University Of Chicago

NIH Research Projects · FY 2025 · 2023-08

PROJECT ABSTRACT (OVERALL) Our nation’s ability to detect, prevent and counter bioterrorism and emerging infectious diseases depends on technologies that are generated through biomedical research on disease-causing microbes and understanding human immune responses to infection. Following bioterrorism events in 2001, the National Institute of Allergy and Infectious Diseases established the Regional Biocontainment Laboratory (RBL) Network, to promote safe research in 12 Biosafety Level 3 (BSL3) laboratories. In turn, Institutions and Universities hosting these RBLs sustained the management of these facilities, fostered a strong Biosafety culture, and fueled research inquiries into the molecular mechanisms whereby microbes cause human disease. The University of Chicago hosts the Regional Biocontainment Howard Taylor Ricketts Laboratory (HTRL) operated by its Department of Microbiology since 2009. When this nation began to implement shutdowns to prevent the spread of COVID-19, essential professionals at the HTRL continued key management operations and pivoted their expertise to study SARS-CoV2. This momentum would not have been possible without the existing expertise and dedication of engineers, biosafety officers, veterinary staff, scientists, as well as financial support from the University. The goal of this proposal is to present a plan to maintain the safe operation and management of the BSL3 space of the Regional Biocontainment HTRL and to continue training professionals who will provide research support services for the development of measures necessary to mitigate and protect the public's health from infectious diseases that may be the result of intentional, accidental, or naturally occurring health emergency. This plan will be implemented by three cores. Core 1 Facility Management, Maintenance and Operations (C1Facilities@HTRL) led by George Langan, describes activities that support continuous BSL3 containment through decontamination, retesting, certification, preventive maintenance, repair or replacement of building systems and compliance with Biosecurity, Environmental Health, and Biosafety regulations. Core 2 BSL3 Practices (C2BSL3Practice@HTRL) led by Joseph Kanabrocki, describes activities for the training of personnel and the development of Standard Operating Procedures as well as activities to sustain a safe and secure environment. Core 3 Biocontainment Research Support Services (C3ResearchSupport@HTRL) led by Dominique Missiakas, describes research capabilities for the study of Risk Group 3 and Select Agent pathogens. HTRL will use a web-based portal to advertise and offer research services such as isolation and characterization of pathogens, virulence and countermeasure studies using in vitro and in vivo assays and animal models. Monthly virtual and annual in-person meetings between RBL Directors will identify opportunities for collaborations, improvements, and cross-training. These interactions will expand the capacity of the RBL network as a whole to respond to public health emergencies, conduct evaluations of threats and countermeasures, and provide education and training to conform with biosafety standards.

NIH Research Projects · FY 2024 · 2023-08

Urinary incontinence and lower urinary tract symptoms (UI/LUTS) are a major healthcare burden. Unfortunately, there are large disparities in knowledge, access to treatment and inclusion in research for minority women with UI/LUTS. One important disparity is the lack of access to evidence-based, non-surgical treatment options (e.g., diet and behavioral modification, weight loss and physical therapy (PT)). Minority women often to not have access to safer, conservative interventions due to poor access and insurance coverage. Additionally, UI/LUTS lead to anxiety and depression, which our preliminary studies have shown, exacerbate organic UI/LUTS symptoms. Given the barriers to accessing PT and the behavioral and mental health impacts on UI/LUTS, this project will evaluate the feasibility and efficacy of a culturally-specific, home- based, community health-worker (CHW) supported, conservative intervention for UI/LUTS. The SUPPORT intervention will include self-managed cognitive behavioral therapy (CBT), behavioral modifications and self-directed physical therapy exercises. We propose to adapt our clinician-guided CBT for UI/LUTS to a self-managed CBT curriculum supplemented with self-directed PT and behavioral retraining and support from a CHW. Our intervention will test the feasibility, efficacy, adherence and acceptability of an intervention like this is in a large, publicly funded hospital in Chicago. Over 4 years, we aim to 1) write a home CBT and PT handbook that is sensitive to patient culture and health literacy and can be followed by the patient at home over 8 weeks to improve UI/LUTS; 2) to determine the efficacy of this intervention in treating UI/LUTS and the acceptability and adherence to this program of our participants. We hypothesize that SUPPORT therapy will significantly improve UI/LUTS and will be satisfying and feasible for patients to complete.

NIH Research Projects · FY 2024 · 2023-08

PROJECT SUMMARY Substance use disorder (SUD) and HIV are synergistic epidemics (syndemics) disproportionately affecting Black Americans. Structural racism related to inadequate access to healthcare, stigma, and criminalization, especially among those with intersectional identities related to gender and sexual minorities, further exacerbate disparities in HIV and SUD outcomes. SUD is often unrecognized and untreated among PLWH. Only about half of HIV care sites routinely screen and refer to SUD treatment. In preliminary work, we found that nearly half of patients assessed in an HIV clinic waiting room met criteria for a SUD, but 65% had not been diagnosed with SUD. A promising strategy to address structural barriers to SUD screening for PLWH is use of electronic patient portals. Portals are secure websites that give patients access to health information and allow for secure messaging with providers. They are associated with improved health outcomes and patient engagement. Importantly, while most SUD screening currently occurs during clinic visits, portals can be utilized for SUD screening to reach patients who miss clinic visits, which is more common among people with HIV and SUD. Our preliminary work has demonstrated the potential of the portal for use in a population health approach to behavioral health screening, but minoritized populations are less likely to enroll in portals. Approaches are need to enhance engagement of Black PLWH for utilization of the portal for SUD screening. Beyond SUD screening, Black PLWH face structural barriers to SUD treatment, including the lack of treatment centers in communities with higher proportions of Black residents. However, a new model of treatment (Collaborative Care Model (CoCM)) integrates a social work care manager and consulting psychiatrist into the primary setting and has been shown improve SUD outcomes. CoCM for SUD could address treatment barriers related to stigma and structural racism for Black PLWH and SUD. This proposal will implement and evaluate multi-level interventions to decrease barriers to SUD screening (clinic-based, in-person) and treatment (referral-focused), a program we call ePORTAL HIV-S. ePORTAL HIV- S will be implemented at the Chicago Department of Public Health-funded South Side Health Home (S2H2), the main provider of HIV prevention and care services for Chicago’s South Side, a majority Black community disproportionately impacted by HIV and SUD. Alongside our Community Advisory Board, we propose to carry out 4 aims: 1) Design and implement a strategy to increase patient portal engagement among Black PLWH; 2) Perform a randomized controlled trial to assess effectiveness of population health vs. usual (clinic-visit) SUD screening among PLWH in an HIV clinic; 3) Implement and evaluate CoCM for SUD in an HIV clinic; and 4) Develop an implementation guide for external dissemination of ePORTAL HIV-S. Our ultimate goal is to achieve health equity in SUD screening and treatment among Black PLWH.

