Johns Hopkins University

NSF Awards · FY 2025 · 2025-05

Concrete is the most widely used building material globally. Around 4.6 billion tons of cement is produced annually to meet growing urbanization, industrialization, and infrastructure demands. However, conventional Portland cement manufacturing is among the most energy intensive industries, primarily due to its high-temperature production process. This Future Manufacturing Seed Grant (FMSG) research project explores a novel, lower-energy approach to cement manufacturing by combining biological and chemical processes that will leverage waterways’ massive capacity to hold onto the key components used in cement production. Photosynthetic microbes called cyanobacteria look to be harnessed to produce solid calcium carbonate, a key component of cement, using sunlight and minerals in water. This microbially produced calcium carbonate plans to then be combined with sand and other materials for a promising alternative route to cement manufacturing. The success of the project will help enhance the competitiveness of US manufacturing and increase the availability of critically needed building materials, ultimately lowering the costs for production of new buildings for homeowners and businesses. The biomineralization of calcium carbonate from water sources using cyanobacteria is currently challenging for manufacturing applications. In this research project, the natural microbial carbonate mineralization process looks to be applied and improved through modification of the producer organisms and by controlling external environments to generate key components for biocement. Calcium carbonate production using microbes requires high carbonate concentrations in concert with elevated calcium levels and availability of chemical conditions that facilitate solid precipitation. Synechococcus elongatus cyanobacteria and other strains important to calcium carbonate formation look to be modified to enhance precipitation of calcium carbonate in the environment. Delivery of calcium carbonate seeks to be improved by increasing nucleation processes that facilitate carbonate precipitation to overcome barriers to solids formation. In concert, manipulation of extracellular conditions through electrochemical adjustment of environmental pH intends to ensure maximum conversion of reactants to calcium carbonate precipitate. Next, an integrated and scalable biocement manufacturing process that combines cyanobacterial growth and precipitation steps plans to be designed and implemented. A final goal will be to include biocement in infrastructure materials and test that these materials are mechanically stable and possess sufficient stiffness and strength. The project will include experts in microbial biomanufacturing, electrochemical engineering, and mechanical testing. Further, this project looks to train future engineers from high school to graduate levels in key concepts including microbial fermentation, electrochemistry, and mechanical testing of materials, and demonstrate how these skills will be applied to design, develop, and implement the next wave of innovative, low-cost manufacturing processes. 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 · 2025-05

Chronic Obstructive Pulmonary Disease (COPD) afflicts 13% of the world’s population and causes 150,000 deaths annually in the United States. Patients with chronic bronchitis, a subgroup of COPD, suffer from lung function decline with significant symptoms. Chronic CS-exposed primary human airway epithelial cells differentiated on an air-liquid interface and COPD-patient-derived differentiated epithelia are unable to form a healthy epithelial monolayer. We have demonstrated that the airway epithelial cells with chronic bronchitis have lower levels of the actin-severing protein, cofilin-1, the loss of which is recapitulated in our in vitro models of chronic CS exposure. Decreasing polymerized actin and restoring cofilin-1 to optimal levels in both COPD and CS injured airway epithelia improves monolayer integrity. We propose that the loss of cofilin-1 and the resulting reduction in actin dynamics impact the mitochondrial quality control required for repair mechanisms with chronic injury and hypothesize that strategies to target this pathway will improve airway epithelial health. In Aim 1, we will dissect the role of cofilin-1 in mitochondrial dynamics. We will determine if the loss of cofilin-1 mitochondrial fission and fusion to maintain healthy mitochondria. In addition, we will determine if the loss of cofilin-1 impairs intercellular mitochondrial dynamics by preventing the transfer of healthy mitochondria between cells and assess the role of the actin dynamics and cofilin-1 on these regulatory pathways. We will determine if these processes regulate the mitochondrial dysfunction evident in COPD patient derived cells. In Aim 2, we will determine if the loss of cofilin-1, either through its role on actin or in an actin-independent fashion, impacts mitophagy and mitochondrial biogenesis. As we see transcriptional changes in critical nuclear-derived proteins required for the mitochondrial machinery, we will determine if cofilin-1 serves as a transcription factor to regulate nuclear transcription of these critical proteins. We will determine if nuclear translocation of cofilin-1 is required for maintaining transcription of the mitochondrial machinery. Aim 3 will investigate the critical role of loss of cofilin-1 in maintaining cell proliferation required for airway epithelial repair after chronic injury. We will determine if the loss of cofilin-1, through its impact on mitochondrial function, stalls progression through the cell cycle and whether this loss of proliferation is due to cell quiescence or senescence. Finally, we will determine if the loss of cofilin-1, via its effects on mitochondria, promotes the epithelial changes observed in chronic bronchitis. We are uniquely positioned to uncover novel mechanisms linking cofilin-1 loss with dysfunctional cellular energetics in the airway epithelium of patients with chronic bronchitis. These novel studies provide preclinical and translational data to better understand the mechanism leading to mitochondrial dysfunction in COPD and to target actin dynamics for therapeutic gains.

