities in an older adult population that includes individuals that may be at risk of Alzheimer's disease and related dementias (ADRD). Age-related hearing difficulties are prevalent, with speech-in- competition difficulties being a common challenge amongst older adults. Critically, these difficulties and frustrations often lead to social isolation and decreased cognitive engagement, and they are associated with an increased risk of developing ADRD. There is evidence suggesting that musical training is associated with cognitive advantages in older adults, including preserved ability for speech-in-competition. However, to date, there is extremely limited knowledge and lack of experimental evidence explaining how music might benefit speech-in-competition abilities, along with more basic auditory processes and/or cognitive functions. We aim to contribute to uncovering the underlying mechanisms driving the potential effects of music and attention through an innovative, attention-based music listening intervention that cultivates auditory and attentional skills akin to those developed during formal instrumental training. To disentangle potential effects of music and attention and to get at the underlying mechanisms of music effects, we will compare outcomes of this attention-based music intervention with those of two active control interventions that consist of either passive music listening or active listening to non-music sounds. Specific aims are to develop and test the feasibility of music and control interventions and assessments targeting auditory processing and cognition (R61; Aim 1); test for intervention- specific improvements in speech-in-competition using a randomized-controlled trial (R33; Aim 2); and determine whether experimental and control interventions differentially impact measures of auditory processing, memory, and attention, and test how these may mediate performance on measures of speech-in-competition (R33; Aim 3). Long-term objectives are to understand the key mechanisms underlying the benefits of music with the overall goal to inform interventions aimed at mitigating the effects of ADRD. This proposal is transformative in that it utilizes an innovative approach to uncover potential benefits and underlying mechanisms of music by testing the added benefits of interventions and testing their benefits against a broad set of outcomes measures that can be used to further understand the malleability of auditory processes and cognition in aging. In addition, the intervention is cost-effective, easily administrable, and accessible to individuals who may not possess the physical capabilities or resources that formal instrumental practice demands. In addition, music has been shown to provide other benefits including mood regulation and psychological well-being, and as such, the intervention may have benefits that go beyond the auditory or cognitive domain. Overall, the proposed work aims to contribute to the amelioration and/or prevention of cognitive decline in individuals that may be at risk for developing ADRD.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY The overall objective of the proposed work is to test the benefits of a music-based intervention on speech-in- competition abilities in an older adult population that includes individuals that may be at risk of Alzheimer's disease and related dementias (ADRD). Age-related hearing difficulties are prevalent, with speech-in- competition difficulties being a common challenge amongst older adults. Critically, these difficulties and frustrations often lead to social isolation and decreased cognitive engagement, and they are associated with an increased risk of developing ADRD. There is evidence suggesting that musical training is associated with cognitive advantages in older adults, including preserved ability for speech-in-competition. However, to date, there is extremely limited knowledge and lack of experimental evidence explaining how music might benefit speech-in-competition abilities, along with more basic auditory processes and/or cognitive functions. We aim to contribute to uncovering the underlying mechanisms driving the potential effects of music and attention through an innovative, attention-based music listening intervention that cultivates auditory and attentional skills akin to those developed during formal instrumental training. To disentangle potential effects of music and attention and to get at the underlying mechanisms of music effects, we will compare outcomes of this attention-based music intervention with those of two active control interventions that consist of either passive music listening or active listening to non-music sounds. Specific aims are to develop and test the feasibility of music and control interventions and assessments targeting auditory processing and cognition (R61; Aim 1); test for intervention- specific improvements in speech-in-competition using a randomized-controlled trial (R33; Aim 2); and determine whether experimental and control interventions differentially impact measures of auditory processing, memory, and attention, and test how these may mediate performance on measures of speech-in-competition (R33; Aim 3). Long-term objectives are to understand the key mechanisms underlying the benefits of music with the overall goal to inform interventions aimed at mitigating the effects of ADRD. This proposal is transformative in that it utilizes an innovative approach to uncover potential benefits and underlying mechanisms of music by testing the added benefits of interventions and testing their benefits against a broad set of outcomes measures that can be used to further understand the malleability of auditory processes and cognition in aging. In addition, the intervention is cost-effective, easily administrable, and accessible to individuals who may not possess the physical capabilities or resources that formal instrumental practice demands. In addition, music has been shown to provide other benefits including mood regulation and psychological well-being, and as such, the intervention may have benefits that go beyond the auditory or cognitive domain. Overall, the proposed work aims to contribute to the amelioration and/or prevention of cognitive decline in individuals that may be at risk for developing ADRD.