University Of Southern California

NIH Research Projects · FY 2025 · 2022-07

PROJECT SUMMARY Cancer remains a leading cause of mortality. Approximately 42% of cancer cases in the U.S. are potentially avoidable, including 15% caused by excess body weight and physical inactivity. However, most U.S. adults are physically inactive. Public health guidelines recommend combinations of activity intensity, frequency, and duration to achieve a “dose” of at least 150 min/week of moderate-to-vigorous intensity physical activity. While this approach produces health benefits, it fails to address features of physical activity that may lead to sustainability such as emotional experiences during behavior. To promote long-term maintenance, evidence- based strategies are needed describing how affect can be incorporated into physical activity recommendations. Although some people experience pleasure during physical activity, it can be extremely unpleasant for others, especially among overweight and inactive individuals. Incentive salience theory proposes affective responses (e.g., liking, disliking) during behavior influence affectively-charged motivations (e.g., wanting, dreading) to engage in future behaviors. However, whether modifying these affective mechanisms is a useful intervention approach for increasing for physical activity is unknown. Using an experimental medicine approach, this Phase 1 trial will test whether affective mechanisms can be experimentally manipulated in real-world settings and whether affective mechanisms mediate the effects of interventions on physical activity behavior among adults who are at elevated cancer risk. Pathways will be tested through a daily self- regulation intervention delivered using interactive mobile technology among physically inactive adults (18-65 years) who are overweight or obese. In an affect-based condition, self-regulation strategies will target daily goals related to enjoyment and feeling good during physical activity. In contrast, an intensity-based condition will target daily heart rate goals during physical activity. Two enhancements to the affect-based condition are: (1) tailored activity type and context recommendations to satisfy personally important psychological needs and (2) savoring practices to increase the saliency of positive emotions during physical activity. A Formative study (N=36) will iteratively test and refine the treatment implementation in terms of acceptability and feasibility of the content, delivery, usage, and engagement. Subsequently, a 16-week Comparison study (N=280) will optimize the treatment effects using a factorial (within x between) cross-over design. Affective mechanisms and physical activity will be measured in daily life using real-time ecological momentary assessment (EMA) and accelerometry, respectively. Specific aims are (1) test treatments to experimentally manipulate affective mechanisms, (2) determine whether affective mechanisms mediate effects of treatments on physical activity, and (3) explore cross-person and cross-situation moderating effects such as self-regulatory capacity and situational factors. Overall, this study is impactful because it fulfills an explicit need for the systematic translation of fundamental behavioral science processes into new health behavioral interventions.

NIH Research Projects · FY 2025 · 2022-07

Project Summary The long-term goal of this project is to improve the health and well-being of preterm infants and their parents. Very preterm infants necessitate medical care in the neonatal intensive care unit (NICU) at birth and can be hospitalized for their first several months of life, where they are exposed to repetitive, painful stimuli, are separated from their parents, and often do not receive positive, timed sensory exposures that are similar to what they would have received if not born early. In addition, parents often do not know when and how to engage with their infant in the NICU. However, early positive sensory experiences are important, as they enhance brain development during an important period of time and can be used as a tool to help parents participate during NICU hospitalization and establish early parent-child relationships to optimize development. Although there is evidence to support positive multisensory interventions in the NICU, these interventions are often applied in an inconsistent manner, reducing their benefit. Through a rigorous and scientific process, we have developed a structured multisensory intervention program, titled Supporting and Enhancing NICU Sensory Experiences (SENSE), which includes specific doses and targeted timing of evidence-based interventions such as massage, auditory exposure, rocking, holding, and skin-to-skin care. The interventions are based on the infant’s developmental stage and are adapted based on the infant’s medical status and behavioral cues. The multisensory interventions are designed to be conducted during each day of NICU hospitalization by the parents, who are educated and supported to provide them. A sensory support team fills in gaps when parents are unable to reach the targeted amount of sensory exposures each day. The proposed work aims to determine the effect of multisensory interventions on parent mental health, parent-child interaction, brain activity (amplitude integrated electroencephalography), and infant developmental outcomes through age 2 years, with specific attention to language outcome. Two-hundred fifteen parent-infant dyads of preterm infants born ≤ 32 weeks gestation and admitted to a Level IV NICU will be enrolled within 1 week of birth. Infants will be randomized to either the SENSE multisensory program or to the standard of care during the NICU stay. The SENSE program combines structured, easy-to-conduct, multisensory interventions with parent engagement to optimize outcomes in the complex medical environment of the NICU. Standardized assessments of parent mental health, infant neurodevelopment, and parent-child interaction will be conducted prior to NICU discharge and at 6 months, 1 year, and 2 years, adjusted for prematurity. Differences between groups will be investigated. Brain activity during NICU stay, including in the presence and absence of different sensory exposures, will also be investigated. The expected outcome is that the SENSE multisensory program will have a positive effect on improving outcomes. Importantly, the SENSE program has been implemented with ease in >250 hospitals in the US and abroad, so there is great potential for broad and long-term impact.

NIH Research Projects · FY 2024 · 2022-07

PROJECT SUMMARY/ABSTRACT Endolymphatic hydrops (EH), a hallmark of Ménière’s Disease, is a cochlear disease caused by either an over- production or under absorption of endolymphatic fluid. As a result of this excess of endolymph, the membranes bounding the endolymphatic space are distended outwards. These notable alterations in cochlear morphology cause disruptions in cochlear mechanics. The early identification and monitoring of EH is critical to preventing progression of this, oftentimes, debilitating auditory/vestibular disease (which is episodic in nature). Clinical diagnosis of EH is primarily made via symptomology, with the most reliable diagnostic marker being a fluctuating, low-frequency sensory hearing loss. EH typically progresses to sensory deficits that no longer recover, resulting in permanent hearing impairment that can eventually span across the audible frequency range. Therefore, early identification and monitoring of the disease process is critical to preventing its progression. Otoacoustic emissions (OAEs) are an ideal monitoring tool. OAEs are low-level sounds measured in the ear canal that have been shown to gauge cochlear function and dysfunction with high accuracy. Along with recent advances in this objective, efficient, and noninvasive probe of cochlear function, OAEs have the potential to be a powerful tool in improving the efficacy of EH diagnosis, given the human cochlea cannot be accessed or manipulated for direct study. We can now measure two distinct classes of emissions jointly — OAEs arising from nonlinear distortion (distortion product OAEs) and OAEs arising from coherent linear reflections (stimulus- frequency OAEs) using rapidly sweeping tones. The purpose of this work is to assess the diagnostic utility of such a Joint-OAE Profile in identifying and monitoring EH while also exploring the mechanism of disease through perceptual tests and phenomenological modeling to improve the efficacy of EH diagnosis in humans. This K01 proposal will first probe cochlear changes during EH using a Joint-OAE profile – a profile comprised of the two classes of emissions measured and analyzed together to access both generation processes (Aim 1). Additionally, we will explore the underlying mechanisms of EH by determining whether EH causes shifts in the cochlear frequency-place map using both a perceptual task (binaural pitch matching between the healthy and diseased ear within an individual) and physiological measurements of SFOAE latency (or group delay) (Aim 2). Finally, data collected from Aim 1 and 2 will be directly compared to model predictions that explore the mechanical effects of EH on the cochlear partition and the consequences for OAE generation (Aim 3). Combined, this physiological, perceptual, and computational approach to understanding endolymphatic hydrops is a comprehensive and bold attempt to understand its clinical manifestations and disease timeline, as well as its underlying mechanisms of pathology.