NIH Research Projects · FY 2025 · 2025-05

1 Project Summary 2 The proposed research aims to identify the drivers of women’s sexual and reproductive empowerment, including 3 male influences and subsequently demonstrate the predictive effect women’s SRH empowerment as a 4 mechanism to reduce unintended pregnancies by increasing their ability to better align their reproductive 5 intentions and behaviors. The project takes place in Burkina Faso, a high fertility and highly patriarchal country 6 in West Africa. It leverages existing data from the Performance Monitoring for Action (PMA) project, which 7 collects nationally representative longitudinal data on a range of SRH measures, including a validated SRH 8 empowerment scale. PMA currently includes 3500 partnered women of reproductive age who responded to four 9 annual surveys between 2019 and 2024. The project will expand the PMA female panel by adding a male 10 component, developed using a sequential mixed model design, including 1) a qualitative study among 120 adult 11 men in 4 communities in Burkina Faso, 2) cognitive interviewing and pilot testing of a novel SRH male module 12 derived from the qualitative study and 3) two new rounds of PMA panel data among 4500 couples, to enrich the 13 understanding of women’s SRH empowerment through a gender lens. Our specific aims are three-fold: 14 Aim 1. Evaluate short- and long-term changes in SRH empowerment and identify predictors of these 15 changes. we will use latent trajectory model and linear growth modeling to identify sociodemographic and life 16 events that predict yearly and long-term changes in SRH empowerment scores based on 4 rounds of existing 17 PMA female data. 18 Aim 2. Understand and evaluate men’s influence on women’s SRH empowerment. We will conduct a 19 qualitative study and use thematic analysis to understand men’s perspectives on childbearing and contraceptive 20 decisions. Findings will inform the development of a new male SRH module, that will be pretested and added to 21 the existing PMA female panel. We will use linear regression models to evaluate men’s influence on the 22 development and exercise of women’s SRH empowerment across the reproductive life span using couple linked 23 data. 24 Aim 3. Evaluate the effect of SRH empowerment on reproductive intentions and behaviors, accounting 25 for men’s influences. Adding an additional round of PMA couple data, we will employ generalized estimating 26 equation models to assess the predictive effect of women’s SRH empowerment in reducing the intentional gap 27 between fertility and contraceptive intentions and the behavioral gap between contraceptive intentions and 28 behaviors. We will also examine if male and couple factors change these associations.

