University Of California, San Diego

NIH Research Projects · FY 2025 · 2024-09

Neurons are highly polarized cells that exhibit distinct moieties that serve to receive (dendrites) and transmit (axons) electrochemical signals. In a variety of neurodegenerative diseases, loss of neuronal polarity represents a hallmark of pathogenesis, and coincides with loss of the endomembrane organization in neurons. Despite a growing inventory of compartment-specific factors and machinery, we lack a fundamental understanding how neuronal polarity is established and maintained. Specifically, a vast knowledge gap exists with regard to how bulk routing of cargo is achieved in neurons. Biosynthetic cargo, such as plasma membrane receptors and channels involved in relaying the electrochemical signals between neurons, must be selectively delivered to either dendritic or axonal surfaces to support neuron function. Biosynthesis of secretory cargo in neurons occurs in the endoplasmic reticulum (ER), a compartment that extends throughout dendritic and axonal parts of the neuron. At nanoscale domains of the ER, the ER exit sites (ERES), cargo is routed via membranous carriers toward the Golgi apparatus. Golgi acceptor membranes remain near ERES, forming a 300-nm, nearly spherical interface that exhibits a high extent of long-range order. In addition to a ribbon-like Golgi in the perinuclear region of the cell soma, recently, additional Golgi elements termed Golgi outposts, or Golgi satellites, have been detected at the base of dendritic arbors – prompting the view that Golgi outposts could route cargo into the dendrite, while putatively, somatic Golgi might route cargo into the axon. In the past years, the powerful framework of biomolecular condensation has gained attention as a mechanism putatively capable of compartmentalizing cytosol and structuring membrane compartments, with proteins forming dynamic and flexible networks by the means of a liquid-liquid phase separation (LLPS). Recent evidence points to the ability of multiple proteins in the early secretory pathway to undergo LLPS – supporting the view that the early secretory pathway may be structured by self-organizing protein collectives. We will differentiate human induced pluripotent stem cells (hiPSCs) into mature cortical neurons that are stably transfected with fluorescently tagged ER-Golgi interface components as molecular ‘beacons’ to enable cryo-correlative light and elecron microscopy (cryo- CLEM) to guide cryo-focused ion beam (cryo-FIB) milling in conjunction with cryo-electron tomography (cryo- ET). Our goal is to dissect the molecular architecture of the dendritic and somatic early secretory pathway at molecular resolution in situ. This will yield an unprecedented opportunity to systematically compare the molecular composition of individual secretory hubs, and to identify the role of condensates in the organization of these critical cellular structures while revealing putative adaptations that might enable selective routing of cargo. Our approach will fill critical knowledge gaps in the organization of secretory compartments in neurons, and lead to the innovation of experimental and computational tools for the community. It will further provide a reference point for the analysis of neuron dysfunction under various neurodegenerative conditions.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Skeletal muscle exemplifies structure-function relationships in biology. The organization of sarcomeres follow hierarchical ordering to form long contractile cells, bundled in extra-cellular matrix, to form larger fascicles and ultimately whole muscles. The tight relationship between structure and function allows muscle performance (and disease) to be inferred from its microstructure. For example, fiber area is directly related to isometric force production in muscle. With injury, microstructural changes in muscle fiber area (size), fibrosis (accumulation of extracellular matrix), membrane damage (permeability), and inflammation (edema) are observed, and impair muscle function. Muscle biopsy, followed by microscopic examination of the tissue (histology), is the gold standard to diagnose and monitor muscle health and disease. This tool is invasive, requiring a large bore needle and tissue removal under sterile conditions, which makes it painful and costly. Therefore, biopsy is not conducive to serial monitoring of muscle health. It is also semi-quantitative, and often difficult to extrapolate to the entire muscle, limiting its scientific and clinical value. For these reasons, there is a need for noninvasive assessment of muscle microstructure, which would facilitate the quantitative examination of muscle injury over time. Magnetic resonance imaging (MRI) has been used to noninvasively quantify changes in volume, fat distribution, and water content in muscle. Diffusion MRI (dMRI) is a version of MRI that measures anisotropic diffusion of water, which is related to tissue microstructure. Many studies have used dMRI to measure restricted diffusion in injured skeletal muscle and have theorized how microstructure relates to diffusion. However, these relationships are not explicitly tested nor carefully validated because the necessary experiments are complicated and difficult to rigorously control. To address this gap in knowledge, the purpose of this proposal is to define the relationship between restricted diffusion and muscle microstructure assessed with classic and innovative new dMRI techniques. Our central hypothesis is that dMRI measurements can be optimized to detect small but clinically relevant changes in muscle microstructure. Aim #1 will investigate a new dMRI pulse sequence and analysis technique that has enhanced sensitivity to muscle microstructure using previously established computer simulation and 3D precision engineered models. In Aim #2, we will utilize animal models of clinically meaningful muscle injuries to evaluate sensitivity of common, less common, and novel dMRI pulse sequences to detecting microstructural differences between models. In Aim #3, we will utilize a multiparametric MRI protocol to assess diagnostic, prognostic, and functional changes associated with a clinically relevant animal model of muscular dystrophy. These experiments will elucidate the relationships between microstructure and diffusion in muscle. The long-term goal is to non-invasively, serially quantify muscle microstructure. This approach is innovative in that it combines state-of-the art imaging, simulation, nanofabrication, and physiology approaches to develop a clinically meaningful measurement tool.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY / ABSTRACT Over 700,000 individuals across the world die by suicide annually. Most individuals who complete suicide suffer from psychiatric illness, of which major depressive disorder (MDD) is most common. Suicidal ideation (SI) is more prevalent in individuals with treatment-resistant depression (TRD) compared to those who respond to treatment. Given treatment limitations of SI in TRD, novel interventions paired with an improved understanding of the neurobiology of SI are needed. Repetitive transcranial magnetic stimulation (rTMS) is efficacious for TRD. Evidence suggests that bilateral rTMS (i.e., targeting both the right and left prefrontal cortex) may be more efficacious for SI in TRD compared to unilateral rTMS, and bilateral brain disturbances are evident from neuroimaging studies in individuals with SI. Recent advances in rTMS delivery have greatly decreased treatment duration: accelerated intermittent theta burst stimulation (aiTBS) condenses 6-weeks of standard rTMS into 1- week. In fact, a unilateral form of aiTBS, the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) System, was recently approved by the FDA for the treatment of TRD. Given the efficacy of bilateral rTMS for SI, and recent advances in accelerated treatment paradigms, investigation of bilateral accelerated TBS (aTBS) for the treatment of SI in TRD is warranted. Compelling evidence suggests that SI in TRD is related to aberrant cortical inhibition bilaterally in the dorsolateral prefrontal cortex (DLPFC) and that rTMS may modulate inhibitory neurotransmission. Mechanistically, cortical inhibition is closely associated with γ-aminobutyric acid (GABA) signaling. Therefore, investigating cortical inhibition in the bilateral DLPFC in conjunction with bilateral aTBS treatment may be key to understanding treatment response. We propose to use transcranial magnetic stimulation combined with simultaneous electroencephalography (TMS-EEG) to investigate cortical inhibition as a biological target of treatment in this study (Aim 1). A randomized double-blind clinical trial will be conducted to test the hypothesis of superiority of bilateral aTBS to unilateral aiTBS on SI in TRD (Aim 2). Seventy-six participants will be recruited over 5 years. The applicant serves as Medical Director of the Interventional Psychiatry Program at UC San Diego Health, and he will facilitate appropriate recruitment of participants into this study. The career development objectives for the applicant are: 1) develop independence as a clinical trialist with relevant statistical approaches; 2) gain expertise in the conduct and analysis of TMS-EEG; and 3) establish working knowledge in MRI functional connectivity analysis to guide future rTMS protocols. The applicant’s primary mentor is the Chair of the Department of Psychiatry at UCSD, neurophysiology and clinical trial expert, Dr. Jeff Daskalakis. Dr. Greg Appelbaum, Research Director of the Interventional Psychiatry Program will serve as co-mentor. Notable consultants include Dr. Yvette Sheline, clinical trials and neuroimaging expert, and Dr. Risto Illmoniemi, pioneer of TMS-EEG. The applicant will develop the skills and gain necessary experience to become an independent interventional psychiatry physician scientist, and his work will lead to an enhanced understanding of suicide.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Cardiovascular disease affects nearly half of all American adults. Achieving cardiovascular health is associated with lower mortality and morbidity, but modifying and adhering to health behaviors such as diet and other healthy lifestyle factors remain challenges to achieving it. Additionally, there are historically marginalized communities of individuals who suffer the greatest burdens of cardiovascular disease and are in urgent need of effective, pragmatic, and culturally appropriate interventions. To address these issues, we must train the next generation of patient-oriented investigators who are rigorously mentored in cardiovascular disease epidemiology, health equity, health disparities, and translational research methods; and who are committed to doing the work with cultural humility and a global perspective. This proposal focuses on necessary steps for developing a novel comprehensive and structured mentorship and research program that will support mentees. This K24 award will provide protected time for Dr. Cheryl Anderson, a mid-career clinical investigator who has her own independent peer- reviewed research support to recruit and mentor a diverse group of trainees in clinical cardiovascular epidemiology and health equity. Dr. Anderson proposes to facilitate a training environment that is rigorous, supportive, creative, and collaborative where mentees develop their research in a manner that capitalizes on her expertise and preserves their independent lines of research. The research program she proposes will build on her current grants and support her ability to pursue developing new skills in health equity and global policy and strategy. More specifically, the award will support the building of two new areas of research: 1) integration of the science of global policy and strategy into multilevel interventions to improve cardiovascular health, and 2) development of skills to train others to be effective change agents to disrupt health inequities via the creation of an “Advocacy Laboratory.” The environment for this K24 is the University of California San Diego, a world-class institution with extensive resources to support research that is patient-oriented and integrated with research in health equity and global policy and strategy.