NIH Research Projects · FY 2025 · 2023-08

ABSTRACT The development of brain-controlled prosthetic arms promises to provide independence to people with paralysis. To date, however, Brain-Computer Interfaces (BCIs) have not conferred on users the ability to use the prosthesis to carry out activities of daily living (ADLs) with adequate reliability and flexibility. This inability can be traced back to at least three shortcomings. First, while we naturally closely coordinate arm and hand movements, current BCI users reach and grasp sequentially, in large part due to the way BCI decoders are built. Second, existing decoders use the component of the neuronal activity that has a direct and immediate relationship with motor output to infer motor intent. While this approach has been successful even for control of an anthropomorphic robotic arm and hand, it does not harness all the behaviorally relevant M1 activity. Indeed, activity that has a direct and immediate relationship with behavior – the so-called output-potent activity – constitutes only a small fraction of the total M1 activity. The remaining neuronal activity – so-called output-null activity – plays a role in generating the output-potent activity but is overlooked by standard decoding approaches. Third, while robotic hands have become increasingly sophisticated and anthropomorphic, no existing prototype approaches the functionality of a human hand, either in terms of actuation or sensorization. The goal of the proposed project is to address each of the aforementioned limitations by building more biomimetic decoders – that allow for coordinated arm and hand movements and more effectively harness M1 activity – and by challenging them in a flexible and realistic virtual reality platform. First, we will build decoding approaches that support coordinated movements of the arm and hand. To this end, we will train decoders while subjects reach to and grasp objects that differ in shape, size, and orientation, forcing significant hand orienting and pre-shaping during reaching. Second, we will further elaborate these decoders so that they leverage both output-potent and output-null activity. To this end, we will leverage recent insights into M1 dynamics and their relationship to behavior to build decoders that harness all the behaviorally relevant activity in M1. Finally, we will test novel decoders in VR by having subjects perform standard tests of arm and hand function as well as tasks that mimic complex activities of daily living and develop performance metrics for these VR scenarios. We are well positioned to achieve these objectives as part of a multi-site clinical trial on BCI with 3 subjects implanted across two locations, with existing funding for two more subjects.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY/ABSTRACT The University of Chicago (UChicago) Center for Asian Health Equity (CAHE) and the Institute for Population and Precision Health (IPPH) put forth this plan to leverage decades of experience enrolling underrepresented minorities, and especially Asian Americans, into health studies and epidemiologic cohorts as a clinic/community field site for the new NIH-funded AsA-NHPI Cohort (NAC). We plan to enroll 2,500 participants from communities in the metropolitan Chicago area with large Asian subgroup representation using a population-based sampling framework. We will specifically target South Asian, Korean, Filipino and Southeast Asians (Cambodian, Vietnamese, and Laotian) in randomized census tracts using a 2-stage sampling design. Our long-term partner, the Asian Health Coalition (AHC) has been serving as the national engagement lead for the All of Us Research Program and has set the national model for community engaged cohorts tailored to Asian inclusion. We have identified active community partners who are already supporting enrollment into a similar protocol. In this proposal, the UChicago MPIs and team enthusiastically propose a collaborative approach to meet the RFA milestones; building on prior success and experience working on national multisite cohorts with an emphasis on racial diversity, scientific rigor, and innovative approaches to improve health disparities. We suggest an approach and methods for consideration for the common protocol during the UG3 period, with full appreciation for the balance of decisions that will need to be made to ensure efficient recruitment, comprehensive yet not burdensome surveys, thoughtful clinical protocols that can be implemented in a community or in-home setting, and high-quality biospecimens processed and banked to support scientific investigation and ancillary studies. We plan to hire bilingual, bicultural individuals from the Asian community and train them to work as “community ambassadors (CAs)” during the entire study period, a model that has proven highly effective in Asian communities previously, promoting both participation and retention. We have an institutional commitment to deploy mobile medical units (MMUs) and study vans to targeted study areas at no cost to the grant to ensure that we can lower barriers to participation. We are confident that our proposed approach will allow us to meet the cohort UG3 and UH3 milestones, short-, mid- and long-term goals, and contribute significantly to this important effort in all phases.

NIH Research Projects · FY 2024 · 2023-08

PROJECT SUMMARY/ABSTRACT The University of Chicago (UChicago) Center for Asian Health Equity (CAHE) and the Institute for Population and Precision Health (IPPH) put forth this plan to leverage decades of experience enrolling underrepresented minorities, and especially Asian Americans, into health studies and epidemiologic cohorts as a clinic/community field site for the new NIH-funded AsA-NHPI Cohort (NAC). We plan to enroll 2,500 participants from communities in the metropolitan Chicago area with large Asian subgroup representation using a population-based sampling framework. We will specifically target South Asian, Korean, Filipino and Southeast Asians (Cambodian, Vietnamese, and Laotian) in randomized census tracts using a 2-stage sampling design. Our long-term partner, the Asian Health Coalition (AHC) has been serving as the national engagement lead for the All of Us Research Program and has set the national model for community engaged cohorts tailored to Asian inclusion. We have identified active community partners who are already supporting enrollment into a similar protocol. In this proposal, the UChicago MPIs and team enthusiastically propose a collaborative approach to meet the RFA milestones; building on prior success and experience working on national multisite cohorts with an emphasis on racial diversity, scientific rigor, and innovative approaches to improve health disparities. We suggest an approach and methods for consideration for the common protocol during the UG3 period, with full appreciation for the balance of decisions that will need to be made to ensure efficient recruitment, comprehensive yet not burdensome surveys, thoughtful clinical protocols that can be implemented in a community or in-home setting, and high-quality biospecimens processed and banked to support scientific investigation and ancillary studies. We plan to hire bilingual, bicultural individuals from the Asian community and train them to work as “community ambassadors (CAs)” during the entire study period, a model that has proven highly effective in Asian communities previously, promoting both participation and retention. We have an institutional commitment to deploy mobile medical units (MMUs) and study vans to targeted study areas at no cost to the grant to ensure that we can lower barriers to participation. We are confident that our proposed approach will allow us to meet the cohort UG3 and UH3 milestones, short-, mid- and long-term goals, and contribute significantly to this important effort in all phases.