NIH Research Projects · FY 2026 · 2025-05

Project Summary The long-term goal of our lab is to understand gene regulatory mechanisms that enable the development of a single cell zygote into a multicellular organism. This proposal focuses on an essential mechanism in all animals, the post-transcriptional repression by microRNAs. MicroRNAs (miRNAs) repress target genes, controlling their protein output in time and space. They provide an essential layer of regulation during development, evidenced in the fact that loss of the machinery that processes these short RNAs causes embryonic lethality in every animal examined. Moreover, mutations in the miRNA biogenesis or effector machinery in humans causes syndromic diseases. Individual miRNAs have also been linked to essential functions in model organisms as well as disease in humans (e.g. mutation in a single miRNA causes progressive deafness in humans). Although the number of miRNAs has increased during animal evolution, a set of 32 miRNAs were present in the last common ancestor of bilaterian animals and have been conserved over hundreds of millions of years. However, with few exceptions, the functional targets of these highly conserved miRNAs remain unknown due to a number of technical challenges associated with: i) the short nature of miRNAs that has made their profiling more difficult than longer mRNAs, ii) the fact that miRNAs exert quantitative, often modest, repression on their targets, and iii) the fact that target predictions that largely rely on short sequence information, produce an excess of false positives. Our research program systematically tackles the roles of conserved miRNAs during animal development. We have developed a research strategy that leverages the experimental system provided by C. elegans, with state-of-the-art molecular biology and genetics approaches. The strategy we have outlined will yield knowledge on the functions of these important regulators at the organismal and cellular level and will bridge that with a deep understanding of molecular mechanism based on our strong focus on identifying functionally critical targets. Knowledge of these targets has allowed us to begin to address how changes in their dosage, even if modest, affect cellular processes and ultimately development and physiology. Our findings in C. elegans are also guiding investigation of these conserved miRNAs in mammalian cell models. Our work will reveal the functions of essential, conserved miRNA genes and will uncover cellular pathways for which dosage control is important. We anticipate that this knowledge will be important to interpret mechanisms of human disease.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY The overall objectives of this study are to (1) develop mRNA lipid nanoparticle (LNP) formulations capable of eliciting dual or biased Type 1 T helper (Th1) and/or Type 2 T helper (Th2) immune responses via a machine learning-aided screening platform, (2) engineer mRNA LNP- loaded microgels as an immunostimulatory niche in vivo to recruit and transfect host immune cells and potentiate antigen-specific immune responses, and (3) demonstrate the efficacy and safety of this new LNP-based vaccine platform in murine cancer models. The success of mRNA COVID-19 vaccines utilizing lipid nanoparticle (LNP) delivery has underscored the potential of mRNA LNP-based cancer vaccines in advancing immunotherapy by training the immune system to respond effectively to tumor antigens. To maximize their potency in eliciting robust immune responses for cancer immunotherapy, it is important to engineer effective approaches for systematic programming of immune activation profile via optimization of LNP compositions and improving delivery for mRNA LNP vaccines. Our preliminary data have demonstrated that LNP compositions and helper lipid structure influence the polarization of immune activation, and LNPs with dual Th1-plus-Th2 activation profile yielded the most potent antitumor efficacy in mouse tumor models. In addition, a candidate mRNA LNP vaccine loaded into a nanofiber-based microgel matrix, which facilitated recruitment and retention of host immune cells, enhanced antigen presentation, and elicited equally strong anti-tumor response with a single dose compared to a standard three-dose immunization regimen. In this proposed study, we will first optimize LNP composition for efficient transfection of antigen-encoding mRNA into antigen-presenting cells (APCs) and non-APCs via an machine learning-guided, iterative design-build-screen/test-learn process, and evaluate antigen presentation, and immune activation profiles in vivo; then develop an LNP-incorporated nanofiber microgel matrix termed LiNx as an immunostimulatory niche for recruitment of host immune cells and assess gene delivery efficiency and immune response profiles; and finally demonstrate the therapeutic efficacy and biosafety of the optimized LNPs and LiNx in suppressing tumor growth in therapeutic models of melanoma, lymphoma, and colon carcinoma in mice, as well as an orthotopic, immunoquiescent, pancreatic cancer mouse model. The innovation in this study lies in programming the immune activation profile generated by mRNA LNP vaccine by tunning cell-preferential transfection activity of LNPs and engineering an immunostimulatory niche using a nanofiber microgel matrix to recruit and retain host immune cells and deliver LNP vaccines, thus potentiating the therapeutic efficacy against cancer. Findings from this study can inspire rational design of new mRNA-based immunotherapies for the treatment of cancer and other diseases.

NIH Research Projects · FY 2026 · 2025-04

Project Summary Maintaining genome integrity is critical for hematopoietic stem cells (HSCs) as they self-renew and differentiate into all blood cells throughout one’s life with enormous regenerative capacity. HSCs depend on the Fanconi anemia DNA repair pathway that removes DNA interstrand crosslinks. Endogenous reactive aldehydes are important sources of DNA damage that patients with Fanconi anemia are vulnerable to. Unfortunately, we do not know all the types and extent of reactive aldehydes that are important in human diseases. Moreover, there are no FDA-approved therapies that reduce aldehydic load and prevent DNA damage for patients with Fanconi anemia. In this R00 proposal, we propose to dissect the role of all the ALDH and ADH isoenzymes in human HSCs using a xenotransplant model and single-cell CRISPR screen. We also aim to uncover novel disease modifiers that can enhance aldehyde detoxification capacity through the CRISPR activation screen. Finally, we aim to prevent endogenous aldehyde-induced DNA damage in Fanconi anemia by activating detoxifying enzymes or extracellular vesicle-mediated delivery of functional enzymes. Knowledge gained through our studies will establish novel therapeutic strategies useful for preventing bone marrow failure and malignancies in Fanconi anemia.