NIH Research Projects · FY 2026 · 2024-09

OVERALL – PROJECT SUMMARY This is a resubmission application for a new U2C/TL1, requesting support to promote high quality, collaborative training in kidney, urology, and hematology research in the San Diego area. The application represents a collaborative submission from the 3 major academic research institutions in the region inducing UC San Diego (UCSD), The Scripps Research Foundation (TSRI), and San Diego State University. This U2C/TL1 is designed to address the KUH mission areas, foster collaboration, and comprehensively address training and mentoring across the continuum of career stages. The San Diego U2C/TL1 builds upon the outstanding local resources and prior experience in pre- and post- doctoral research training. It builds upon recent successes fostering nephrology training through a T32 (2016- 2021), and recent post-doc successes at TSRI and SDSU. TSRI in an outstanding research institute, with 2 of the last 5 years’ Nobel Prizes in Chemistry, and is ranked in the top 10 for graduate training in biology and chemistry and has an outstanding track record for recruiting and training both pre- and post-doctoral scholars. SDSU offers a pool of over 30,000 undergraduate 3000 graduate students annually, with nearly 30% from under-represented minority (URM) backgrounds, and is a federally designated Hispanic serving institutions. It already has multiple joint programs with UCSD and is heavily invested in expanding pre- and post-doctoral training. UCSD is also a top 10 graduate program, offers over 6000 graduate students annually, and the only academic medical school in the region, providing a link to outstanding Departments and Divisions of Nephrology, Urology, Hematology, and other affiliated programs. With only 5 years of support, UCSD Nephrology’s T32 graduated 66% of its post-doc scholars with K-series or VA Career Development Awards (CDAs) – all of these individuals also secured faculty positions at research intensive institutions. Similar parallel successes occurred at TSRI and SDSU. These scholars came from a wide variety of disciplines but all focused on KUH research careers, demonstrating our abilities to guide young scientists to KUH research pathways. The grant is structured around 5 core pillars learned and carried forward as best practices from our recent training experiences, as we now expand our focus to hematology and urology, and across the career continuum. With highly successful and engaged TL1 faculty, pilot grants to foster collaboration across KUH disciplines, and to drive young scientists into KUH research careers, a vibrant network, substantial and well developed programs for professional development, and robust infrastructure and administrative support, this U2C/TL1 is uniquely positioned to train outstanding scientists in KUH research topics, and supply the workforce with innovative scientists making groundbreaking discoveries in KUH throughout their careers.

NSF Awards · FY 2024 · 2024-09

Although many communities across the United States seek greater access to high-quality STEM (science, technology, engineering, and mathematics) learning, sustained and well-coordinated informal STEM learning opportunities remain limited in many community-based settings. To address this need, this project establishes a planning partnership among an institution of higher education, the University of California San Diego; a nonprofit educational organization, the Teaching and Learning Collaborative; and a community-based organization, the Karen Organization of San Diego. Together, the three partners will plan and participate in a series of informal STEM learning activities in which they learn more about the strengths, lived experiences, wishes, and educational goals of the community to ensure the informal learning experiences align with their community needs. Through a series of co-design workshops and pilot activities, the partners will collaboratively develop maker-based learning experiences focused on building computer science and artificial intelligence literacy with the community members. In parallel, the project will generate a transferable framework for collaboration that documents effective strategies for planning, implementing, and studying community-driven informal STEM learning. The project will result in a widely disseminated partnership-development model that can be adapted by other community-based organizations and learning institutions seeking to expand informal STEM learning opportunities for the community members they serve. Over the long term, this work is expected to strengthen participation in STEM learning pathways among various community members, including the youth and families, across the United States. Organizations with complementary expertise will engage in joint learning activities to better understand the educational goals of the youths, caregivers, elders, and leaders of the community. Partners will collaboratively plan, implement, evaluate, and improve/refine multigenerational maker activities designed to build participants' STEM, computer science, and artificial intelligence literacies. Research will examine how community-based organizations and educational institutions form productive partnerships, establish shared decision-making processes, and sustain collaborative planning structures that support high-quality informal STEM learning. Data sources will include detailed documentation of planning meetings, reflective journals from leadership team members across all partner organizations, brief participant questionnaires, and group interviews with the community members. Inductive analyses will generate evidence-based insights into partnership development processes and informal learning design, forming the foundation for future research and practice agenda on community-driven, technology-rich informal STEM learning. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-09