NIH Research Projects · FY 2025 · 2022-07

5R25DC019700-04 (PI - John Oghalai) Basic science, translational, and clinical research in Otolaryngology – Head and Neck Surgery is making remarkable advances that affect the way we treat patients. A critical component of nourishing and expanding such improvements in patient care is to facilitate the partnership of clinicians and basic scientists. One way to achieve this is by training more clinician-scientists. Herein, we propose to implement an otolaryngology research training program designed to cultivate clinician-scientists. Our Otolaryngology Clinician-Scientist Training Program is designed to provide residents and medical students with intense research experiences, a structured didactic program, and close mentorship and guidance in how to integrate clinical and research activities. Trainees will be ingrained with the philosophy that research is intrinsic to an academic surgeon’s career and that they should build their career by sustaining excellence in both research and clinical care. If our training program is successful, our graduates will become independent NIH-funded investigators in faculty positions in academic departments. The ultimate long-term goal, of course, is for them to improve human health by advancing our field via scientific discovery that is translated to clinical care.

NIH Research Projects · FY 2025 · 2022-07

Summary/Abstract: This application to establish a postdoctoral T32 training program in Translational Research in Hepatology to be administered at the University of Southern California (USC) Keck School of Medicine in conjunction with the Children's Hospital Los Angeles (CHLA), with affiliations at the USC Schaeffer Center for Health Policy and Economics. This training program leverages substantial university and department level investments in research infrastructure and faculty recruits, a steady rise in the quality of the training-grant-eligible applicant pool and the rich diversity of patient populations in Los Angeles to provide a robust research training experience. This Program is focused on training physician-scientists who are accepted to USC/CHLA Gastroenterology fellowships and will provide up to 3 years of support for intensive laboratory or clinical research training and mentored research for 10 MD (or MD/PhD) trainees over five years. Trainees will conduct laboratory, clinical and/or translational research (T1-T4 spectrum) under the mentorship of 16 highly qualified research mentors who have a solid track record of NIH (NIDDK) funding and exceptional mentoring accomplishments. Research themes of (i) Hepatic Immunology, Injury and Regeneration; (ii) Hepatic Steatosis and Fibrosis; and (iii) Clinical Outcomes and Community/Healthcare Implementation reflect the research strengths and training opportunities within well-established research collaborations at USC/CHLA. An individualized curriculum will focus on building each trainee’s research knowledge base, critical investigative abilities and technical skills, with diligent oversight of the training progress by primary mentors, as well as mentoring and executive committees. The institutional environment at USC/CHLA and affiliates provides abundant resources (research institutes and centers with a wide range of cores), a rich intellectual milieu for training in digestive diseases research including masters’ level training in clinical research methods, and dedicated trainee-mentor activities including an annual fellow-led symposium, biweekly work-in-progress meetings, and monthly journal clubs. Further, this training program occurs in the multi-ethic environment of Los Angeles, providing a unique educational opportunity to study liver diseases in minority populations. The ultimate goal of this T32 Training Program is to prepare GI trainees to assume a faculty-level position and compete successfully for independent research funding across the spectrum of translational liver diseases research to address the significant burden of liver disorders in the U.S. and globally.

NIH Research Projects · FY 2025 · 2022-06

ABSTRACT The goal of this project is to develop a broad-spectrum dry powder inhalation teixobactin-lipopeptide hybrid aimed at preventing and treating lung infections caused by bacterial `superbugs'. The successful use of any antibiotic is compromised by the potential development of resistance to that compound from the time it is first used. The world is facing an enormous and growing threat from the emergence of pan-drug resistant (PDR) bacteria that are resistant to all available antibiotics. New antibiotics with 1) novel mechanisms of action and 2) against which bacteria cannot easily develop resistance are urgently needed to treat lung infections caused by the PDR Gram-negative pathogens like Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae and Gram-positive strains of methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae. Teixobactin is a recently discovered new antibiotic that possesses a novel mechanism of action (MOA), albeit, a narrow spectrum of activity against Gram-positive bacteria. The most notable property of teixobactin is that it is the first and only antibiotic that bacteria cannot easily develop resistance against. We have developed novel teixobactin-lipopeptide hybrids that are superior to native teixobactin as they retain this key anti-resistance property and in addition have a broader-spectrum, with potent activity against PDR Gram-negatives, as well as PDR Gram-positives. Our preliminary data show that our teixobactin-lipopeptide hybrids delivered as a dry powder inhalation have significantly improved efficacy for the treatment of lung infections by virtue of their unique MOA, no detectable resistance, high local exposure in the lungs with low systemic exposure and low toxicity. Importantly, the hybrids displayed superior in vivo efficacy compared to treatment with the combination of the individual compounds or each compound per se. This is a significant development in the field as the teixobactin-lipopeptide hybrid represents the first-in class broad-spectrum `resistance-proof' dry powder inhalation antibiotic for the treatment of PDR bacterial lung infections. Our internationally recognized track records in antibiotic discovery, pharmacology, anti-infective dry powder formulation, pharmacokinetics/pharmacodynamics and state-of-the-art facilities for antimicrobial development provide extremely strong support for this project. The proposal will employ a purpose designed funneling approach to identify a lead candidate (plus one back-up) that is active against PDR Gram-negative strains of P. aeruginosa, A. baumannii and K. pneumoniae and Gram-positive strains of MRSA and S. pneumoniae for preclinical development and IND-enabling studies.