NIH Research Projects · FY 2025 · 2023-08

Risk-stratified breast cancer screening strategies are a paradigm shift from the one-size-fits-all screening approach. Previous age-based screening strategies proved to be disadvantageous to specific high-risk populations, particularly BRCA1 and BRCA2 mutation carriers and individuals at high risk for aggressive interval breast cancers based on polygenic risk scores. This is an unmet clinical need as women at high risk of aggressive interval breast cancer would have a poorer long term outcome without intensive surveillance. Since joining the Women informed to screen based on measures of risk (Wisdom) Study (clinicaltrials.gov: NCT02620852) in 2020, the UChicago site has enrolled 1691 participants in Chicago. A growing number of studies have demonstrated the diagnostic equivalency of abbreviated MRI to the full MRI protocol. We launched the Chicago Alternative Prevention Study for BReast CAncer (CAPSBRACA; clinicaltrials.gov:NCT00989638) as a P20 Breast Cancer Disparities SPORE population science project to test the hypothesis that state-of-the-art genomic testing to identify women at increased risk, combined with state-of-the-art MRI techniques, could effectively detect and downstage aggressive interval breast cancers, and provide a personalized approach for management of high-risk women.  At our single Institution, 130 genomically defined higCSAYGINh-risk participants (mean age 42 SD+12) have been enrolled including 44 BRCA1, 42 BRCA2, 7 PALB2 and 25 with PRS >30%, suggesting common genetic variants can identify extremely high-risk women in practice. We have demonstrated the feasibility of our approach and the proposed study will test that it is clinically effective, adaptable, and can scale to optimize a comprehensive surveillance program for high-risk women at multiple clinical centers outside the University of Chicago. Our overall objective is to expand to additional imaging centers to broaden study sites and participants. The specific aims are to: 1) Implement biannual abbreviated MRI that includes ultrafast- DCE-MRI, with multicenter standardization; refine and expand our high-risk biannual abbreviated protocol to be fast, while both clinically accurate and generalizable across imaging facilities; 2) perform correlative science and quantitative analysis of MRI images and build an analysis package that can be disseminated to other centers; and 3) Develop and evaluate self-supervised deep learning (SSL) methods using UF DCE-MRI to enable fast and accurate computational biomarkers of breast cancer risk. CAPSBRACA translates innovative genomics and imaging research from the laboratory into meaningful clinical interventions and has the potential to address an unmet clinical need for early and accurate detection of aggressive young-onset breast cancers. It will impact the nearly 10,000 unscreened women in the US diagnosed each year with symptomatic breast cancer under 40 years of age, and the thousands of screened women at high risk of aggressive interval cancers.

NIH Research Projects · FY 2025 · 2023-08

Project Abstract Nearly 800,000 people in the United States (US) each year experience acute stroke, which remains the leading cause of adult disability and 5th leading cause of death. Despite the proliferation of stroke centers nationwide, almost half of the US population lives beyond a 60-minute drive of a comprehensive stroke center (CSC) and most patients are initially evaluated at a primary stroke center (PSC). While a key treatment, alteplase can be delivered at most US hospitals, advanced diagnostics and treatments are only available at CSCs. However, the PSC “Door-in-Door-Out” (DIDO) evaluation process for patients who need to be transferred to a CSC can be time consuming and inefficient, contributing to inability to receive treatment. Building upon our prior work to reduce PSC DIDO time, this proposal, “Implementation of a Stroke Protocol for Emergency Evaluation and Disposition (I-SPEED)” seeks to (1) Implement a novel, evidence-based, multi-component DIDO intervention in eight diverse stroke systems of care across multiple regions of the US and (2) Conduct a dual evaluation of its effectiveness in reducing median DIDO time (primary outcome) and disability (secondary outcome) and of the fidelity and quality of implementation. The I-SPEED study will definitively establish the effectiveness and generalizability of a multi-component evidence-based DIDO intervention and provide information about contextual adaptations for high-quality implementation and widespread dissemination. This study benefits from our well-established interdisciplinary expertise in stroke, emergency and prehospital medicine, systems and quality engineering, health services research, and strong multicenter research collaborations. Findings from I- SPEED will have substantial implications for a wide range of hospitals and stroke systems of care worldwide.

NIH Research Projects · FY 2026 · 2023-08

Microbial communities are complex systems whose emergent metabolic properties play a key role in determining human health. Metabolic processes enabled by host-associated microbiota play a defining role in individual health outcomes, and the emergent metabolism of microbial consortia affects environmental processes such as eutrophication, impacting human health on a global scale. Therefore, humanity would benefit from a quantitative understanding of the rules by which the genomic composition of a microbial community, and the environment in which it resides, determines its emergent metabolism. Discovering the principles by which environmental variation alters community structure and determines metabolic function is a necessity if we are to manipulate or design communities to improve health outcomes. However, this task is challenging for existing methods. In preliminary work, we establish a new quantitative framework for predicting the emergent metabolism of a bacterial community from its genomic composition using denitrification as a model metabolic process. Combining quantitative bacterial phenotyping, modeling, and a simple statistical approach we demonstrated a method that quantitatively maps gene content to metabolite dynamics in microbial communities. This insight provides a route to quantitatively connecting the genes present in a community to metabolite dynamics. The next challenge is to use this insight to understand how community function and structure depend on the environment. We propose to extend this success by understanding how environmental gradients, complexity, and dynamics impact community structure and function. We accomplish this by developing denitrification as a model metabolic process. The outcomes of the proposed work will be three-fold. First, microbiome studies have documented ubiquitous associations between environmental conditions and community composition, but we do not understand the ecological or physiological origins of these emergent patterns or their metabolic consequences. Using denitrifying communities across a pH gradient, I will show that such patterns emerge from ecological interactions. I will show that these interactions arise generically from the presence of physiological trade-offs on microbial traits, providing a generalizable route to understanding the functional impact of environmental variation on communities. Second, our preliminary study connected genomes to community metabolism for a simple metabolic pathway. I will extend this success to complex pathways and environmental conditions by constructing a method for predicting carbon utilization by communities in complex nutrient conditions directly from genomes. I will utilize a powerful blend of genome-scale metabolic modeling and multi-view machine learning, with impacts ranging from host physiology to ecosystem-scale processes. Third, I will use denitrifying communities to test the idea that, like cells and organisms, microbial communities exhibit predictive behaviors in dynamic environments. I propose that communities assembled in environments with distinct schedules of aerobic respiration and anaerobic respiration (denitrification) adapt to facilitate the prompt utilization of electron acceptors. I will test the hypothesis that community-level learning emerges from ecological interactions and distinct gene regulatory programs, providing a new conceptual lens through which we can view community adaptation to dynamic environments.