NIH Research Projects · FY 2025 · 2025-04

Without movement, we would be utterly unable to interact with the world. All behaviors, including speech, writing, reaching, grasping, gaze, walking and posture require the coordinated activities of many motor areas. Further, sensory signals provide essential feedback to these motor areas, enabling accurate motor control and motor learning, as well as providing information vital for deciding future behaviors. As a result, understanding the sensorimotor control of even the most basic movements, like orienting toward a sudden sound or reaching to pick up a glass of water, is complex. Damage to these sensorimotor pathways can produce a wide range of debilitating neurological disorders including tremor, Parkinson's disease, ataxia, dystonia, and spasticity - all of which markedly decrease quality of life. The Society for the Neural Control of Movement (NCM) is an international community of scientists, clinician-investigators and trainees engaged in research whose common goal is to understand how the brain controls movement and to address the deficits that occur in disease. NCM promotes a broad range of research using interdisciplinary approaches (e.g., neurophysiological, anatomical, molecular, computational, and behavioral), different animal models, and studies of intact subjects and those with neurological disorders. The inaugural NCM Meeting took place in 1991. The success of the society and its annual meeting has led to a continual growth in membership, meeting attendance, and the breadth of scientific content. With support through the NIH, the 2025 NCM meeting will make substantive progress towards furthering three main goals of the society: Aim 1) Stimulate new research approaches and collaborations among NCM meeting attendees by identifying new topics and appropriate scientists as speakers, Aim 2) continue to increase the gender and ethnic diversity within the NCM leadership and in meeting programing, and Aim 3) promote and support the development of the next generation of motor control researchers by providing financial and career support for graduate students and post-doctoral fellows. Overall, the unique format of the annual NCM meeting, with its focus on interdisciplinary approaches, discussion, and scientific interaction in an intimate meeting environment, is of immeasurable value to furthering worldwide understanding of how the brain controls movement in both health and disease.

NIH Research Projects · FY 2026 · 2025-04

Project Summary/Abstract Initiation of very early antiretroviral therapy (ART) in neonates with in utero HIV-1 leads to the possibility of long-term ART-free control in a small subset of neonates. In the IMPAACT P1115 clinical trial, very early ART has led to four cases of long-term, ART- free control in children. In addition to this outcome, sex differences were observed with respect to plasma viral load, cell-associated HIV-1 DNA concentrations, and the ability to maintain sustained virologic suppression. These observations are consistent with previously published research in other cohorts that revealed sex differences in HIV-1 replication capacity and interferon resistance with respect to in utero HIV-1 transmission. To further interrogate the virologic determinants that lead to the formation of the viral reservoir, we propose to create infectious molecular clones from the gag-pro and env regions of the near full-length single genome sequences from the proviral HIV- 1 DNA of IMPAACT P1115 participants. These recombinant viruses will be assayed for replication capacity and interferon resistance, which will be examined against early life biomarkers of in utero HIV-1 transmission such as plasma viral load, HIV-1 DNA concentrations, and biological sex. In addition to employing the conventional TZM-bl and CEM-GXR-25 immortalized cell lines to determine viral infectivity and replication capacity, we propose to also compare HIV-1 interferon resistance in primary CD4+ cells isolated from adult males and females or cord blood cells to also investigate the role of target cell type on interferon resistance. Altogether, these studies will fill a critical gap in our understanding of retroviral infection in fetal cells and by biological sex and their implication for sustained virologic control in postnatal life.