NIH Research Projects · FY 2025 · 2022-06

ABSTRACT Childhood acute lymphoblastic leukemia (ALL) is most common cancer in children (age 0- 14 years). Despite improvements in treatment, survivors face a lifelong battle with negative health effects of treatment, making prevention a priority. The lack of modifiable etiological factors has been a major barrier to prevention, but we recently made a groundbreaking (albeit preliminary) discovery that neonatal cytomegalovirus (nCMV) infection is a strong risk factor for childhood ALL (estimated odds ratio = 3.7) in a small study with 268 cases and 270 controls. In the same study, we also found CMV sequences within pre-treatment diagnostic tumor tissue. In addition, we conducted a population-based study linking medical records and cancer registry data in Sweden, which revealed a relative risk over 10 for early CMV infection and the child’s hematologic malignancy diagnosis. We propose here to definitively assess the epidemiology of CMV and ALL including CMV’s impact on the ALL tumor genome. We hypothesize that nCMV will contribute to ALL incidence and create specific mutational signatures present in ALL tumor genomes known to be associated with viral and infectious etiologies. In our first aim, we will better define the role of nCMV infection as an ALL risk factor in a study with over 3800 cases and 4897 controls, accounting for other risk factors such as birthweight, birth order, mode of delivery, polygenic risk score for ALL and parental ages neonatal immune phenotype, as well as the role of maternal CMV infection status during pregnancy. We will also assess whether CMV contributes to the higher risk of ALL in Latinos compared to other groups. As a second aim, we will test 1,020 children for CMV involvement at birth and within their matched ALL tumor genomes collected at diagnosis. We will investigate the presence of the APOBEC and Recombinase Activating Gene (RAG), virally-associated mutational signatures, within tumors that were nCMV positive compared to those from children negative for the virus. This research will leverage exceptional resources, including archived newborn blood specimens and population- based childhood ALL cases and controls, and maternal blood specimens collected during mid-pregnancy. In addition, the proposed study benefits from a high fraction of Latinos in the study population who carry a disproportionate burden of childhood ALL, include advanced laboratory techniques to identify neonatal and maternal CMV infection that have been refined in our laboratory, and will evaluate directly a mutation signature putatively caused by the virus. CMV is a highly adept immune manipulator. Identification of CMV as an etiologic agent in childhood ALL could create an unprecedented target for leukemia prevention, either by vaccination against CMV infection or manipulation of the host response to CMV infection after birth. In either scenario, this proposal will better characterize the role of CMV in the genesis of childhood ALL and have profound impact from a prevention perspective. As CMV is also responsible for congenital hearing loss and a host of other neurological outcomes, our research will impact childhood health apart from leukemia.

NIH Research Projects · FY 2026 · 2022-06

PROJECT SUMMARY Age is the major risk factor for most chronic human diseases, including Alzheimer’s disease (AD). Neural stem cells (NSCs) are particularly vulnerable to cellular aging and undergo functional decay in the mature brain. As a result, adult neurogenesis and its contributions to memory in health and AD are compromised at early ages. A central goal in regenerative medicine for AD is to determine the factors that rejuvenate endogenous NSCs and augment cognition. Yet, NSCs are commonly perceived to be a poor target for anti- aging interventions. A daunting challenge remains for NSC rejuvenation: to restore older NSC proliferation, increase their numbers, alter NSC fate for neurogenesis and sustain these changes. Systems biology offers a potential solution by integrating information from multiple fields. We propose to develop computational network and pharmacogenomics approaches to prioritize and modulate key age-related changes for NSC rejuvenation. Our prior work utilized single cell transcriptomics to define molecular cascades that initiate adult neurogenesis and are compromised during aging. Preliminary data now identifies a new transition signature that distinguishes quiescent from active NSCs and is altered with age. Our new single cell pharmacogenomics approach utilizes the transition signature to identify a compound that rejuvenates NSC function by expanding the NSC pool, increasing neurogenesis and sustaining NSC proliferation. Animal behavioral studies also demonstrate improved cognition in older mice. Thus, data detailed in this proposal strongly suggests we can apply combined “omics” approaches to reprogram older NSC function and provide a new understanding of adult neurogenesis in aging. The mechanisms mediating this NSC reprogramming remain enigmatic. We will advance the new pharmacogenomics with systems biology techniques in network connectivity and co-expression to prioritize mechanisms by which NSC aging is reversed (Aim 1), older NSC function is augmented (Aim 2) and how these changes are sustained (Aim 3). Together, this study will reveal evidence of NSC rejuvenation and demonstrate proof-of-principle utility of new single cell pharmacogenomics and gene networks for enhancing neurogenesis in the aged hippocampus. These results would provide a paradigm shift in NSC capacity for regeneration, as well as mechanistic insight into NSC vulnerability to aging, resilience to their decline, and building cognitive reserve.

NIH Research Projects · FY 2024 · 2022-06

The Gerontology Enriching MSTEM (GEMSTEM) to Enhance Diversity in Aging program will meet the challenges of the increasing size and diversity of the U.S. older population by attracting, encouraging, and supporting undergraduates from diverse backgrounds – especially racial and ethnic minorities and other health disparities populations – into careers in aging research. We will provide these trainees with the skills and experience to pursue advanced MSTEM degrees and research careers in aging by providing research training, education, career development, mentoring, and peer socialization activities that emphasize integration between geroscience and health disparities research. Our program is designed to overcome longstanding financial, social support, and cultural barriers that have limited opportunities for diverse undergraduates in aging research. The GEMSTEM program is a paid research and professionalization opportunity over the entire four-year undergraduate experience. We will target recruitment of underrepresented minority students from the USC student population, from underrepresented minority serving 2-year and 4-year colleges, and from the local K-12 schools in the greater LAUSD. GEMSTEM will create an undergraduate-centered geroscience research community modeled for sustained program enhancement by the continuous assessment of programmatic components by students, expert geroscience faculty, and professional staff. The goals of the GEMSTEM program are to (1) expand research access to emerging undergraduate researchers from racial and ethnic minority and other health disparity populations and (2) increase the number of researchers conducting gerontological research to reduce health disparities in older adult populations. GEMSTEM aims include: (1) recruit a diverse group of USC undergraduate students from Gerontology and other MSTEM degree programs, over the entire undergraduate experience, to participate in GEMSTEM; (2) engage student participation in active research on aging and introduce them to diversity in aging research through socialization and engagement activities that will build passion for and commitment to a disparities-informed geroscience; (3) facilitate structured education and research training opportunities in aging; provide sustained mentorship; and prepare program participants for future success in graduate and medical school research training and careers; and (4) create a community GEMSTEM students and alumni to provide ongoing support as they embark into careers in MSTEM. Importantly, The USC GEMSTEM Program will help NIA achieve its mission to promote diversity in the scientific workforce and maintain its leadership in geroscience discovery and innovation.

NIH Research Projects · FY 2026 · 2022-06

Project Summary There is an urgent need for improved therapies for Alzheimer’s Disease and Related Dementias (ADRD). Critical to the mission to develop treatments for and curb the public health impact of ADRD will be a new generation of ADRD scientists, especially scientists with the unique training and skills necessary to design and perform clinical trials. This training is rarely provided through the traditional course of medical or biostatistical education. Moreover, to develop improved therapies for ADRD, multidisciplinary expertise in clinical trials will be necessary, including medical specialists but also expertise in biostatistics, biomarkers, trial design, participant recruitment, study organization, and trial ethics. This proposal requests support for a first-of-its-kind training program in the essential elements of design and conduct of ADRD trials that will leverage the full infrastructure and expertise of the Alzheimer’s Clinical Trials Consortium (ACTC) and be conducted annually to enable a diverse range of clinicians, scientists and researchers to receive modern and robust training on ADRD clinical trials.