NIH Research Projects · FY 2025 · 2023-08

The role of B cells in infectious disease, autoimmunity, and allergy is critical. Modern sequencing technologies, such as single-cell RNA sequencing (scRNAseq) and spatial transcriptomics, have emerged as powerful techniques for studying the transcriptional states of individual B cells in a variety of biological contexts. These technologies generate massive amounts of complex data that necessitate use of powerful, sophisticated computational methods. The analysis of such data is hampered by numerous technical and biological biases embedded in the data. In scRNAseq, for example, the non-uniform capture of cells along some developmental trajectory, as well as the expression of multiple concurrent transcriptional programs, pose a challenge to current single cell clustering and trajectory inference methods. These biases are exacerbated when studying B cell compartments with complex dynamics, such as those found in lymphoid tissues. To address these issues, we propose a novel toolbox of algorithms for modeling B cell activity that combines prior, validated biological knowledge with computational algorithm design. In Aim 1, we develop tools to elucidate temporal B cell developmental processes. And in Aim 2, we develop tools to elucidate B cell spatial transcriptional programs. In Aim 3, apply our tools to a variety of important clinical scenarios, such as mapping the immune correlates of higher affinity antibodies and characterizing the heterogeneity observed in IBD. Overall, our research will create much-needed computational tools for analyzing immune signals in scRNAseq and spatial transcriptomics data, as well as show that incorporating prior knowledge greatly improves the ability of computational algorithms to reveal the full spectrum of immune system changes that occur in response to vaccination, infection, and immune-mediated diseases.

NIH Research Projects · FY 2025 · 2023-08

Hypertension (HTN) is a highly prevalent, chronic condition which disproportionately affects socioeconomically disadvantaged individuals and their communities. Individual- and neighborhood-level social risk factors influence the self-management and access to care essential for HTN control. Mobile health (mHealth) strategies may contribute to behavioral changes but are largely understudied in disadvantaged communities. Further, the engagement of the residents of such communities is critical for the successful development and implementation of contemporary mHealth interventions. This Mentored Patient-Oriented Research Career Development (K23) Award will investigate and develop a participant-informed, mHealth behavioral approach to individuals living in disadvantaged communities at high risk for adverse cardiovascular outcomes. Specific aims: (1) Use qualitative assessments to determine how neighborhood deprivation affects HTN control; (2) Adapt a mHealth intervention to incorporate lifestyle modifications and self-management for individuals living in adverse community settings using a validated, human-centered design (HCD) approach to adapt the intervention until we reach participant consensus; (3) Assess the adapted mHealth intervention for feasibility, as defined by acceptance, usability, and practicality in a randomized-controlled pilot study. The investigations build on and leverage the core infrastructure of an active, funded health services research program; the resources of a large, regional health care system; and expert mentorship in qualitative methods, community engagement, systems science, and clinical trials. Training goals: (1) Integrate the candidate’s prior training with new methodological tools to examine neighborhood-level social determinants of cardiovascular health; (2) Cultivate skills in community-informed cohort development; (3) Develop the methodological skills to conduct rigorous research in chronic disease behavior change; (4) Enhance grant writing, presentation, team science, and leadership skills to support the candidate’s transition to an independent investigator. As such, the career development agenda will include synergistic efforts between the candidate’s strengths and future goals. The proposal advances key objectives of the NHLBI Strategic Vision to address health disparities in disadvantaged communities and the career development of a physician-scientist. Expected results: The project will: (1) Develop and test an innovative, practical, and scalable mHealth intervention program grounded in behavioral theory and tailored for underserved communities; (2) Develop and refine a model to improve engagement and satisfaction for mHealth intervention programs using an iterative process; and (3) Collect preliminary data to inform the design of an R01 application to expand a behavioral intervention tailored for individuals residing in disadvantaged communities. The research and career development activities outlined in this proposal will enable the candidate to launch and conduct an independent research career as a future expert in community-engaged, clinically meaningful interventions to promote cardiovascular health.

NIH Research Projects · FY 2026 · 2023-08

PROJECT SUMMARY Eukaryotic trans-Golgi network (TGN) has been extensively studied for its role as the major sorting compartment and the center for terminal processing and modifications of newly synthesized proteins. While the TGN is known for its dynamic nature associated with the constant flux of traffic, whether its structures can be altered in microbe-eukaryote interactions and the subsequent consequences have remained elusive until recently. Our previous study has discovered that multiple microbial factors (e.g., bacterial antibiotics nigericin and gramicidin) are able to induce the disassembly of the TGN into vesicles. These dispersed TGN vesicles then serve as a signaling platform for the assembly and activation of the NLRP3 inflammasome. NLRP3 pathway induces proinflammatory cytokines, and its hyperactivation has been closely associated with a wide variety of human diseases, including autoimmune diseases, cancers, neurodegeneration, and metabolic disorders. Importantly, these stimuli do not affect the closely associated cis- and medial-Golgi, indicating that it is a tightly regulated reorganization event specifically targeting the TGN. Dissection of the detailed cellular and molecular basis has been challenging because these stimuli are either small molecules or nonribosomal peptides not encoded by genes. Recently, we have discovered two groups of microbial factors, i.e., pore- forming toxins from bacteria and viroporins from viruses, as highly specific TGN-dispersing stimuli. The protein nature of these stimuli has allowed us to easily track their translocation and genetically manipulate them to study the effects on TGN remodeling. In addition, we found evidence that TGN remodeling is not only important for inflammatory signaling, but also results in altered glycosylations. The ultimate goal of this MIRA R35 proposal is to use these protein microbial factors as tools to study the detailed mechanisms and functions of TGN remodeling. We will pursue three major questions: (1) What are the regions/motifs that are critical for these stimuli to remodel the TGN? Our identification of novel TGN dispersion peptide motifs will greatly facilitate future screening and identification of other TGN dispersion ligands in both microbes and eukaryotic organisms. (2) What eukaryotic factors (e.g., TGN-localized GTPases and golgin family proteins) are involved in TGN remodeling, and how conserved are their functions in other eukaryotic species such as yeast? (3) How does TGN remodeling affect various eukaryotic cellular processes, including inflammatory signaling and proteins modifications? Our proposed studies will help fill a critical knowledge gap on the mechanisms and functions of TGN remodeling, as well as providing invaluable insights into the rational design of innovative therapeutics to mitigate a wide range of human health problems.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY/ABSTRACT Millions of women worldwide have undergone mastectomy and breast reconstruction procedures. Simple (also called total) mastectomy, the most common mastectomy procedure for women with breast cancer, amputates all of the breast tissue, including the third through sixth intercostal nerves, leaving the breast numb. Loss of sensation is a distressing symptom (affecting more than 60%) that leads to major adverse effects, including elevated risk of injury, disembodiment (a feeling that the breasts no longer are part of one's body), loss of touch- based affective communication (e.g., the feel of an embrace), and loss of erogenous sensation. Mastectomy also often results in chronic neuropathic pain (25-60%), a costly and burdensome condition that standard interventions cannot reliably alleviate. Our solution, the Bionic Breast Device (BBD), combines a neural stimulation approach (successfully deployed to restore touch in bionic hands and feet in limb amputees) with a novel tissue-like stretchable sensor that detects pressure applied to the nipple-areolar complex. The BBD will trigger stimulation of intercostal nerves, evoking a sensation experienced on the otherwise insensate breast. The objective of the present Phase 0 trial is to characterize, for the first time, the sensory consequences of electrically activating the intercostal nerves that innervate the breast in women who have recently undergone a mastectomy. In this study, we will implant cuff electrodes on intercostal nerves T3 and T4 in women during their mastectomy procedure. Participants will all be women undergoing bilateral mastectomy with two stage alloplastic (implant) reconstruction for early breast cancer (unilateral in situ or T1N0, <2cm) or breast cancer risk reduction. Following a 4-6 week recovery period after mastectomy with electrode implantation, participants will undergo twice-weekly psychophysical testing sessions during which electrical stimulation will be applied to the nerves through the electrodes via percutaneous leads. Participants will have the electrodes and percutaneous leads removed during their planned second stage reconstructive surgery 12-20 weeks after mastectomy. The specific aims of this research are to: (1) Establish the parameters of electrical stimulation of the intercostal nerves that evoke perceptible and distinguishable sensations and characterize the projected fields on the body; (2) Characterize the features of the sensations evoked via activation of the intercostal nerves, including their quality and perceived naturalness; and (3) Gauge the short (during implantation) and longer-term (6 months following explantation) impact of intermittent electrical stimulation of the intercostal nerves on post-mastectomy pain. This trial will establish that touch sensation can be restored to the breast via neural stimulation. Data will also be obtained to inform future feasibility (including safety), efficacy, and acceptability trials. The Bionic Breast Project proposes enormous benefit at relatively low cost and risk and thus has the potential to be truly transformative.