The NAIRR Pilot NVIDIA DGX Cloud offering allocates research groups sizeable single-tenant clusters of DGXs for several weeks, or even months. The allocations are restricted to a single research project per cluster at any given time. The configuration offers excellent interconnect performance within the cluster and provides a scalable solution to train production-ready models faster, decreasing the time-to-insights for science researchers. It provides a unique cloud offering in that each allocated system is like a typical batch scheduled HPC system. NVIDIA provides initial support for setting up the cluster, backend maintenance of cloud resources, and with the security infrastructure encompassing it. There is a need for ongoing system monitoring, configuration changes, in-depth user support for porting and performance tuning that is provided on typical national HPC systems for research communities. This project aims to support NAIRR Pilot researchers with on boarding activities, porting of workflows, user management, cluster management, and software installs (via containers); and explores profiling and performance tuning, and data movement strategies on the single-tenant compute clusters NVIDIA is providing for NAIRR Pilot projects. This project thus provides the type of support researchers expect from a national HPC system of this kind. The goal of the project is to advance AI and scientific research at-scale by exploring system configuration, usage modalities, performance monitoring and tuning aspects on the cloud resources. The single tenant aspect allows for testing of configurations that may not be possible on a multi-tenant on-premises cluster with thousands of users. For example, some profiling tools may require settings that are typically not easily enabled on shared resources. The NVIDIA DGX cloud cluster supports the use of the enroot tool that converts container/OS images into unprivileged sandboxes enabling researchers to easily develop their customized software environment. Once a container image is finalized, it is usable on both the cloud resource and on-premises clusters enabling performance comparisons with nearly identical software stacks. The project explores data movement strategies for large datasets to/from various offsite locations with different data movement tools. This data movement work is required to support quick turnarounds for moving allocated projects on and off the DGX clusters with minimal downtimes between projects. The goal of the project is to develop usage guidelines, training and documentation for profiling and performance optimization, and optimal data movement strategies. The NVIDIA DGX Cloud provides significant hardware and software options for NAIRR Pilot projects. The project’s work enables use of these resources by a wide range of NAIRR Pilot researchers and the development of usage guidelines, documentation for profiling/performance optimizations, and data movement strategies. All of these provide impact beyond the specific NVIDIA DGX cloud clusters and simplify the use of future cloud-based systems. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY A group of neurodegenerative diseases referred to as tauopathies, which includes Alzheimer’s disease (AD), are characterized by the presence within brain neurons of inclusions comprised of hyperphosphorylated forms of tau protein. Tau is normally a microtubule (MT)-associated protein that appears to provide stability to MTs in axons, and excessive phosphorylation of tau in tauopathies promotes its disengagement from MTs and misfolding into oligomeric and fibrillar structures. This results in increased MT dynamicity, reduced MT density and altered axonal transport in transgenic (Tg) mouse tauopathy models, with evidence of similar MT deficits in AD brain that likely contribute to neurodegeneration. We previously demonstrated that administration of the brain-penetrant MT- stabilizing natural product, epothilone D (EpoD), to Tg tauopathy mice resulted in dramatic improvements in several key endpoints, including increased MT density, reduced axonal dystrophy, diminished tau pathology and a lowering of neuron loss with improved cognitive performance. Although EpoD progressed to a small Phase 1b clinical trial in AD patients, its future clinical advancement is uncertain. Thus, there would be considerable value in identifying alternative MT- stabilizing agents that could undergo more thorough testing in AD and tauopathy patients. Towards this end, we evaluated additional MT-stabilizing compounds from different classes, with the goal of identifying alternative and potentially improved candidates for development as disease-modifying drugs for AD and other tauopathies. This effort led to the identification of a preferred subset of brain- penetrant MT-stabilizing triazolopyrimidines (TPDs) that compared to EpoD and other MT-stabilizing natural products, offer notable advantages, including oral bioavailability and easier synthesis. With NIH/NIA support (U01/AG061173), a systematic exploration of the structure-activity relationships of TPDs ultimately led to the identification of a structurally novel compound (CNDR-51997) that exhibits improved MT-stabilizing activity and pharmacokinetic profile. Based on extensive characterization of this compound, including efficacy testing in two different AD mouse models, we believe that CNDR- 51997 qualifies as a candidate compound for further development. Accordingly, the primary objectives of this three-year, late-stage U01 proposal are to develop CNDR-51997 through IND-enabling studies and submit an IND application.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Looking back to move forward: The overall goal of this proposal is to examine the role of specific phenotypes, or subgroups of people based on a given characteristic, such as sex/gender, APOE4 status, baseline AD biomarker levels, or polygenic hazard scores (PHS), on response to drug or lifestyle interventions in existing Alzheimer’s disease clinical trials datasets. The precision medicine approach of understanding the role of different phenotypes such as men vs. women, APOE4 carrier vs. non- carrier, and AD polygenic hazard score in understanding Alzheimer’s risk and pathology has gained traction. There is clearer recognition of sex/gender and APOE genotype differences in tau accumulation, cognitive decline, and most recently in anti-amyloid immunotherapies. Findings from our studies began to hint at critical sex/gender and genetic differences that reside in Alzheimer’s disease risk. Additionally, our team has developed polygenic hazard scores using factors relevant to AD risk, such as sex/gender, tau PET burden, and multiple risk genotypes. With tremendous strides in advanced technology and methods for genetic analyses, plasma- based biomarkers, and harmonized brain imaging, in this proposal, we will examine the role of key factors in clinical trials outcomes by leveraging existing Alzheimer’s clinical trials datasets from the last 30 years. These clinical trials largely followed a harmonized set of outcomes focused on cognition and function, with a large subset containing neuroimaging and fluid biomarkers, both in derived and raw form. Data from 14,602 participants who were randomized to treatment or placebo will be included in this proposal. All datasets are de-identified and were collected within the guidelines of their respective institutional regulations. This sample will be augmented as more data become available from newly completed trials over the project period. Statistical models will include interaction terms for phenotype-by-arm on ADAS-Cog, PACC (Preclinical Alzheimer’s Cognitive Composite), CDR-SOB (Clinical Dementia Rating Scale Sum-of-Boxes), ADCS-ADL (Activities of Daily Living), in addition to brain MRI, PET, and plasma/CSF levels. Datasets will be analyzed individually, and collectively in meta-analyses by grouping datasets according to primary mechanism of action. All derived data from biofluids, genetics, and harmonized data will be openly shared with the scientific community as a new resource.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY. While artificial saliva products are available in the market, they need to replicate natural saliva's essential protective roles in maintaining a healthy oral environment. One of the primary reasons saliva is so beneficial is the presence of mucins, a densely glycosylated protein found in this biological fluid. Mucins in saliva serve multiple purposes: they provide lubrication during chewing and swallowing, create a protective shield against harmful acids from food and microbes, and play a pivotal role in maintaining the balance of the oral microbiome. However, mucins' intricate structures and functions still need to be fully understood. Factors such as the length of the mucin backbone, the repetitive nature of its peptide subunits, the specific types of glycan side chains attached, the density of its glycosylation, and the extent of its crosslinking all potentially influence the role of mucins in saliva. Given the pressing need for more effective artificial saliva – ideally containing mucin analogs – this project aims to create advanced mucin substitutes. This will be achieved through a cycle of informed synthesis based on testing results. The ultimate vision is to custom-design and produce artificial mucins that closely emulate the physiological functions of their natural counterparts found in human saliva. To achieve this, the project has set specific objectives: (1) Craft artificial mucins that mirror the physicochemical properties of natural salivary mucins, (2) design these mucins to offer protection against tooth demineralization, and (3) fine-tune the glycosylation patterns of these artificial mucins to ensure they interact optimally with the oral microbiome. The anticipated outcomes of this endeavor are manifold. Firstly, by incorporating these tailor-made mucin analogs into enhanced artificial saliva formulations, we can offer relief to patients afflicted with dry mouth disease. Furthermore, the insights garnered from this research can pave the way for designing artificial mucins suitable for other mucosal areas impacted by dryness. Lastly, these mucin-inspired therapeutics could serve as targeted modulators or scavenger molecules, intervening with microbial colonization in the human mouth and ensuring a healthy oral environment.