NIH Research Projects · FY 2025 · 2022-06

The volume of patients who meet national criteria for germline genetic testing based on a cancer diagnosis alone, regardless of family history (i.e. ovarian, pancreatic, advanced prostate, etc.) is rapidly growing. Germline genetic test results can inform oncology and surgical treatment decisions, as well as early detection and prevention for the family. However, traditional pre- and post-test genetic counseling approaches may not be sufficient to meet the growing need. Additionally, traditional pre-test counseling may be a barrier, leading to decreased uptake, especially in those with advanced disease. Patients cared for in settings with limited or no genetic services, already face challenges in access to care. As such, innovative strategies to optimize genetic counseling approaches are needed. Relational Agents (RAs) are an effective means of automating health education and counseling, as well as overcoming literacy barriers in the use of information technologies. RAs, animated computer characters, simulate face-to-face conversation between a patient and a provider using verbal and nonverbal conversational behavior. Overall Goals. This study will develop an RA to communicate personalized pre-test genetic education to a cohort of cancer patients who meet established cancer-based genetic testing criteria across two clinical settings. We hypothesize that the use of an RA will increase the proportion of patients who receive genetic test results within 90 days of initiating cancer care, compared to usual care. Aim 1 is to develop an RA using a patient-driven approach. Aim 2 is to conduct a multisite randomized controlled trial of the RA to deliver pre-test education versus usual care to compare the proportion in each arm who receive genetic test results in 90 days at Los Angeles General Medical Center and University of Rochester Medical Center. Aim 3 is to understand the implementation context and identify facilitators and barriers to utilizing the RA in these clinical settings. Impact. Our deliverable will be patient-facing RA to deliver pre-test genetic education. This RA will be developed and evaluated in two distinct patient populations and clinic workflows, can be rapidly updated as practice evolves, and will ultimately be available on the internet for clinics and patients to utilize. If successful, this would be a novel, effective, and scalable means of providing genetics education that could improve patients’ decisional preparedness, knowledge, and satisfaction, ultimately leading to increased access. Understanding the implementation context and identifying facilitators and barriers to integrating a RA will increase sustainability and generalizability.

NIH Research Projects · FY 2026 · 2022-06

Project Summary/Abstract Because of the staggering complexity of biological systems, biomedical research is becoming increasingly dependent on knowledge stored in a computable form. The Gene Ontology (GO) is by far the largest knowledgebase of how genes function, and has become a critical component of the computational infrastructure enabling the genomic revolution. The GO knowledgebase encodes a computational model of biological systems using modern semantic technologies, and this is the key to its broad adoption and application. It stores vastly more knowledge than one person can know, and therefore enables computational analyses that would otherwise be impossible. It has become indispensable in the interpretation of large-scale molecular measurements in biological research. Crucially for human health research, GO is also one of a suite of complementary ontologies constructed in such a way to maximally promote interoperability and comparability of data sets. It represents the gene functions and biological processes that can be perturbed in human disease, helping researchers or clinicians to identify genetic contributions to disease. GO is a knowledgebase that can be statistically mined, either standalone or in combination with data from other knowledge resources, which enables researchers to discover connections and form new hypotheses from the biological networks GO represents. All knowledge in GO is represented using semantic web technologies and so is amenable to computational integration and consistency checking. To ensure the knowledge environment meets the requirements of biomedical researchers, we will: 1) Develop and refine the Gene Ontology to reflect current biological knowledge; 2) Coordinate, integrate, and provide GO assertions from multiple sources; 3) Enhance usability of the GO resources for multiple research communities. We will extend the reach of our Consortium of contributors, to efficiently expand the content of the knowledgebase, and develop test sets and challenges to spur the development of machine learning methods for knowledge capture. Our aims reflect the essential requirements for realizing the overarching objectives for a biomedical knowledgebase: efficiently capturing and integrating biological knowledge and adhering to the highest possible standard for accuracy and detail; constructing and providing a robust, flexible, powerful, and extensible technological infrastructure available not only for internal use but just as easily by the wider community; and lastly, leveraging state-of-the-art social media, web services and other technologies to disseminate the GO resource to the entire biomedical research community.

NIH Research Projects · FY 2026 · 2022-06

PROJECT SUMMARY Michelle S. Keller, PhD, MPH is a health services researcher with Assistant Professor appointments at Cedars- Sinai Health System (CSHS) and UCLA. Dr. Keller’s research focuses on reducing inappropriate medication use in older adults, particularly in populations with high levels of medication use, such as older adults with Alzheimer’s Disease and Related Dementias (ADRD). Reducing inappropriate medication use in older adults has been shown to reduce mortality, but evidence is limited on whether interventions that reduce inappropriate medications reduce hospitalizations and emergency department visits. More than half of older adults in the U.S. receive their care from health systems and provider groups which contract with Medicare Advantage plans or are part of Accountable Care Organizations, organizations which are financially accountable for Medicare beneficiaries’ health costs. These organizations proactively manage chronic conditions such as diabetes, hypertension, and high cholesterol to prevent unnecessary avoidable hospitalizations. This proposal aims to create a similar approach to managing medication use through the development and validation of a risk prediction model and registry that identifies older adults with a large number of potentially inappropriate medications and other conditions that place older adults at risk for hospitalization, including age, cognitive decline, frailty, and risk of falls. This proposal will use this registry and risk model as part of a feasibility and acceptability study to identify, refer, and enroll older adults with ADRD in a pharmacist-led medication review intervention aimed at reducing inappropriate medications. Dr. Keller’s career development and training plan includes coursework in embedded, pragmatic clinical trials and geriatrics. Dr. Keller will accomplish the proposed research and training aims with the support of a strong multi-disciplinary mentoring team from UCLA and CSHS: Catherine Sarkisian (geriatrics and deprescribing), Zaldy Tan (ADRD) Teryl Nuckols (health systems science), Joshua Pevnick (medication management), and Nicole Brandt (pharmacy and deprescribing). These efforts will be supported by the outstanding research environment and infrastructure of CSHS and UCLA. Given the strong mentoring, institutional, and infrastructure supports in place, the proposed K award program is ideally designed to provide the PI with the experience needed to launch her career as an independent investigator and future leader in deprescribing research.