NIH Research Projects · FY 2026 · 2023-08

Project summary/abstract The success of life on earth derives from its use of molecules to carry information and implement algorithms that control chemistry, allowing organisms to respond adaptively to their environment. The ability to transduce information and respond adaptively ultimately relies on molecular systems being able to selectively recognize one molecular signal from among many other similar signals. The signal could be a molecule (molecular specificity), a combination of molecules (combinatorial specificity), or a time varying concentration pattern (temporal specificity). Further, these molecular systems need to remain adaptable to switch their specificity as needed. The central goal of this proposal is to understand the molecular basis of information processing by building predictive models of molecular, combinatorial and temporal specificity and adaptability of such specificity. We will combine biophysically grounded models, information theory and dynamical systems frameworks for signaling to create data-driven models of molecular, combinatorial and temporal specificity. We will pursue questions on three scales: (1) molecular specificity: how do proteins like antibodies recognize a specific partner, such as an epitope on a viral spike protein, and yet can rapidly change its specificity through mutations? We will develop a biophysically informed machine learning-based toolbox to exploit evolutionary trajectories observed in directed evolution experiments to understand the origin of such adaptability. (2) combinatorial specificity: how do developmental pathways like BMP and TGF-beta resolve specific ligand combinations to determine cell fate, even though each ligand promiscuously binds multiple receptors? We will use an information theory framework for molecular cooperativity to build models of many-many signaling architectures and validate using cell atlas data and experiments that co-express novel combinations of receptor subunits. (3) temporal specificity: how do molecular circuits respond to specific time-varying patterns of concentrations but not others in cytokine signaling and in circadian rhythms? We will develop dynamical systems-theory guided models of stochastic resonance that allow NF-kB to respond to otherwise undetectable levels of cytokines and models of circadian clock-metabolism coupling to understand how cells buffer nutrient fluctuations. Our work is distinguished by combining biophysical models which provide understanding and insight with statistical models that are better able to leverage modern high- throughput data and provide predictive power. In addition, our inference toolboxes and related theory-experiment workflows can used by other labs for similar conceptual questions about alternate systems, such as, molecular specificity for antibodies and spike proteins, combinatorial specificity in the TGF-beta pathway or temporal specificity in EGF signaling respectively for the three thrusts above.

NIH Research Projects · FY 2024 · 2023-08

Project Summary/Abstract: This proposal describes a research and career development plan for Zhengjie Zhou, Ph.D., to transit from a postdoctoral fellow to an independent investigator position. This proposal will be based on Dr. Zhou’s past years of multidisciplinary research in nanomedicine and vascular research. Dr. Zhou will be trained at the University of Chicago by a superb advisory committee of experts who are world-renowned scientists including Dr. Yun Fang (primary mentor), Dr. Matthew Tirrell (co-mentor), Dr. Jeffrey Hubbell, Dr. Gökhan Mutlu and Dr. Glenn Randall. This proposal tests the overall hypothesis of fabricated novel lung-targeting liposomal nanoparticles to deliver therapeutic mRNA in a cell-specific manner for the treatment of acute respiratory distress syndrome (ARDS), which is the major cause of death for severe influenza and SARS-CoV-2 infection. Currently, efficient medicines are still lacking for ARDS therapy. ARDS is characterized by the dysfunction of endothelial cells (ECs), epithelial cells and the following uncontrolled cytokine storm. Based on our recent research about a vascular cell adhesion molecular-1 (VCAM1) targeting nanotherapeutic study, I rationally designed and optimized a targeting liposomal nanoparticle that enables robust mRNA delivery in vivo in a cell- specific manner. Leveraging this mRNA delivery platform, We propose to (i) promote endothelium health by endothelial cell-specific delivery of KLF2 mRNA to restore KLF2, a transcription factor, that plays a key role in facilitating endothelial health and vasculature homeostasis. KLF2 was demonstrated significantly reduced in mice lungs induced by LPS, influenza H1N1, SARS-CoV-2, and COVID-19 patients lungs; (ii) activate epithelial cells innate immune pathway by epithelium-specific delivery of 2’-5’-oligoadenylate synthetase 1 (OAS1) mRNA to augment epithelium interferon (IFN) response through OAS/RNase L pathway to defense respiratory viral infection. Our data demonstrated that KLF2 mRNA/VCAM1-targeting liposome targeted the inflamed mice lungs endothelium and significantly reduced the ARDS induced by H1N1 and SARS-CoV-2. Our preliminary data demonstrated the OAS1 mRNA/epithelium-targeting liposome targeted the mice inflamed lung epithelium and significantly reduced the H1N1 replication and lung ARDS. In this project, I will comprehensively evaluate the therapeutic potency of VCAM1-targeting liposome to restore endothelial KLF2 and lessen ARDS induced by (i) H1N1, or (ii) SARS-CoV-2 in mouse models (Aim 1, K99), and in a clinically relevant rat ARDS model induced by high-tidal ventilation (HTV) (Aim 2, K99/R00). I will determine how epithelium-targeted delivery of OAS1 activates the innate immune response and exerts antiviral effects in mice by OAS1 mRNA/epithelium-targeting liposome and will determine its therapeutic effect to treat respiratory virus induced ARDS (Aim 3, R00). Successful complete these projects will provide a promising mRNA therapeutic treating lung disease and provide an “effective responder” in viral pandemics regardless of virus evolution and mutation. This mRNA delivery platform is adaptable and potentially beneficial for various diseases treatment.