NSF Awards · FY 2024 · 2024-09

One of the great mysteries in modern astronomy is the process by which stars form. Stars can be much larger or smaller than the Sun, yet somehow all originate from the same clouds of gas and dust. In many cases, these forming stars will come in twin pairs called binary stars. It is uncertain how binary stars form, whether they are more likely to be close to each other or far apart, and if they are more likely to be "fraternal or identical". In this study, the researchers will search for new binary stars in the nearby Orion stellar nursery. They will look for binary stars that are closer to each other than Saturn is to the Sun. These close binary stars have been difficult to find in the past, and the researchers will use new techniques to discover them. The investigator seeks to motivate a wider group of students to pursue science research by creating a workshop on data science, based on their research efforts. The investigator would recruit students from underserved communities. The Orion Nebula Cluster (ONC) is an ideal laboratory for this work, as it is the nearest site of massive star formation. Previous binary star surveys of the cluster have only been sensitive to separations > 10 Astronomical Units. These surveys have found a significant decrease in multiple systems at the widest separations, in contrast to stars in the field. Using the W.M. Keck observatory, the research group will target sources in the inner ONC with high resolution, near-infrared spectroscopy coupled with adaptive optics. This work will be enhanced by the use of a laser frequency comb for precision wavelength calibration, improving radial velocity uncertainties by a factor of 10. The group will determine the fraction of very close binaries (separation < 10 AU) for the first time in the central ONC, and compare the results to both measurements in other clusters and N-body simulations. Ultimately, this research will determine whether binary star properties are universal and which processes are dominant in shaping those properties. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-09