NIH Research Projects · FY 2025 · 2022-05

PROJECT SUMMARY/ABSTRACT Nearly 30% of patients with Fetal Alcohol Spectrum Disorder (FASD) have a congenital heart defect (CHD). Outflow tract (OFT) defects are over-represented, though with variable incidence and severity. The majority of prenatal alcohol exposure (PAE) research focuses on the hallmarks of FASD, chronic drinking and neurologic defects. The most common form of PAE in the population, acute exposure during the periconceptual period, and its effect on cardiac development have not been studied. We will study the effects of acute, periconceptual drinking both through a multi-institutional clinical study and with our acute PAE murine model, in which mice receive two intraperitoneal injections of 3g/kg of 30% ethanol at a point critical to cardiac organogenesis. We hypothesize the variable incidence and severity of PAE-induced OFT defects can be explained by a combination of PAE and otherwise non-deleterious mutations that result in a genetically permissive background. We believe mutations in the Notch pathway establish such a genetically permissive background, and that PAE acts synergistically with these mutations via epigenetic regulation of Notch to result in OFT malformation. Aim 1 of this study will address the specificity of the deleterious effects of PAE to OFT alignment and define the molecular pathways disrupted in individuals with PAE-induced OFT defects. We will achieve this through relative risk analysis of PAE and CHD diagnoses and pathway and subsequent logistical regression analyses of whole genome sequencing data. Aim 2 will define alcohol driven epigenetic regulation as the mechanism by which acute PAE and otherwise non-deleterious Notch pathway mutations synergistically disrupt OFT development. Using a combination of molecular assays and histologic analysis in vitro and in vivo, we will test the impact of this combined teratogenic insult on second heart field (SHF) viability and ability to migrate into the OFT. We will establish PAE driven epigenetic regulation, disrupting Notch gene accessibility and transcription, inhibits Notch signaling and use a pan-histone acetyltransferase inhibitor in vitro to demonstrate prevention of PAE induced hyperacetylation is sufficient to rescue Notch signaling and SHF viability. Similarly, rescue of SHF viability by overexpression of notch intracellular domain (NICD) in vitro will cement the point of acute PAE and Notch mutation synergy as loss of Notch signaling prohibiting SHF viability. As one of the first studies to examine the interaction of clinically relevant acute PAE with heart development, this study addresses the priorities of the NIAAA to define the impact of non-chronic exposure and alcohol’s effects on understudied organ systems. The genetic pathways identified by this study, including novel validation of the Notch pathway as significant in PAE-induced CHD, will provide targets for disease prevention and identification of those most at risk to develop the world’s most common and deadly birth defect. Completion of this project is ensured by the technical training and mentorship by the sponsorship team, the training site’s cutting-edge facilities, and education provided by the principal investigator’s M.D.-Ph.D. program.

NIH Research Projects · FY 2026 · 2022-05

Abstract The elucidation of potentially modifiable molecular pathways involved in Alzheimer’s disease (AD)/Alzheimer’s Disease Related Dementia (ADRD) is of great scientific interest and offers hope for improved public health. Mounting evidence points to the role of calcium-dependent phospholipase A2 (cPLA2) in ADRD. Indeed, cPLA2 expression is increased around amyloid plaques in patients with AD and is associated with a brain inflammatory response. And, reducing cPLA2 gene expression improves learning and memory in AD mouse models. Further, APOE4, the strongest genetic risk factor for late-onset AD, has been shown to promote and accelerate brain inflammation, while the underlying mechanisms are not well understood. The overall goal of this project is to test the hypothesis that cPLA2 activation is associated with faster cognitive decline in APOE4 carriers by accelerating brain inflammation and AD and vascular pathology. Leveraging brain biospecimens and detailed clinical and neuropathological data from the Religious Order Study (ROS) cohort, we propose the following three Aims. In Aim 1, we will examine the patterns of cPLA2 activation and signaling pathways in older subjects across a range of cognitive function, stratified by APOE4 using frozen human brain samples and single brain cell types isolated from a subset of samples. In Aim 2, we will use ex vivo stimulation to study cPLA2 activation and signaling mechanisms in neurons and glia of post-mortem brain tissues, stratified by APOE4 and cognitive function. In Aim 3, we will investigate whether the association between the prodromal decline in global cognitive and APOE genotype is mediated by cPLA2 activation. In addition, we will explore if inflammation, AD neuropathological markers (Aβ, pTau, or both) and other vascular pathological markers mediate this association. This project will elucidate a novel mechanism for APOE4 induced brain inflammation in AD/ADRD. The study of available brain tissues from well-characterized autopsied persons with a range of clinical and pathologic phenotypes will provide deep insights into cell specific cPLA2 activation profiles in relation to APOE4 and markers of inflammation. Identifying a role for cPLA2 activation in AD inflammation is a significant step toward the development of cPLA2 inhibitors, and ultimately improved treatments for AD/ADRD.

NIH Research Projects · FY 2024 · 2022-05

ABSTRACT: The elucidation of potentially modifiable molecular pathways involved in Alzheimer’s disease (AD)/Alzheimer’s Disease Related Dementia (ADRD) is of great scientific interest and offers hope for improved public health. Mounting evidence points to the role of calcium-dependent phospholipase A2 (cPLA2) in ADRD. Indeed, cPLA2 expression is increased around amyloid plaques in patients with AD and is associated with a brain inflammatory response. Reducing cPLA2 gene expression improves learning and memory in AD mouse models. Further, APOE4, the strongest genetic risk factor for late-onset AD, has been shown to promote and accelerate brain inflammation, while the underlying mechanisms are not well understood. This project aims to test the hypothesis that cPLA2 activation is associated with faster cognitive decline in APOE4 carriers by accelerating known pathology (AD and vascular) and brain inflammation. Leveraging brain biospecimens and detailed clinical and neuropathological data from the Religious Order Study cohort, we propose the following three Aims. In Aim 1, we will examine the patterns of cPLA2 activation and signaling pathways in older subjects with and without dementia (clinical AD), stratified by APOE4 using frozen human brain samples and single brain cell types isolated from a subset of samples. In Aim 2, we will use ex vivo stimulation to study cPLA2 activation and signaling mechanisms in neurons and glia of post-mortem brain tissues, stratified by APOE4 and dementia. In Aim 3, we will investigate whether the association between the decline in global cognitive and APOE genotype is mediated by cPLA2 activation. In addition, we will explore if AD neuropathological markers (Aβ, pTau, or both) and other vascular pathological markers mediate this association. This project will elucidate a novel mechanism for APOE4 induced brain inflammation in AD/ADRD. The study of available brain tissues from well-characterized autopsied persons with a range of clinical and pathologic phenotypes will provide deep insights into cell-specific cPLA2 activation profiles in relation to APOE4 and markers of inflammation. Identifying a role for cPLA2 activation in AD inflammation is a significant step toward the development of cPLA2 inhibitors, and ultimately improved treatments for AD/ADRD. The focus of this supplement plan will be to expand on cPLA2 research by studying it in the context of cellular senescence with two particular aims: AIM 1: Identify whether cPLA2 is required for lipid-induced senescence in iPSC- derived astrocytes. And, AIM 2: Assess senescence phenotypes in a patient-derived-iPSC population.