NIH Research Projects · FY 2024 · 2023-08

Summary Oral cavity squamous cell carcinoma (OCSCC), the most common subtype of head and neck squamous cell carcinoma (HNSCC), is a devastating disease, causing substantial morbidity and mortality. Consumption of alcohol and tobacco products increases the risk of OCSCC. Prevalence of human papilloma virus (HPV) infection outside of oropharyngeal cancer is low, and its significance remains debatable. Only a handful of targeted therapies are available for patients with HPV-negative HNSCC (which include many oral cavity cancers), and the 5-year overall survival remains ~50%. While strategies are being designed to improve risk assessment, detection, and therapeutic intervention, these approaches are limited by our incomplete understanding of HNSCC biology, particularly in its early development. Thus, it is crucial to identify novel targets of therapeutic interest. PDCD10 is a multifaceted protein shown to be overexpressed in several solid malignancies. It was reported that PCDC10 regulates numerous oncogenic pathways and may contribute to tumorigenesis and chemoresistance by promoting cell proliferation, anti-apoptosis, epithelial-mesenchymal transition, and inhibiting anti-tumor immune responses. Recently it was suggested that PDCD10 is involved in regulating cancer stem cells (CSCs) maintenance in breast and lung cancers. In line with these observations, our studies suggest that PDCD10 plays an important role in promoting Wnt/β-catenin mediated stem cell maintenance in small intestines. Notably, preliminary data outlined below provide strong evidence for an equivalent role of PDCD10 in HNSCC, and suggest that upregulation of its expression is an important event in neoplastic progression, posing PDCD10 as a valuable prognostic biomarker and a potential therapeutic target. While PDCD10 is being actively studied in several preclinical settings, there is limited data on its role in head and neck tumorigenesis. In this proposal we will use in vivo and organoid based preclinical models, coupled with comprehensive bioinformatics analysis of longitudinally collected primary human specimens, to evaluate the role of PDCD10 in HNSCC evolution and driving aggressive tumor cells behavior. Our project pursues three independent Aims. Specifically: Aim 1 will use mice model with inducible Pdcd10 knockout in tongue epithelia to evaluate the ability of PDCD10 depletion to inhibit oral cancerogenesis in vivo; Aim 2 will use human OCSCC organoid models to assess the ability of PDCD10 to promote CSCs survival and self-renewal; while Aim 3 will use a unique already existing RNA-Seq dataset of longitudinally collected oral dysplastic lesions and OCSCC samples to delineate key PDCD10 dependent signaling pathways that drive malignant transformation. Given the devastating nature of HPV- HNSCC and dearth of effective treatment approaches, providing new insights into the cancer driving molecular mechanisms regulated by PDCD10 and using this knowledge for developing therapeutic approaches targeting its activity may ultimately improve patient prognosis.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY Multiple myeloma (MM) affects ~35,000 adult patients in the United States and causes ~12,000 deaths each year. Novel immunomodulatory drugs and effective multidrug combinations have improved the prognosis for patients, but the vast majority of patients eventually relapse. Even among patients achieve a complete response, ~25% progress within 2 years. Most MM relapses can be attributed to the persistence of measurable (minimal) residual disease (MRD). MRD status has emerged as one of the most important prognostic markers, has therapeutic implications, and is incorporated in the International Myeloma Working Group response criteria for therapeutic response assessment. The gold standard of MRD assessment includes multiparameter flow cytometry and next-generation sequencing (NGS) based on bone marrow aspirates. However, evaluation of MRD using only bone marrow aspirates is prone to false-negatives due to patchy disease involvement, hemodilution of bone aspirate, and extramedullary disease. In addition, bone marrow biopsy is an invasive procedure, hence cannot be performed frequently to monitor MRD. Positron emission tomography/computed tomography (PET/CT) is complementary to bone marrow assessment although gaps remain. We have shown that the 5-hydroxymethylcytosine (5hmC), a stable epigenetic marks generated from active DNA demethylation, in plasma cell-free DNA (cfDNA) could be complementary to PET/CT and was associated with overall survival of patients with MM. Here we propose to apply the highly sensitive mapping of genome-wide 5hmC in cfDNA to identify the optimal combination of serial cfDNA-based 5hmC markers with PET/CT for detecting emergence of MRD. Our central hypothesis is that altered 5hmC signatures in cfDNA are associated with clinically detectable disease by PET/CT and/or NGS, thus offering opportunities for accurate yet less invasive approaches to complement bone marrow-based MRD assessment by NGS. Specifically, we propose to identify 5hmC in cfDNA associated with MRD-positivity (Aim 1), determine cfDNA-based temporal dynamics of 5hmC and fluorodeoxyglucose (FDG)-PET/CT changes associated with MRD (Aim 2), and evaluate performance of different MRD modalities in real-world patients (Aim 3). To address these aims, we have assembled an interdisciplinary team with extensive and complementary expertise. The study leverages the established resources of the UChicago Myeloma Epidemiology Study and our leadership in three clinical trials with banked serial blood samples, bone marrow-paired peripheral blood, and known MRD status by NGS. The knowledge gained from this application may improve clinical utilization of MRD in clinical decision making by proper combination of serial MRD assessments (i.e., cfDNA, PET/CT, and bone marrow) for sensitive tracking of MRD as well as provide novel insights into the epigenetic contribution to MM progression. Identifying patients at high risk of progression after successful treatment will allow for timely implementation of additional therapeutic strategies that may ultimately reduce morbidity and mortality among MM patients.