SUMMARY Obesity-Induced Inflammatory Mediators Predict Lack of Response in Patients with Rheumatoid Arthritis Starting Biological Therapies There is an unmet need to identify predictive biomarkers in rheumatoid arthritis (RA) with respect to outcome and response to therapy. Numerous efforts to identify patients who will respond well to specific biologic agents have begun to yield profiles that might allow more personalized use of these agents, but much more work needs to be done. Given the complexity and heterogeneity of RA, it seems doubtful that a single cytokine or biomarker will be sufficient to inform the optimal choice of therapy. Instead, the inclusion of multiple biomarkers into ‘biomarker signatures’ may represent a more fruitful approach for the future of personalized therapeutic approaches. While clinical factors predicting disease outcomes are few, prior studies have highlighted strong associations between body weight and RA outcomes, although the mechanisms behind these associations are not defined. Obesity-induced inflammatory mediators include both proteins (such as adipokines) and lipids (such as fatty acid–derived bioactive lipids). Both types of obesity-induced mediators have been hypothesized to predict clinical responses in patients with RA, either by directly contributing to lack of response by promoting subclinical inflammation and disease relapse, or by describing metabolic phenotypes that may have prognostic value. Prior studies from our and other groups have described bioactive lipids disturbances in early stages of RA that are linked to therapeutic response. Additional preliminary results on samples from Comparative Effectiveness Registry to Study Therapies for Arthritis and Inflammatory (CERTAIN) cohort, revealed that distinct bioactive lipid profile (including those in the prostaglandin, leukotriene, resolvin, and eicosatrienoate pathways) was associated with response to different biologic therapies (categorized by minimal clinically important difference (MCID) in Clinical Disease Activity Index (CDAI) at 6 months after treatment initiation). Of interest, one of them, the 15-oxoEDE, which derives from eicosadienoic acid, a n-6 polyunsaturated fatty acid (PUFA) that has been associated with obesity and diabetes, was associated with both lack of response to anti-TNF therapy and obesity in the CERTAIN cohort. Taken together, our work suggests that obesity-induced inflammatory mediators profiling has the potential to identify metabolic phenotypes and effectively predict patient response to therapy prior to administration, and has also the potential to identify metabolic pathways that relate to response to biological therapies with distinct mechanisms of action.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Pulmonary arterial hypertension (PAH) is an enigmatic and morbid disease where insights are emerging regarding genetic susceptibility to disease. Genome-wide Association Studies (GWAS) have identified single nucleotide polymorphisms (SNPs) that are associated with PAH risk and severity. Yet, the GWAS-reported SNPs are only tags of haplotype SNPs in linkage disequilibrium (LD). Thus, the tag SNP may simply be linked to the true disease-causing functional SNP (fSNP). GWAS also only reveal statistical associations, and it has been challenging to define the mechanisms underlying the contribution of the PAH-associated fSNPs, which are mostly located in the non-coding regions, to the pathogenesis of PAH. Using our recently developed post-GWAS functional genomics platform, I identified a non-coding fSNP rs4738801 in the genomic locus of SOX17 gene, a known endothelial effector increasingly being studied in PAH pathogenesis. I identified that the transcription factor FUBP1 binds to the rs4738801 risk allele C in an allele-imbalanced manner, with lower affinity to risk allele C than non-risk allele G, providing an underlying mechanism how this fSNP regulates the PAH pathogenic gene SOX17 and contributes to the PAH risk. FUBP1 controls PAH-associated pathophenotypes in pulmonary arterial endothelial cells (PAECs). Downregulated by the major acquired PAH trigger hypoxia, FUBP1 and its target gene SOX17 are decreased in lungs and isolated pulmonary ECs from PAH patients and mouse models. A 3.77- fold enrichment of fSNP rs4738801 risk allele C was found in patients with PAH induced by hypoxia, supporting a pathogenic mechanism of a hypoxia-sensitive pathway (FUBP1-SOX17) combined with a disease susceptible genotype (risk allele C) for clinical manifestation of this disease. Based on these data, I hypothesize that the allele-imbalanced binding of transcription factor FUBP1 to fSNP rs4738801 defines the genomic architecture contributing to the SOX17-dependent genetic susceptibility of PAH. I further postulate that the downregulation of FUBP1-SOX17 by hypoxia contributes to the acquired pathogenesis of PAH. To test this hypothesis, I propose 2 specific aims: 1) To define the allele-specific role of fSNP rs4738801 in promoting endothelial dysfunction in PAH in gene-edited iPSC-ECs and PAH patient lung tissues; and 2) To determine the role of FUBP1 in controlling SOX17 and PAH in mouse models. Accomplishing these aims will facilitate my enduing career goal of becoming an independent physician-scientist in PAH functional genomics research. Immediate scientific development objectives include: 1) To develop expertise in PAH genetics and functional genomics; 2) To develop expertise in iPSC-EC biology and CRISPR-Cas9 gene-editing techniques; and 3) To develop skills of in vivo gene expression manipulation and become proficient in the assessment of PAH in animal models. The proposed training plan will provide me with the opportunity to expand my knowledge base to include advanced research techniques in PAH pathogenesis. The resources and expertise of my mentors, contributors, and the rich research environment at the University of Pittsburgh will assure my successful transition to an independent investigator.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract: This proposal details a 5-year plan to provide the candidate, Dr. Taha Gholipour, with the knowledge and expertise to become an independent investigator. He is a board-certified neurologist and epileptologist with research training in neuroimaging. The candidate's training will be guided by established mentors with expertise in the field of epilepsy research, functional imaging, advanced statistics and machine learning, and an advisory committee of scientists with collective expertise in clinical neuroscience and image analysis across prominent institutions. Uncontrolled seizures from epilepsy are associated with high morbidity, mortality, and cost. Current clinical and imaging predictors of response to surgery are inadequate, and surgical treatment outcomes are mixed. Predicting treatment outcome is critical for clinical decision making. Functional MRI (fMRI) offers noninvasive and accessible means for assessment of brain networks and may complement current methods of surgical planning to guide treatment. Statistical constraints from abundance of variables and data heterogeneity in fMRI analysis can be addressed by application of novel statistical and machine learning methods. The candidate will conduct a study with retrospective analysis of large multicenter datasets of resting state fMRI studies from adult and pediatric focal epilepsy patients, and a prospective arm to identify preliminary predictors of treatment response to guide future multi-site studies. The candidate will use functional anomaly mapping method to identify associations of this method with commonly used functional connectivity analysis and treatment outcomes 12 months after surgery. Post-surgical resection masks, clinical outcomes of seizure control and cognitive decline from surgery are collected in prospective arm. The goal is to identify common features in patients who become seizure-free following surgery. This study will use innovative methods to improve non-invasive evaluation of patients with refractory epilepsy, which can expand surgical candidacy for patients with or without apparent lesions on MRI. This project aims to help overcome current barriers to personalized care for people with epilepsy. The innovative use of advances statistics for solving clinical challenges in epilepsy imaging will have a fundamental impact on designing future investigations focused on developing biomarkers, predicting response to treatment, and understanding the disease mechanisms in epilepsy, as advocated by the 2021 AES/NINDS Epilepsy Research Benchmarks.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY (See instructions): Overview: Animal genomes provide instructions for producing an amazing diversity of cell types during development, perhaps especially in the brain. One of the most surprising findings in the genome-sequencing era has been how few genes there are - only about 25,000 in most animal genomes regardless of their size or complexity. How do these genes interact during development to produce the incredible diversity of cell types? What kinds of genetic changes have allowed neural cell types to be modified or to increase in number across species over evolutionary time? In order to address such questions, we propose to use the insect retina as a model to understand the genetic basis of neural cell type evolution. Insect eyes can be incredibly diverse in some ways and yet rigidly conserved in others. Compound eyes are highly recognizable given their characteristic structure. Yet these structures can vary in morphology and underlying organization in sometimes dramatic ways to help adapt insects to thrive in diverse environments around the world. For example, butterflies have expanded color vision using a more complex retinal mosaic, while house flies have a novel neural type that improves target detection and tracking. Hidden underneath the surface, mosquito eyes have dramatically rearranged and highly regionalized retinas, potentially for host and water detection. We present preliminary data which suggests that, overall, insect eye patterning is incredibly highly conserved and uses the same transcription factors and signaling pathways to define core cell types across species. This begs the question: What kinds of genetic changes underlie the dramatic differences found in some groups? How does this deeply conserved, highly organized feature evolve modified or novel functions? We will use a combination of new genomic and genetic tools such as single cell sequencing and CR IPSR/Cas9 genome editing to characterize differences across species, test the function of candidate genes directly in species of interest, and to identify and test gene regulatory regions responsible for neural cell type evolution. We will uncover how gene regulatory networks can be modified to reorganize tissues and to produce novel types of eel Is. Intellectual Merit: The Drosophila retina has been a premier model for the study of cell fate specification for many years. Now, new tools have opened the door to asking questions about how this exquisitely patterned structure evolves across species. The field is primed to understand how genetic networks specify an incredible diversity of neural fates and how changes in genome sequence shape that diversity. Our comparative approach will determine how the insect visual system has been modified over time in response to natural and sexual selection to produce new arrangements, modified functions, and novel types of neurons. Key questions include: 1) What types of genes are responsible for neural cell type evolution, and how are changes in their expression achieved? 2) How do novel neural types arise, increasing neural complexity? 3) How are deeply conserved developmental processes modified or added to without disrupting core ancestral function? 4) How do such changes influence animal behavior? We will identify fundamental principles by which processes such as cell fate specification evolve. This research will enhance our understanding of the evolution of complex traits and has broad implications for understanding how the genome encodes neural diversity and function. Broader Impacts: Using butterflies as a charismatic means of engagement, this project will enable educational activities at three levels: Citizen Science, 5th-12th graders, and undergraduate students. 1) Citizen Science research will engage dozens of regional students and adults annually in collaboration with the San Diego Botanic Garden and the UC Reserve System. This project will use group butterfly walks at the Gardens and at Scripps Coastal Reserve to survey and monitor local butterflies and investigate differences in visual function. Cataloging insect interaction in the field has inspired several projects in our lab, and community members are regular contributors to efforts aimed at rearing new species. Results of the survey will be used in conservation and resource management efforts as well as inspire science in the lab. 2) Focusing on underrepresented groups from under-resourced schools, we will introduce middle and high school students to "what it means to be a scientist" through a combination of lab and classroom visits. 3) In collaboration with the UCSD Green Initiative, an undergraduate-led effort will install a native pollinator garden on campus as a resource for student research, education, and outreach projects.