NIH Research Projects · FY 2026 · 2022-05

Project Summary This proposal centers on uncovering intrinsic physical properties of DNA duplex (i.e., DNA shape) and elucidating their roles in CRSIPR Cas9 and Cas12a target discrimination. CRISPR (Clustered-Regularly- Interspaced-Short-Palindromic-Repeats) systems have been adapted into versatile and programmable agents for manipulating nucleic acid targets in a genome-wide fashion, unleashing a revolution in genome editing and manipulation that is still rapidly advancing. CRISPR-based technology is built upon specific recognition of nucleic acids, and a major obstacle hampering its applications in therapeutic settings is the “off-target effect”, in which uncontrolled and undesired actions of CRISPR on aberrant gene targets result in deleterious consequences. Significant improvement of CRISPR specificity is required, and this depends on further in-depth understanding of mechanism of CRISPR target discrimination. Proposed work focuses on Cas9 and Cas12a that are most widely used for engineering DNA genomes. Cas9 and Cas12a both use an effector protein-RNA complex to cleave double-stranded DNAs, and select their cognate targets based on: (i) base-pairing between the RNA guide and a segment of the DNA target-strand designated as protospacer and (ii) a short protospacer-adjacent-motif (PAM) within the target DNA. Ca9/Cas12a target discrimination rely on intrinsic DNA shape, which is determined collectively by the local “core” base-pair(s) and many other factors including (distal) peripheral sequences and topological constraints (e.g., supercoiling). However, current studies on Cas9/Cas12a target selection focus on DNA features at the core segment spanning the PAM and protospacer, and have not yet accounted for impacts of peripheral sequences beyond direct RNA/DNA pairing or DNA topological constraints. We have developed unique site-directed spin labeling methods to obtain sequence-dependent conformation (shape) of free duplexes as well as DNAs bound by proteins including Cas9 and Cas12a. Our recent work shows that DNA sequences not involved in RNA/DNA pairing can modulate Cas9-induced DNA unwinding and cleavage, and the information enables gene editing in cells with short RNA guides that are known to enhance specificity. Building on these findings, we will investigate how DNA peripheral sequences and supercoiling modulate Cas9/Cas12a target discrimination as well as affect the shape of free DNA core segments. Information learned will be incorporated into algorithms for enhancing CRISPR targeting specificity, as well as for predicting three- dimensional DNA shape from the linear one-dimensional sequence in a genome-wide setting. The project will advance understanding on DNA specific recognition that is fundamental to biology, and will contribute to development of the next generation of scientific workforce.

NIH Research Projects · FY 2025 · 2022-05

ABSTRACT Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and, despite advances in treatment, it is still one of the leading causes of childhood death in the United States (US), and survivors face significant lifelong treatment-related morbidities. Children of Latino ethnicity have the highest and fastest-increasing risk of ALL in the US, and have lower survival than non-Latino whites; however, this ethnic disparity in incidence and outcome is not fully understood. Elucidating the increased risk of ALL in Latino children may reveal novel insights in the etiology of ALL in both Latino and non-Latino populations, and may highlight potential avenues for disease prevention. We hypothesize that germline genetic variation plays an essential role in the increased ALL risk in Latinos, that this risk is imparted via Native American ancestry, and that ALL risk alleles were selected in Native Americans during European colonization of the Americas due to their beneficial effects on immune response to new infections. We have assembled the largest ever case-control set of childhood ALL in Latinos, including over 5,400 cases and 27,000 controls from three independent studies in California, plus studies in Texas, Children’s Oncology Group/St. Jude Children’s Research Hospital, and Guatemala. In our first aim, we will perform three complementary approaches to discover novel common risk loci associated with childhood ALL: i) a genome- wide association study (GWAS) meta-analysis, ii) admixture mapping to capitalize on the recently admixed nature of Latino genomes, and iii) a transcriptome-wide association study to identify novel loci and to pinpoint causal genes at known and novel risk regions. In our second aim, we will characterize the genetic variants in terms of their association with local Native American ancestry and whether they exhibit evidence of directional natural selection on the Native American branch of the human population tree. We will also characterize the aggregate effects of common variants on childhood ALL risk and how this varies by ethnicity, via comprehensive modeling of polygenic risk scores (PRS) for ALL in Latinos and in non-Latino whites. Finally, we will incorporate our genetic findings into epidemiologic analyses, by accounting for common (PRS) genetic variants in ALL risk models for immune-related risk factors in Latinos and non-Latino whites, including cesarean delivery and in utero cytomegalovirus infection, both of which have shown stronger effects on ALL risk in Latinos and are potentially modifiable risk factors. The results of this study will shed light on the etiology of childhood ALL in general and of the increased risk of ALL in Latino children, which will help to alleviate this ethnic disparity and may inform future approaches for childhood leukemia prevention.

NIH Research Projects · FY 2025 · 2022-04

Project Summary Peroxisomes are metabolic organelles that serve as a central hub of cell signaling pathways and have essential roles in the normal development and functions of all human organ systems. Peroxisome dysfunction is causally responsible for a large group of rare monogenic disorders where some individuals with the same deleterious alleles can show dramatic differences in clinical phenotypes that suggest the existence of genetic modifiers. Furthermore, peroxisome dysfunction contributes to the pathophysiology of a diverse group of common disorders. Despite their relevance to numerous facets of human health and disease, the limited number of well- annotated publicly available mouse models and immunological resources required to investigate peroxisome structure, assembly, and downstream functions has hindered the research community. Moreover, the impact of many existing mouse models has been lessened since they often are placed on suboptimal genetic backgrounds or are not readily available to the public because the investigators who generated them do not have the infrastructure necessary to distribute them or are encumbered with restrictions or licensing fees to for-profit companies by the originating research institutions. Here, we will establish the Mouse Peroxisome Research Resource (MPRR) at The Jackson Laboratory (JAX) that will provide a central resource for mouse models and monoclonal antibodies for basic and translational research relevant to peroxisome biology and disorders caused by peroxisome dysfunction. The MPRR will be a community-driven effort that leverages a world-leading knowledge of mouse genetics, gene editing, and monoclonal antibody production capability as well as expertise in model development and disease model repositories to accelerate the creation, distribution, and proper use of high-impact mouse models and monoclonal antibody reagents. By leveraging the JAX Genetic Resource Sciences Repository infrastructure, the MPRR will ensure that all deposited mouse models are on standardized genetic backgrounds to control for the presence of genetic modifiers. These strains will be made available as well-annotated resources with as few legal restrictions as possible. Based on community input and the guidance of its External Steering Committee, the MPRR will also produce novel high-priority mouse models with defined genotypes on standardized genetic backgrounds, cryopreserve them, and distribute them to the public. Moreover, the MPRR will also assist in the targeted phenotyping of these models, including measurement of relevant peroxisomal metabolite levels. Furthermore, based on community input and the guidance of the External Steering Committee, the MPRR will produce and publicize validated monoclonal antibody reagents for peroxisome research, including characterizing relevant mouse models, that are made available to the public upon request. Overall, the MPRR will dramatically increase the number of available mouse models and monoclonal antibody reagents based on community-driven priority and accelerate preclinical testing of rationally designed therapeutic interventions for disorders caused by peroxisome dysfunction.