NIH Research Projects · FY 2024 · 2023-08

PROJECT SUMMARY/ABSTRACT Immune checkpoint inhibitors (ICIs) have revolutionized cancer immunotherapy but remain effective in only a subset of patients and tumor types. The successful treatment of tumors that lack T cell infiltration, known as immunologically cold tumors, remains a major roadblock in cancer immunotherapy. Tumor mutational burden has been correlated with ICI efficacy due to the abundance of neoantigens that are recognizable by the immune system after ICI. This proposal aims to enhance the visibility of multiple tumor types with low mutational burden by inducing the expression of neoantigens through RNA editing approaches. Our preliminary data in a highly aggressive, immunologically cold model of murine melanoma show that the combination of RNA editing and anti-PD-1 ICI results in a significant survival benefit over anti-PD-1 alone. We hypothesize that the induction of neoantigens enhances T cell infiltration into the tumor and promotes epitope spreading such that the immune system recognizes endogenous tumor antigens in addition to induced neoantigens. We will test this hypothesis with two specific aims. Aim 1 will elucidate the mechanism of action of this novel cancer immunotherapy through transcriptomic profiling of isolated tumor cells, analysis of tumor- infiltrating immune cells, and evaluation of the abscopal effect whereby growth of a distant tumor is suppressed following localized treatment of the primary tumor. Aim 2 will determine the generalizability of this approach to additional immunologically cold murine cancer models as well as its translation to human cancers through evaluation in multiple patient-derived tumor organoids. The successful completion of these aims would provide preclinical validation and further support the advancement of this innovative approach. This strategy has the potential to diversify the neoantigen repertoire and expand ICIs as frontline therapies in many tumor types, improving clinical outcomes for cancer patients.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY Hepatocellular carcinoma (HCC) is a lethal solid tumor that is highly dependent on recruitment of new blood vessels and has no common genomic targets. As for most solid tumors, metastasis causes a disproportionate degree of morbidity and mortality. LIN28B – an RNA-binding protein expressed in tumors and in developing tissues – is essential for HCC development and elevated LIN28B expression in HCC correlates with an increased risk of death. We recently identified LIN28B as a novel driver of pancreatic cancer metastasis and propose in Aim 1 to use an integrated series of molecular, cellular, and animal experiments to determine if HCC metastasis is driven by LIN28B. In Aim 2, I propose to couple robust co-culture (HCC cell and endothelial cell) in vitro and in vivo models to define how LIN28B expression in HCC cells modulates its effect on endothelial cells, which in turn stimulate the HCC metastatic phenotype. In Aim 3, I will utilize our expertise in novel circulating tumor cell purification/analysis technologies and computational analysis of conventional and novel tissue staining technologies to characterize the metastasis-driving and endothelial regulatory roles of LIN28B using primary human circulating tumor cell and tumor tissue specimens. Collectively, this work will provide functional rationale for the development of new therapies targeting the LIN28B pathway and linked vascular-regulatory pathways in HCC and for the development of novel matched biomarkers. The applicant, Dr. Joseph Franses, is an oncologist at the University of Chicago Cancer Center. He will spend 75% of his time performing translational research and 25% in clinical practice caring for patients with cancer. He has outlined a five-year career development plan to meet his goal of becoming an independent investigator in translational research. Dr. Franses has assembled an Advisory Committee of internationally recognized experts to provide scientific and career mentorship. He has established collaborations with experts in cancer genomics, molecular biology, tumor animal modeling, and computational biology to provide experimental advice and specific training in the field. Dr. Franses will conduct this research and leverage the exceptional research and teaching environment at the University of Chicago Cancer Center. The University of Chicago harbors an outstanding research community and has a long track record for successful mentorship of independent physician-scientists. This will be an ideal environment for successful completion of these experiments and the realization of Dr. Franses’ career goal of becoming an independent physician-scientist dedicated to improving the care of patients with gastrointestinal cancers.

NIH Research Projects · FY 2025 · 2023-08

Abstract All organisms including humans are constantly exposed to various environmental agents that cause damage to the DNA as well as other biomolecules, and thus threaten genomic integrity and cellular homeostasis, leading to the development of various diseases such as cancer. During the past few years, supported by NIEHS funding, my lab has carried out several screening studies, leading to exciting discoveries on the role of RNA modifications in DNA repair, cellular homeostasis, and tumorigenesis induced by UV irradiation and arsenic, two known carcinogenic agents. These results focus particularly on the most abundant internal mRNA methylation, N6- methyladenosine (m6A) mRNA methylation. However, the major challenge is that how environmental agents interact with the epitranscriptome in disease pathogenesis remains poorly understood. Based on the discoveries made in our published work and our unpublished findings, I propose to test this overarching hypothesis: environmental insults dysregulate the epitranscriptomic machinery and thus impair genomic integrity and cellular homeostasis, leading to tumorigenesis. The focus of my R35 application is to determine the epitranscriptomic mechanism of environmental stress response and tumorigenesis in biochemical systems, cells, and mouse xenograft/orthotopic/genetic tumor models. As the research program evolves, we will then establish the relevance of these discoveries in human samples. Furthermore, we will also expand our investigation to explore how RNA modifications are modulated by other environmental carcinogenic agents, in skin cells and in epithelial cells of other tissue origins that are targeted by these carcinogens. We will employ the novel m6A methylome sequencing technology developed by our collaborator’s lab, as well as other sequencing technologies to map the environmental epitranscriptome. In addition, we will continue to create new genetic mouse models to investigate the role of RNA modifications in environmental tumorigenesis. My broad research program will pursue the following goals: (i) establish the mechanism by which m6A RNA methylation regulates tumorigenesis following UVB radiation and arsenic exposure; (ii) discover new enzymes that regulate m6A mRNA methylation in environmental stress response and tumorigenesis; (iii) explore the roles of other RNA modifications in environmental stress response and tumorigenesis; and (iv) identify new molecules that modulate RNA modifications as probes/therapeutics. The resultant discoveries can vastly expand our knowledge to further establish the role of environmental epitranscriptomics in stress response and cancer, and open up new opportunities to develop new epitranscriptomics-based probes/therapeutics to improve prevention and therapy for cancer as well as other diseases.

NIH Research Projects · FY 2026 · 2023-08

PROJECT ABSTRACT The objective of our research is to access new chemical spaces in drug discovery and development by reimagining the catalytic conditions for electricity-driven organic transformations. We propose a synthetic platform to couple every major class of C(sp3) organic halide electrophile with aldehyde and ketones. By fine- tuning the key electrophile interactions with the electrode material by interfacial design, we propose to forge C(sp3)–C(sp3) bonds with high selectivity and stereoselectivity. Our approach will provide direct and catalytic access to new chiral alcohol and α,α-difluorobenzylic derivatives, prevalent motifs in several high-profile pharmaceuticals, from accessible feedstocks. Our synthetic methods will provide complementary and direct approaches to access (enantio)selective C(sp3)–C(sp3) bonds that are restricted to non-catalytic or multi-step reactions. Non-catalytic reactions require either the generation of highly reactive reaction intermediates that degrade bioactive functional groups or the use of expensive and rare elements that limit wide-spread adoption. In addition to increasing the accessibility to prepare and diversify pharmaceuticals via electrocatalytic C(sp3)– C(sp3) bond formation, our mechanistic and structural analyses of electrified interfaces will dissect the fundamental properties that control interfacial reactivity in complex electrosynthetic manifolds. Thus, our program will reveal how new mechanisms to construct C(sp3)–C(sp3) can be accessed by engaging a recoverable and infinitely reusable solid electrocatalyst interface; an inherently sustainable synthetic approach that can be readily adoptable by medicinal chemists.