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY This award will accelerate my long-term goal to develop microphysiological systems to improve human pharmacological efficacy with reduced toxicity and reliance on small animal models. Models of the cardiovascular system (vascular, myocardium, adrenal medulla) in vitro have primarily been limited to simplified 2D structures and have not evaluated for tissue-tissue interactions. As such, the structure/function relationships, and the cell-cell interactions driven by tissue organization and innervation remain poorly understood. Thus, MPS that recapitulates key components of the human cardiovascular system, including physiologically relevant shear flow, oxygen saturation, bioelectric stimulation, primary human endothelial, smooth muscle, cardiomyocytes, chromaffin cells, and human autonomic neurons would be a valuable tool for advancing scientific discovery, healthcare, compound screening, and biomedical research. Current MPS generally utilize specialized equipment and traditional microfabrication techniques via soft lithography with polydimethylsiloxane (PDMS), making microfluidic plumbing difficult as well as nearly impossible control of oxygen, and potential for analyte loss. Therefore, new fabrication approaches that deviate from PDMS are needed. Our approach here describes the application of a laser-fabricated, cut and assembled MPS for a fully humanized system. There is a scientific and clinical urgency for the development of new tools to identify compound toxicity and decrease new compound attrition during clinical trials. By applying my strengths in biomaterials, organ-chip design, bioelectronics, and neuroengineering, we will accelerate the development of robust 3D, instrumented MPS platforms of the cardiovascular system. A fundamental issue addressed in this project will be the ability to integrate, in a scalable platform, instrumentation for stimulation and recording of neural, adrenal, and cardiac activity to better elucidate the impact of the autonomic nervous system and compound toxicity. We will harness a statistical model to identify driving factors in cell fate, function, and identify sex-based differential responses in autonomic balance on the MPS. These innovative models will integrate recent advances in stem cell differentiation and our proven ‘cut & assemble’ fabrication method to broadly disseminate these organ platforms.

NIH Research Projects · FY 2024 · 2021-09

Exposure to early life adversity (ELA) confers significant risk for psychiatric disorders that are often unresponsive to traditional treatments. Importantly, most ELA-attributable psychopathologies involve heightened responsivity to potential threats, yet our mechanistic understanding of this susceptibility remains incipient due to insufficient knowledge about how experience, sex, and age interact to affect the development of threat-responsive circuits. Thus, this project aims to identify causal mechanisms initiated by ELA that drive heightened corticolimbic connectivity and enhanced threat responsivity. Our long-term goal is to enable translation of these findings into individualized intervention strategies. Our groups have shown that ELA leads to development of heightened anatomical (innervation) and functional (BOLD; local field potential) connectivity between the basolateral amygdala (BLA) and the prefrontal cortex (PFC) in early adolescence, as well as higher anxiety-like behaviors. Several of these effects emerged earlier in females than in males, and our preliminary findings suggest that pubertal sex hormones may impact the sex-specific development of BLA-PFC connectivity following ELA. We will therefore test the central hypothesis that ELA disruption of peri-pubertal BLA activity and hormonal signaling accelerate development of BLA-PFC connectivity in a sex-specific manner, altering PFC-regulated threat responsivity across the lifespan. Our studies will first use electrophysiological and chemogenetic approaches to reveal sex-specific critical periods of BLA activity that drive hyper-connectivity with the PFC (Aim 1), enhanced responsivity to potential threat (Aim 1), and glutamate receptivity in the PFC (Aim 2). Aim 3 will investigate a peri-pubertal neuroendocrine mechanism using RNA silencing to determine whether estrogen receptor signaling in the BLA drives hyper-connectivity to the PFC, glutamate transmission in the PFC, and heightened threat responsivity. Together, these studies will fill critical gaps in knowledge about the developmental and sex-specific nature of ELA effects on BLA-PFC circuitry and are expected to have significant impact on the development of specific targets for prevention in ELA-exposed populations.