NIH Research Projects · FY 2026 · 2022-04

ABSTRACT Bipolar disorder (BD) is a devastating and poorly understood illness. Its burden exceeds $202 billion a year in direct treatment, societal and family costs. With no known cure and limited therapeutic options, 50% of patients attempt suicide at least once; up to 30% of patients do not respond to first-line treatment - even with the latest medications and psychosocial therapy - yet bipolar disorder has only received a small fraction of the amount of research attention that goes into serious non-psychiatric illness. Differentiating BD from major depression is crucial for understanding BD pathophysiology. Advances in imaging are beginning to offer the first detailed, reproducible, and reliable data on brain changes in BD and how they progress, but the lack of global initiatives in bipolar disorder has stalled research. The high cost of data collection - few studies scan more than a hundred patients - has led to underpowered studies whose findings often fail to replicate, cannot adequately model confounds, and often lack power to identify factors that modulate disease progression or recovery. Our ENIGMA Bipolar Initiative offers a new, cost-effective, innovative global approach - a new source of power to unblock this logjam by merging resources, capital infrastructure and talents of leading BD centers including data from 48 cohorts across the world. ENIGMA’s Global Alliance for Worldwide Imaging Genomics in Bipolar Disorder - builds on our thriving ENIGMA Consortium. ENIGMA’s approach merges data from tens of thousands of individuals and “gives us a power we have not had”, and is “breaking the logjam in neuroscience” (New York Times). The Lancet hailed ENIGMA as “Crowdsourcing meets Neuroscience”. In designing the ENIGMA-Bipolar initiative, we identified the most productive activities in the ENIGMA Bipolar working group, and organized them into 3 themes - imaging, genomics, and cross-disorder comparisons. This global initiative tackles key questions in BD: how does the illness affect the brain? What imaging and genomic biomarkers assist diagnosis, monitor treatment, and predict outcomes? How do BD genetic susceptibility loci affect the brain? With global data and expert teams from 15 countries (see Support Letters), we tackle imaging, genomic, and predictive questions about BD with unprecedented power. Across Brazil, Japan, the US, Canada, Norway, The Netherlands, Germany, France, Australia, and South Africa - what brain differences do we reproducibly detect in BD (with structural/diffusion MRI, connectomics and resting state fMRI)? How do they vary across life, with illness duration, by demographics, in women versus men, by age of onset, subtype and treatment? Using ENIGMA’s harmonized protocols, we will analyze the largest collection of multisite neuroimaging data in BD - diverse in age, ethnicity, treatment response - to track disease worldwide. In a new Cross-Disorder partnership of ENIGMA-BD and MDD, we use ENIGMA’s data-driven models to detect imaging and genomic biomarkers to distinguish the 2 disorders and identify subtypes. After harmonizing data elements across disorders, we will create a ranked list of actionable factors that affect prognosis in BD.

NIH Research Projects · FY 2026 · 2022-04

PROJECT SUMMARY/ABSTRACT Dental fear and anxiety (DFA) characterizes up to 42% of the pediatric population and predicts negative behaviors in the dental clinic, irregular appointment attendance, need for general anesthesia, and poor oral health. Sensory over-responsivity (SOR), which occurs in up to 33% of the pediatric population, is a likely contributor to DFA and may also occur independently from DFA. In the dental clinic, children with SOR may exhibit behavioral overreactions to lights, sounds, touch, and other sensory stimuli, leading to disruptive behaviors akin to those associated with DFA. This project will test the Sensory Adapted Dental Environment (SADE), a novel intervention which provides soothing visual, auditory, and tactile input to reduce children’s anxiety or fear during dental treatment. In our previous NIDCR-funded R34 study, SADE reduced physiological anxiety and behavioral distress in both children with autism and typically developing children. Because SADE utilizes sensory modifications as its key active ingredient, it complements – and could be combined with – anxiety-reducing strategies such as modeling, a strategy based on social observation and imitation. Research participants will be 312 ethnically diverse children aged 6-12 years, 156 with DFA and 156 without. Using a randomized counterbalanced study design, each child will undergo two dental cleanings 4-6 months apart in two of four conditions: SADE in conjunction with video-based modeling (SADE-VBM), SADE alone (SADE), video-based modeling alone (VBM), and a regular dental environment (RDE). As acceptability and feasibility of the SADE intervention and procedures have been established in our pilot work, in our UG3 planning phase we will assess only the three new elements of the proposed study – content and delivery of VBM videos, use of a weighted blanket, and recruitment techniques in new settings. In the UH3 phase, the specific aims are to conduct a randomized clinical trial to: test SADE-VBM, SADE, VBM, and RDE’s relative effects on physiological anxiety and behavioral distress during dental cleaning, as well as on secondary outcomes (Aim 1); assess whether physiological anxiety mediates each interventions’ effect on behavioral distress, and if DFA and SOR moderate intervention effects on physiological anxiety and behavioral distress (Aim 2); and conduct exploratory analyses to examine DFA and SOR’s unique and interactive contributions to overall levels of in-clinic physiological anxiety and behavioral distress, the intervention’s cost implications, and other methodological issues such as treatment sequencing effects (Aim 3). This project is significant because it is the first full-scale RCT of a sensory adapted intervention to modify the dental environment for typically developing children. Completion of the study aims will enable refinement of the SADE-based approach to provide a simple, inexpensive, and highly scalable treatment model that we will later test in a multi-site effectiveness trial. Long-term project outcomes will have excellent potential to benefit countless children in the US who manifest disruptive anxiety reactions in the dental clinic.

NIH Research Projects · FY 2026 · 2022-04

Abstract Alzheimer’s disease is a devastating progressive neurodegenerative disease that leads to a profound loss of brain and cognitive functions. There is an urgent need to identify factors that can decrease risk, including modifiable lifestyle behaviors. Exercise and physical activity (PA) have shown promise in reducing rates of cognitive decline, brain structural atrophy, and risk of developing Alzheimer’s disease and other related dementias. However, despite decades of work, and recommendations to improve exercise participation, levels of PA and engagement in purposeful exercise have not increased greatly. In contrast to PA, the effect of sedentary behavior (SB) or time spent sitting on Alzheimer’s disease risk has received less attention. SB may have independent physiological effects on health which may not be fully ameliorated by engaging in PA, and there is growing evidence that SB may have detrimental effects on cognition and brain structure. Understanding the effects of SB on Alzheimer’s disease risk may provide a key target for behavioral modification since reducing time spent sitting may be easier to implement compared to increasing exercise levels in older adults. In this proposal, we will determine whether time spent in SB is associated with brain health and the risk of developing Alzheimer’s disease and all-cause dementia. Here, we focus on the effects of SB on cognition, brain structure, and Alzheimer’s disease incidence in the largest prospective cohort analyzed to date, the UK Biobank. We will analyze associations between markers of SB including self-report and objective measures from wearable accelerometers, and cognition, brain health, and incident Alzheimer’s disease and all-cause dementia. This unique dataset will allow us to determine the best SB predictors of brain aging outcomes, including Alzheimer’s disease incidence so that interventions can focus on reducing the most harmful aspects of SB in older adults. Using this dataset along with three replication datasets, we will test our overarching hypothesis that high levels of SB are associated with increased cognitive decline, poorer brain health, and increased Alzheimer’s disease risk that is not fully mitigated by complementary engagement in PA. To test this hypothesis, this proposal will address the following specific aims: 1) to determine how SB is associated with incident Alzheimer’s disease and all-cause dementia, 2) to evaluate the cross-sectional and prospective relationships between SB and aspects of cognition and brain structure associated with Alzheimer’s disease risk, and 3) to investigate how displacing SB with time spent in different PA levels modifies the association between SB and Alzheimer’s disease risk. By evaluating a novel, comprehensive set of SB markers and testing their associations with cognition, brain structure, and Alzheimer’s disease risk, this proposal provides a unique opportunity to obtain key data needed to help advance efforts in developing effective interventions for Alzheimer’s disease prevention.