NIH Research Projects · FY 2025 · 2024-09

Because over 50% of adults in the United States take complementary and integrative health (CIH) natural products for their health, the training of CIH practitioners and scientists to produce high-quality clinical research is imperative to identifying effective products for the safety of the public. As such, this proposal requests a K24 mid-career development award to expand and support mentorship in clinical natural product research by Dr. Ryan Bradley, ND, MPH. Dr. Bradley has demonstrated effective mentorship by the publication of all past mentees, and the progression of multiple mentees from graduate students to formal NIH post-doctoral training awards, and independent training awards. Dr. Bradley is currently a co-Director of the Scholars program within the RAND REACH Center where he provides mentorship for 10 Scholars, and a Program Director and mentor in the NCCIH-funded T90/R90 Building Research across Interdisciplinary Gaps (BRIDG) clinical research training program. Additionally, Dr. Bradley provides mentorship for numerous post-doctoral trainees, including CIH clinicians and PhD scientists. Dr. Bradley is a primary mentor for a trainee in the University of Michigan HEAL K12 program; a T90 trainee who has progressed onto a KL2 award at the UW, a CIH practitioner supported by an NICCH administrative supplement to gain research experience on Dr. Bradley's R01-funded clinical trials, and two post-doctoral trainees from CIH backgrounds in the ORCCAMIND T32 program at Oregon Health & Sciences University. In addition to his position as an Associate Professor in the School of Public Health at UC San Diego, he retains affiliate and adjunct appointments at 2 US-based and 2 international universities, thus Dr. Bradley is extremely well connected to assist mentees in identifying resources and collaborators for their research. The Specific Aims of this proposal are for Dr. Bradley to: 1. Dedicate consistent effort in the mentorship of promising trainees in T32, T90, R90, K and REACH Scholar programs in order to facilitate their progression in research training and independent research (Aim 1); 2. Refine and develop mentoring skills by pursuing additional training in research mentorship and cutting-edge translational science methodologies (Aim 2); and 3. Provide exposure to translational science methods and provide publication opportunities for mentees through the collection of additional preliminary data related to recent clinical trials of specialized pro-resolvin mediators (SPM) and xanthohumol natural products, including product quality assessment, measurement of relevant biomarkers in stored biologic samples, and measurement of additional transcription factors (PCSK9) to extend the research to new clinical populations (Aim 3).

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY The tremendous diversity across human lung diseases presents significant clinical challenges, but also offers remarkable opportunities for capturing high-resolution disease mechanisms to more effectively treat these conditions. Adhering to the mission of LungMAP phase II, our Research Center has generated, curated, and made publicly available a rich array of high-quality single nucleus RNAseq and single nucleus ATACseq datasets, focusing on normal developing lung and pediatric lung diseases. In LungMAP phase III, with the extension into adult lung diseases, we will leverage our expertise on lung biology and single cell technologies to embark on direct cross-disease comparisons, a recognized bottleneck in the next-stage disease mechanism discoveries. We have assembled an interdisciplinary team with strong expertise in lung biology, pulmonology, surgery, pathology, single cell technology and computational biology, with a track record of working together within and beyond the LungMAP consortium. Guided by the scientific premise that different lung diseases can be distinguished by a finite set of signatures, we will test the hypothesis that these diseases differ in cell type/cell state composition, transcriptomic and epigenomic profiles, signaling and extracellular matrix dynamics, among other dimensions. Capturing cutting-edge technologies, we present robust preliminary data demonstrating the feasibility of using single nucleus Multiome (RNAseq and ATACseq from the same nucleus) and spatial transcriptomic MERFISH (Multiplexed Error-Robust Fluorescence in situ Hybridization) technologies on tissues procured using an ultra-low ischemia time protocol. Critical to achieving precise cross- disease comparisons, we show preliminary data demonstrating effective addition of multiplexing to these technologies, which eliminated batch effect which was the major roadblock in previous comparison efforts. We expect that the datasets that we will generate and make publicly available in LungMAP phase III will facilitate paradigm-shifting studies by the collective lung research community.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT The proposed R36 dissertation research project will identify trends and multilevel determinants of transitioning from injecting to smoking drugs (predominantly fentanyl and methamphetamine) in the San Diego- Tijuana border region to inform service delivery for people who use drugs (PWUD). People who inject drugs (PWID) face a high burden of overdose and infectious diseases (e.g., HIV, viral Hepatitis), especially in the border region where binational disease transmission and drug trafficking create challenges for prevention efforts. Some PWID in California, including San Diego, have recently shifted to smoking instead of injecting opioids. Many syringe services programs (SSPs) offer safer smoking supplies (e.g., glass pipes, silicone mouthpieces), the use of which has been linked to reduced sharing of injection and smoking equipment and the use of ‘make-shift’ supplies like plastic bottles. However, some SSPs are struggling to meet the already high and increasing demand for safer smoking supplies, especially in resource-constrained settings like Mexico. We will use a Social Ecological Model-enhanced Exploration, Preparation, Implementation, and Sustainment (SEM-EPIS) framework to identify individual- (e.g., overdose experience), interpersonal- (e.g., peer norms), community- (e.g., access to SSP services), and structural-level (e.g., city policy) determinants of transitioning from injecting to smoking heroin, fentanyl, and methamphetamine and examine internal (i.e., SSP) and external (e.g., local public health and law enforcement factors) implementation considerations for distributing safer smoking supplies. Using an explanatory sequential mixed-methods approach guided by SEM- EPIS, this dissertation will meet the following specific aims: Aim 1: (a) examine the extent to which people who inject heroin, fentanyl, and methamphetamine are transitioning to smoking and (b) identify the multilevel determinants of these transitions; Aim 2: explore experiences with and perspectives on multilevel determinants of transitioning from injecting to smoking among PWUD, including the use of safer smoking supplies; and Aim 3: investigate the internal (i.e., SSPs) and external implementation considerations for distributing safer smoking supplies in the San Diego-Tijuana border region. We will leverage the ongoing binational La Frontera cohort study (R01DA049644; n=612) and use latent transition analysis to identify PWUD with respect to patterns in the frequency (low vs. high) of injection and smoking over time and multilevel determinants of these transitions (Aim 1). We will then purposively sample ~30 PWUD and ~25 internal (i.e., SSP staff) and external key informants (e.g., public health officials) to participate in Aim 2 and 3 qualitative interviews to further contextualize and expand upon findings from Aim 1. Our proposed study will provide context around substance use trajectories for PWID to enhance the implementation and scale-up of safer smoking supplies at a time when evidence-based strategies are urgently needed to address the rising harms of injection drug use.