NIH Research Projects · FY 2024 · 2023-08

Abstract Differential responses to viral infections are influenced by the genetic makeup of the host. As a result, sensitivity of humans to viral infections varies considerably, with some individuals withstanding strong viral pathogens, such as the retrovirus, human immunodeficiency virus (HIV). Studies of inherited resistance to retroviruses in human populations are enormously complicated, making it difficult to dissect strong antiviral effector mechanisms that can be taken advantage of when developing therapeutics and vaccines. However, the variations in the susceptibility of inbred mice to viral infections make the mouse an excellent model for mapping mechanisms and genes driving mammalian susceptibility and resistance to retroviruses. Exogenous mouse mammary tumor virus (MMTV) represents a well-studied model of mucosally transmitted retrovirus. The virus is acquired through the milk in the gut of suckling pups and is passed to the mammary glands by lymphocytes, where it induces mammary gland tumors after several cycles of re-infection/re-integration. Susceptibility to exogenous MMTV infection and subsequent mammary tumorigenesis differs drastically among different mouse strains, ranging from absolute resistance to high susceptibility. Mice from the MMTV-resistant YBR/Ei (YBR) strain become virus-infected, but do not develop mammary tumors, produce reduced virus titers, and efficiently eliminate the pathogen in successive generations. In our preliminary studies we found that the unique mechanism of virus control in YBR mice is unrelated to anti-virus antibodies (Abs), virus-specific CD8+ cytotoxic T lymphocytes, natural killer (NK) cells, and NK T cells, but depends on Thy1+ lymphoid cells. Moreover, the virus restriction is controlled by a single, dominant locus, which we named attenuation of virus titers (avt) and have mapped to chromosome 18. Using genetic studies and computational analyses, we will identify the gene responsible for this remarkable effector mechanism.

NIH Research Projects · FY 2025 · 2023-08

Project Summary Mobile genetic elements (MGEs) provide bacterial populations with an accessory genome, the “mobilome,” that helps them survive antibiotics, phage infections, and other stresses. Understanding the core machinery encoded by MGEs can help explain how accessory genes flow within a microbiome and can also reveal interesting new enzymes, often with potential as biotech tools. Furthermore, MGE-encoded enzymes are often simplified or modified variants of chromosomal machinery that, through comparison, can illuminate the evolution of both. Mechanistic studies of MGEs have lagged far behind the bioinformatics. Our work focuses on conserved machinery encoded by two families of staphylococcal MGEs that are of particular importance to human health: SCCs, which are chromosomal islands implicated in the MRSA epidemic, and pathogenicity islands. Our ongoing efforts have defined a set of conserved core SCC genes and assigned biochemical activities to most of them, discovering new enzymes and following the interesting questions they raised along the way. For example, we have discovered a new group of potentially anti-phage DNA glycosylases and a new type of primase that raises the question of how it evolved as well as how DNA polymerases are normally prevented from initiating DNA synthesis de novo. We also found that these MGEs encode helicases with surprising similarity to the eukaryotic and archaeal MCM helicases, but with interestingly different pathways for loading the helicase onto DNA at the origin of replication. In addition to building on the work above, we will broaden our questions to the roles of SCC-encoded machinery in phage defense, horizontal transfer, and copy number expansion. Recent advances in the field combined with our biochemical groundwork position us to mechanistically dissect the horizontal transfer of SCCs to new strains. We will also dissect the mechanism by which antibiotic resistance-carrying SCC elements can form tandem repeats to increase resistance in response to antibiotic treatment.

NIH Research Projects · FY 2024 · 2023-07

Public understanding of respiratory virus transmission and prevention is shaped by a wide range of information sources, including social media. As social media platforms play an increasingly central role in shaping health communication, it is critically important to define best practices to disseminate reliable information online. This is especially important when considering the lives of susceptible groups who may not have easy access to culturally relevant and language-concordant reputable sources. Although access to health care remains a significant barrier, access to reliable health messaging is a significant predictor of immunization against respiratory viruses. Yet, little is known about community-level differences in how narratives about respiratory virus protection emerge, how they are shared, and how they ultimately affect decision-making in favor of proven infection prevention strategies. Social media posts that include personal narratives are effective at reliably communicating health recommendations, especially those that come from a trusted peer. Therefore, communication strategies that leverage neighborhood and interpersonal relationships can prove extremely effective at health communication. Community health workers are trusted community members who serve as links between health/social services and a defined region to improve access to health services and quality of service delivery. Community health workers can diffuse reliable information in the neighborhoods they serve and can be essential to address concerns about health recommendations, increase trust, and improve health outcomes; they have been at the forefront of addressing lower rates of testing for respiratory viruses and inform decision-making to promote evidence-based immunization practices in communities with unmet health and social needs. Community health workers are uniquely positioned as trusted messengers to disseminate reliable information through strategic use of social media and principles of health communication. Dime La Verdad (Tell me the truth) is an innovative social media capacity-building program based on theoretical frameworks related to health communication that empowers community health workers to disseminate reliable information about respiratory virus protection strategies through the use of personal narratives on social media. The proposed work will use a rigorous stepped wedge design to 1) deliver a scalable program of science communicators using an adapted curriculum grounded in principles of health communication, 2) evaluate how diffusion of health messaging is perceived on social media, and 3) discern how use of personal narratives to enhance science communication can encourage informed decision-making to promote evidence-based immunization practices and improve health outcomes.

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY Certain key processes in the HIV-1 viral lifecycle are still poorly or incompletely understood. These processes include the release of the virion from infected cells, the virion maturation, and the genome packaging within the virion as it matures. These processes are highly complex, involving sequential multiprotein and nucleic acid assembly and disassembly, as well as protein-mediated membrane interactions. Computationally simulating these processes thus requires the use of both all-atom (AA) and coarse-grained (CG) molecular dynamics (MD) methods in an innovative multiscale fashion in order to access the relevant spatial and temporal scales. The Voth group will develop and carry out both AA and CG simulations to study the large viral protein complexes relevant to these important problems in the HIV-1 life cycle. The specific processes to be studied are involved in the viral release and maturation processes, specifically the proteolytic cleavage of Gag and capsid assembly within the virion (Aim 1), the virion component reorganization and ribonucleoprotein complex condensation upon maturation (Aim 2), and the latter stage dynamics of virion release from infected cells (Aim 3). The computational model development and multiscale simulation efforts will be integrated and iterated with the experimental studies of two leading experimental investigators (John Briggs and Hans-Georg Kräusslich) and one independently funded collaborator (James Hurley). These novel and powerful multiscale computer simulations – and the collaborative effort with experimentalists – will provide new insight into the dynamical aspects of HIV-1 release and maturation which are not readily accessible to the experimental (or computational) efforts alone.