NIH Research Projects · FY 2025 · 2022-03

Abstract NF-B plays a causative role in the inflammation and pathogenesis of various diseases such as lung disease, the third leading killer in the United States responsible for one in seven deaths. However, we have been unable to successfully target it for clinical treatment due to its equally important roles in physiology, and in particular, innate immunity and host defense. Teasing apart these functions of NF-B will overcome this barrier resulting in a powerful means to fight lung and other diseases. Although the core mechanism driving NF-B activation has been well defined and is the same under most physiological and pathogenic conditions, the mechanistic difference in physiologic versus pathogenic NF-B remains largely unknown. Recently, we have demonstrated, for the first time, that NF-B exhibits different activation patterns in normal and malignant lung epithelial cells, the first line of defense and a key component of the innate immunity in the lung. Furthermore, we have revealed, also for the first time, the PDZ-LIM domain-containing protein PDLIM2 as a tumor suppressor and ubiquitin E3 ligase that selectively degrades the ‘pathogenic’ form but not the ‘physiologic’ form of NF-B (thereby preventing pathogenic activation while allowing physiologic activation of NF-B by inflammatory stimuli) and can be targeted as mono- or combination therapy in authentic mouse models of human lung cancer. Like in human lung cancer, of note, PDLIM2 is repressed in the lungs of patients with chronic obstructive pulmonary disease (COPD) or interstitial lung diseases (ILDs), and PDLIM2 repression is associated with disease severity and poor patient survival. Lung epithelial-specific or global deletion of PDLIM2 renders mice highly susceptible to spontaneous and induced lung cancers as well as acute lung injury and death by the bacteria endotoxin lipopolysaccharide (LPS). Based on these trailblazing discoveries, in this proposal we will identify the functional partners of PDLIM2 and determine the structural and biochemical mechanisms by which they act as a ubiquitin E3 ligase complex to dichotomize the differential activation of NF-B in lung epithelial cells. We will also determine in vivo and in vitro the roles and molecular mechanisms of this regulation in lung disease and host defense against pulmonary infection using conditional and inducible knockout (KO) or knock-in (KI) mice and cells of PDLIM2 and/or NF-B. These studies will improve our understanding of normal lung physiology and pulmonary diseases, and open new avenues to study NF-B regulation and action. They may also lead to new clinically feasible approaches to selectively target pathogenic NF-B and reveal new therapeutic targets for better lung disease treatment.

NIH Research Projects · FY 2026 · 2022-03

PROJECT SUMMARY Data science methods provide an exciting opportunity to significantly improve the reproducibility and replicability of rehabilitation research. However, a key barrier to implementing data science methods in rehabilitation research is a lack of fundamental programming knowledge. In particular, many clinical and basic scientists have not received formal training in programming skills required for data science. For this target audience, the most efficient way to get started in data science is to receive personalized guidance from an experienced mentor who can provide hands-on assistance and identify which skills are the most beneficial given a specific research goal. However, many rehabilitation researchers do not have access to these types of mentors. The proposed program (Reproducible Rehabilitation, or ReproRehab) addresses this need by providing personalized, rehabilitation-specific, hands-on training in data science skills with direct, weekly support from experienced mentors. The ReproRehab program will blend hands-on assistance, personalized mentorship, and a uniquely rehabilitation-focused curation of online resources for self-guided learning, with three specific aims. Aim 1 is to build a national workforce of rehabilitation researchers equipped to apply data science skills to their own rehabilitation research. To accomplish this Aim, over the 5-year grant a total of 100 learners will undergo a personalized, 6-month program consisting of a 2-month TA-guided, hands-on bootcamp in which learners are assigned to small groups with similar research needs, followed by a 4-month self-guided learning segment to integrate the skills into their own research. By the end of the program, learners will demonstrate the implementation of this knowledge into their own research, including but not limited to the sharing of open-source rehabilitation datasets, open-source analysis code or methods, and more rigorous research products. Aim 2 is to develop data science rehabilitation researchers who have the capacity to teach and train others. To accomplish this Aim, over the grant’s 5 years a total of 40 TAs will refine their teaching skills by administering bootcamps and providing hands-on training to learners. In addition, while the learners pursue self-guided learning, TAs will develop and host their own bootcamps in their rehabilitation communities, thereby fulfilling a train-the-trainer model for exponential growth and dissemination of data science skills. Aim 3 is to broadly disseminate knowledge by creating an online repository of curated, rehabilitation-specific data science resources, organized by rehabilitation research area, including program materials. To accomplish this Aim, the leadership team will develop a public web database of existing online data science resources, including training materials, public data archives, and all course materials from this program, organized by specific rehabilitation research areas and needs. Successful accomplishment of our aims will increase capacity in data science across the rehabilitation research community and will improve the rigor, reproducibility and replicability of research needed to move the field forward.

NIH Research Projects · FY 2026 · 2022-02

PROJECT SUMMARY This project will develop new technology for high-resolution soft-tissue MRI immediately adjacent to orthopaedic metallic implants, an area that is “invisible” to current imaging techniques. We will leverage a novel high- performance 0.55 Tesla MRI platform and will develop new software and tools that are optimized for this platform and application. Finally, we evaluate the new metal MRI technology in two patient cohorts where it can immediately impact patient management: hip replacement and spinal fixation. Rationale: Orthopaedic metal implants are used extensively to treat late-stage osteoarthritis (total joint replacements), degenerative disc disease (spinal fixations), and fracture stabilization following trauma or bone resection. These implants fail in 10%-40% of cases, and accurate non-invasive imaging with soft-tissue contrast is essential for the evaluation of the underlying cause of hardware failure, and in surgical decision making and planning. At present, there is a major unmet need for high quality soft tissue imaging immediately adjacent to the metal surface to assess, for example, adverse local tissue response or nerve root impingement. State-of-the-art multi-spectral imaging (MSI) led to major improvements ~10 years ago, and the technology has plateaued. Innovation: We leverage a novel 0.55T MRI system that will soon be commercially available, which alone promises reduced image artifacts, because it provides much stronger imaging gradients relative to the susceptibility-induced gradients and field shifts, higher-bandwidth RF pulses, uniform RF transmission, and new opportunities for improved encoding and reconstruction. We also propose reimagined MSI pulse sequences to offer further improvements in signal-to- noise ratio, encoding time, and artifact. Approach: Our specific aims are: 1) to adapt standard metal MSI approaches for the 0.55T MRI platform to primarily assess the improvement of the 0.55T system alone due to reduced off-resonance; 2) to redesign improved metal MSI approaches that leverage the gradient-to-B0 and RF performance of the 0.55T MRI platform to compensate for lost SNR efficiency, while improving spatial resolution and artifact suppression and offering fat/water separation; and 3) to compare 0.55T MRI and 3T MRI protocols in patients with hip and spine implants, both to assess the improvement from the system alone and from redesigned MSI sequences. Broader Impact: This project aims to demonstrate improved capability to image closer to implant surfaces than what is possible at conventional 1.5T and 3T field strengths, and the impact in the context of post-surgical evaluation of hip-replacements and spinal fixations. This will broadly benefit the use of MRI in patients with metal, including orthopedic and non-orthopedic implants.