NSF Awards · FY 2024 · 2024-09

This project develops novel causality-guided approaches for reliable threat detection and forecasting in complex event streams. Understanding causality is crucial because it allows us to identify the true drivers behind anomalies and pinpoint critical events that will significantly impact future event streams. For instance, to swiftly adapt to extreme climate shifts, it is essential to detect unusual earth movements or severe weather patterns that causally induce these shifts. Recognizing these causal relationships enables the implementation of preemptive countermeasures and enhances long-term forecasting. Similarly, in the context of information hazards, identifying latent patterns in social media posts that causally drive the spread of misinformation is vital. Understanding these causal drivers allows for quicker assessment and recognition of future threats, making it possible to take timely and effective action to ensure public safety. Moreover, the benefits of such methods extend far beyond security applications. They can unlock mechanistic insights into scientific event streams like neural activities, enriching the collection of techniques for scientific discovery. This project opens new lines of research, expanding the domain and scope of algorithmic threat detection. Specifically, it focuses on three key research topics: (1) causal inference for observed event streams with latent confounders and nonstationarity, (2) causal representation learning for latent event streams, and (3) causal anomaly detection and long-term forecasting. Leveraging the Hawkes process model—a self-exciting point process model—the investigators will establish a formal framework to determine when and how causal links can be inferred from partially observed and potentially non-stationary event sequences. The identified causal relationships will enable comprehensive situational awareness while pinpointing anomalies and providing long-term forecasts. The mathematical theory, algorithms, and software produced through this research will be transformational. This project aims to establish a foundational understanding of causality for algorithmic threat detection, provide principled algorithms for analyzing complex event streams, and broaden the application of these methods to diverse social and scientific domains. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2024-09

TRAINING CORE – PROJECT SUMMARY The NRSA Training Core TL1 submitted here is in conjunction with the 3 cores of the U2C in this combined U2C/TL1 submission. The TL1 will recruit and support outstanding and diverse scholars training in in kidney, urology, and hematology research in the San Diego Area. The TL1 represents a collaborative submission from 3 major academic research institutions in the region inducing UC San Diego (UCSD), The Scripps Research Foundation (TSRI), and San Diego State University. After a 2-year ramp-up, the TL1 will support 10 scholars (6 pre- and 4 post-doc) annually, with at least 2 dedicated to hematology research, 2 dedicated to urology research, and at least 1 from a pediatric background. The TL1 draws upon the outstanding pool of available scholars from the 3 institutions, collectively providing a very large source of predocs with a high proportion from URM backgrounds, and leverages the state-of-theart training (including two CTSIs) offered at the 3 institutions, combined with additional sources of scholars and expertise of outstanding clinical departments in KUH. The 61 TL1 faculty members have been carefully recruited not only for their scientific expertise in KUH, but for their commitment to mentorship, and balance in regards to focus of research across KUH, basic to clinical, from across the 3 institutions, and for balance by gender and URM backgrounds, to foster a training environment with considerable breadth from all perspectives. The TL1 is led by 3 MPIs, each representing 1 of the 3 institutions, and each with substantial mentorship experience and passion for training the next generation. Preliminary data for this TL1 comes from our recent successes in training post-docs in Nephrology (with recent completion of a highly successful T32), and in multiple recent successes in developing scholars to K awards and faculty positions at all 3 institutions over the past 5 years. The TL1 now proposes to coalesce these successes into a collaborative effort, supported by the outstanding professional development, networking, and administrative support from the U2C, to continue these successes, further deepen our successes in hematology and urology specifically, and to focus on training across all career stages. The TL1 has outstanding institutional financial support to bolster training for KUH scholars above and beyond what the TL1 can provide, and we have invested heavily in developing opportunities and local grants that can facilitate transitions off of TL1 support as the scholars complete their training. Supported by these resources, the TL1 will provide Aim 4 of the overall U2C/TL1, “to provide outstanding research training in nephrology, urology, and hematology to highly talented trainees who are diverse in terms of their prior scientific and medical disciplines of training, demography, and career stage.”

NIH Research Projects · FY 2024 · 2024-09

Abstract: Current 2D in vitro monocultures and animal models fall short in accurately modeling cardiovascular genetic disorders, leading to inadequate therapeutic development. Recent advances have now centered on 3D organoid models due to their improved cellular heterogeneity. However, cardiac organoids still lack crucial structural characteristics, cell types, and cellular organization which limits their utility. While recent approaches focus on modifying morphogens, none have used mechanical cues as guides for the differentiation process. Preliminary data presented within reveal that microconfining stem cell colonies on compliant substrates facilitates cardiac organoid generation and release, with substrate stiffness and geometric asymmetry influencing the spatial organization of organoid structure. The research proposed in this fellowship will explore these findings further to develop a roadmap for engineering-in the missing structural components. By modulating matrix mechanics, we aim to replicate developmental stiffness, guiding traction stresses and cell polarization during early differentiation stages. Gradients and temporal changes of stiffness may push towards cardiac mesoderm specification via presentation of a more physiologically representative mechanical environment. Controlling local cell densities and geometric confinement may further play a role in guiding final organoid architecture and cell heterogeneity and distribution. Overall, the goal is this work is to establish a platform that can reproducibly create cardiac organoids with tunable spatial control for drug screening applications, with scope for application towards other organoid types.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY (See instructions): Intricate cellular morphology is essential for neuron function. Axons in particular form thin and extremely long cables with synaptic contacts along their length to communicate with their target neurons. This cable property of the axons allows rapid conduction of electrical signals, or action potentials, to activate synaptic communication. Traditionally, axon diameter is thought to be relatively uniform. However, recent studies suggest that axon diameter is highly dynamic and can be controlled by neuronal firing. Our preliminary data further the view of dynamic axon morphology by revealing that axons are not simple cylindrical tubes, but rather exhibit peals-on-a-string morphology between synaptic varicosities. This structure is reminiscent of lipid bilayer pearling, generated through a tension-driven instability. In support of this, in silico modeling suggests that axon pearling depends on membrane mechanics such as bending modulus and tension. In fact, axon pearling is lost when hyperosmotic solution is applied, while it is exacerbated in hypoosmotic conditions. Thus, pearled axon morphology is tightly coupled to the biophysical properties of membranes. Two of the major determinants of membrane mechanics are lipid composition and cytoskeletal structure. Importantly, lipid composition and cytoskeletal structure also control the localization of transmembrane proteins such as voltage-gated sodium and potassium channels, essential for action potential firing. Therefore, membrane properties likely regulate both axon morphology and function. In this proposal, we will test this hypothesis by 1) determining the contribution of lipid composition and cytoskeletal structure to the axon morphology, channel localization, and action potential firing, and 2) determining how these factors change with plasticity induced by repetitive neuronal firing. Since many factors controlling membrane mechanics are implicated in neurological disorders such as epilepsy and depression, this study will potentially reveal the underling mechanisms by which misregulation of biophysical factors leads to pathophysiological conditions. We will achieve these goals with the expertise in theoretical modeling by Pl Rangamani and the expertise in ultrastructural analysis of neurons by co-Pl Watanabe. Together, we will elucidate the fundamental biophysical principles governing axon morphology and function.

NIH Research Projects · FY 2024 · 2024-09

Late talking in toddlers is not only a common reason for pediatrician concern and referral for developmental evaluation, but it can be a precursor of either persistent language disorder; worsening functional ability such as autism or global delay; or, oddly enough, the opposite: a neurotypical outcome. Yet, predictors of such dramatically divergent, heterogenous outcomes remain elusive. Literature reviews reveal substantial lack of replication in the field, even among the strongest findings, perhaps because many studies tend to have samples too small to address heterogenous trajectories; use non-comparable ascertainment and recruitment; and engage limited language, clinical, social, and neurobehavioral assessments. In contrast, our existent sample: (a) is very large and includes N=1,667 toddlers (552 late talkers), (702 ASD) and (413 typical); (b) were all ascertained, recruited and clinically characterized in a uniform procedure by licensed clinical psychologists; (c) is representative of the spectrum of late talkers and typical toddlers; and (d) were longitudinally phenotyped at toddler (mean age 20 months) and preschool ages (mean age 36 months) using the same language and clinical tests. In our sample of N=552 late talking toddlers defined using a cut-off of expressive language (EL) < -1 SD, 51% had persistent expressive language delays or worsening language outcomes such as ASD or global delay by preschool. Yet, 49% of our late talkers made rapid and substantial expressive language advances, achieving neurotypical levels by preschool. AIM 1 will leverage this unique sample to identify toddler-age precursors predictive of one of 5 divergent language & clinical outcomes at preschool ages (Transient EL Delay; Persistent EL Delay; Conversion to LD; Conversion to GDD; Conversion to ASD). Nine commonly reported predictors of expressive language outcomes will be analyzed using linear regression specifically: receptive language ability at intake; expressive vocabulary size at intake; % nouns and shape nouns in vocabulary composition; SES, sex, socialization, mean length of utterance (MLU) and % verbal initiations. Multinomial logistic regression will determine which of the toddler-age variables are most strongly associated with clinical and language outcome group membership. Change across time for each measure within each outcome group will also be analyzed. AIM 2: Social and language development are inextricably linked, and measures of attention to social speech such as motherese and social images have been shown to be associated with language ability. To go beyond commonly examined predictors, AIM 2 will leverage previously collected eye tracking (ET) data of auditory and visual social attention in late talking, ASD, and TD toddlers. Using our large TD sample, reference standards for levels of social auditory and social visual attention based on 7 key metrics (e.g., level of attention to motherese speech) across 2-month age bands will be created. Deviations from these norms will be used to reveal novel predictors of preschool outcomes. Using unsupervised Similarity Network Fusion, multimodality late talker ET- clinical subtypes will be defined, and predictors associated with each subtype identified.

NIH Research Projects · FY 2024 · 2024-08

PROJECT SUMMARY Uncontrolled disease fluctuations in a subset of joints, referred to as flares, can be a common experience in autoimmune arthropathies even in the context of overall good disease control with disease-modifying anti- rheumatic drugs (DMARDs). Standard-of-care non-steroidal anti-inflammatory drugs and/or corticosteroids can provide temporary symptomatic relief, but these are ineffective at preventing recurrence and flare-mediated joint damage. An unmet need exists for durable flare control agents that potentially complement standard-of-care DMARDs. The objective of the fellowship application is to develop and test a nanoparticle-based immunomodulatory agent for enhancing local flare control while avoiding generalized immunosuppression. The agent is delivered to the lymph nodes proximal to the inflamed joint where pre-existing antigen presenting cells, widely recognized as key activators of autoreactive cells, are harnessed to promote flare protection. Aim 1 will optimize the agent and measure local and systemic concentrations to identify the safe dose range for achieving modulation of antigen presenting cells and durable flare control. Aim 2 will identify potential biomarkers for agent responsiveness and assess flare control in combination with a standard-of-care DMARD. The results of this project will assess feasibility of promoting immunomodulatory antigen presenting cells to improve flare control in a well-established mouse model of autoimmune arthritis. If successful, in the longer term, the project will pave the way for a new approach to treat flares and advance the NIAMS mission of developing new treatments for unmet needs in arthritis. The training program will enrich the applicant's knowledge and skills in immunoengineering, drug delivery and autoimmune disease. Gaining expertise and scientific competency in the subject matter through the project will prepare the applicant for a career in rheumatic disease research.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ ABSTRACT Recurrent urinary tract infections (rUTI) are a common problem in kidney transplant recipients (KTR), especially women, and lead to serious consequences – pyelonephritis, bacteremia, kidney dysfunction, and death. Escherichia coli and Klebsiella pneumoniae are usually implicated. Antibiotics are associated with adverse events, increased multi-drug resistance; and they do not prevent a future recurrent UTI (rUTI) due to microbiome persistence of the uropathogen. New strategies to combat rUTI are critically needed. Bacteriophage (phage) therapy consists of administration of viruses that specifically bind to target bacteria leading to an intracellular replicative lytic cell cycle causing bacterial cell death; phage therapy is currently in clinical trials for a variety of indications. Phages are highly specific to their target bacteria; this relatively narrow host range is a significant advantage that has the potential to precisely target the causative pathogen in the gut and urinary microbiome and thus remove the reservoir of rUTI. We hypothesize that phage therapy directed against E. coli and K. pneumoniae in female KTR will be safe and lead to a reduction in UTI event rate via a targeted impact on the gut and urinary microbiome. We plan to conduct a randomized phase I/II pilot clinical trial to compare the safety, tolerability, and feasibility in addition to efficacy and microbiome effects of phage therapy vs. placebo administration in asymptomatic female KTR with a history of rUTI due to E. coli or K. pnuemoniae. Participants will be randomized to receive a 7-day course of twice daily intravenous phage therapy (16 participants) or normal saline placebo (16 participants) and will be followed for 180 days for assessment of study outcomes. Primary outcome of safety and tolerability will be measured by the incidence of adverse events, abnormal vital signs and clinical laboratory tests; feasibility will be assessed with specific goals for enrollment, phage match, study drug administration, and follow-up. The main efficacy endpoint is number of UTI events due to the original infecting pathogen (E. coli, K. pneumoniae) over the 180-day study observation period (event rate), calculated for the intent to treat population. Participants will also undergo sampling (urine, stool) at baseline and during various timepoints to determine microbiome characteristics before, during, and after phage, and to establish a biospecimen repository for further hypothesis-driven research. We will use our significant expertise in kidney transplantation and UTI, unique experience with the microbiome and virome, and visionary phage therapy infrastructure to evaluate the feasibility of moving rUTI therapy in KTR towards a successful individualized approach. This research has major potential to reduce allograft injury and improve bladder health in KTR, while reducing morbidity and mortality. The results of this pilot clinical study will directly inform the design of a larger, phase III randomized trial.