NSF Awards · FY 2025 · 2025-04

When navigating in complex environments, fixed landmarks and moving obstacles are crucial features that influence efficient and robust path planning, optimal route finding, and minimization of navigational errors. Autonomous vehicles are severely limited by their inability to reliably anchor their navigation to landmarks and predict and avoid the movement of others. The research team proposes to develop and refine a computational model of spatial navigation and spatial representation using neural data obtained wirelessly from animals navigating in the two largest electrophysiology-compatible rodent mazes in the world, which are known as “megaspaces.” These studies explore the influence of stationary landmarks and moving objects as rats optimize their routes: a classic paradigm (the Traveling Salesperson Problem) in Computer Science. In addition to their technological impact in robotics and autonomous vehicles, these investigations can be extended to human mental health dysfunctions that are often accompanied by deficits in spatial processing such as in early onset Alzheimer’s disease, attentional deficit hyperactivity disorders, schizophrenia, or depression. This investigation is novel and unique in trying to understand how the interactions between the hippocampus and entorhinal cortex, two main components of the brain’s ‘GPS’ system, facilitate navigation, learning, and complex decision making in very large spaces. The research involves using experimental data to constrain a detailed biophysical neural model and testing experimentally its predictions about the properties of neural representations of megaspaces in challenging navigational tasks. The model will provide a new tool for the detailed study of the use of fixed landmark and moving obstacles in very large environments for efficient navigation. The work will contribute to robotics and computational neuroscience along two different axes: (1) using data-constrained modeling to propose concrete mechanisms explaining the nature of the interactions between self-motion and landmark-based navigational information and (2) using neural representations of large space to achieve efficient solutions or approximations for generally hard spatial navigational problems that could have significant impact in many disciplines. A companion project is being funded by the Department of Science and Technology, India. 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 · 2025-04

PROJECT SUMMARY Most research on Alzheimer’s Disease and Alzheimer’s-Related Dementias (AD/ADRD) is set in higher income contexts in North America, Europe, and Asia, yet (1) the burden of AD/ADRD is rapidly increasing in low- and middle-income countries (LMICs), particularly in sub-Saharan Africa (SSA); (2) the field can learn more about the etiology of AD/ADRD from studying it in contexts that have different patterns of exposure: for example, older individuals in SSA are more likely to live in rural areas, have longer labor force participation, and different disease vulnerabilities; and (3) there is relatively little expertise in neuroscience and AD/ADRD research outside of high-income contexts. To address these issues, we propose a collaboration between Johns Hopkins Bloomberg School of Public Health (JHBSPH) in the United States and École Nationale de Statistiques et d’Economie Appliquee (ENSEA) in Cote d’Ivoire to jointly build the research infrastructure to study AD/ADRD in a new context by creating a set of reusable tools that will be employed by the ENSEA team independently for continued research after this project is completed. This collaboration will also yield insights into genetic, environmental, and social factors associated with AD/ADRD that can inform prevention and treatment strategies in the United States. This project will proceed in two phases. In the first, the UG3 phase, our goals are to establish data collection and research protocols for the 40+ population in Cote d’Ivoire and develop a network of stakeholders involved in aging-related policies and programs. For the second phase (UH3), we intend to collect data on dementia for a representative sample of approximately 4500 adults aged 40 and older in Cote d’Ivoire and conduct research that identifies risk factors for AD/ADRD in Cote d’Ivoire.

NSF Awards · FY 2025 · 2025-04

This Designing Materials to Revolutionize and Engineer our Future (DMREF) project aims to revolutionize the creation of novel engineering alloys by focusing on the relationship between the process of production and the material's resultant microstructure - the internal structure invisible to the naked eye. This relationship is a crucial but less-explored segment of the material science lifecycle, yet directly connects processing to performance. Using cutting-edge machine learning and data science, the project team will build a platform, named as DRAGONS (Data-driven Recursive AI-powered Generator of Optimized Nanostructured Superalloys), to discover these connections, enabling more nuanced control over material production. DRAGONS will prescribe ideal processing conditions to achieve a specific material microstructure. This project carries broad significance, with the potential to drive advancements in diverse sectors that rely on novel materials including electronics, healthcare, energy, and transportation. Additionally, the project's educational outreach activities aim to inspire the next generation of scientists and engineers by providing a more diverse, inclusive, and sustainable pathway into these fields. Hence, this research carries potential to catalyze scientific advancement, foster economic growth, and enhance educational outcomes. This DMREF project focuses on harnessing machine learning and data science to advance understanding of the processing-microstructure relationships in the production of novel materials, a key, yet underexplored facet of the Materials Genome Initiative (MGI). The research team will develop a data-driven platform, named as Data-driven Recursive AI-powered Generator of Optimized Nanostructured Superalloys (DRAGONS), to demystify the complex relationships inherent in the creation of multi-phase, heterogeneous nanostructured materials (HNMs). DRAGONS will utilize predictive models to interpret microstructure attributes based on given processing conditions and, in a reciprocal manner, provide processing parameters required to generate a predefined microstructure. Capitalizing on expertise in magnetron sputtering and heat treatment (MS+HT), the research team aims to engineer intricate heterogeneous designs in Ni-based superalloys. An iterative research framework encompasses synthesis and microstructural design, microstructure characterization, atomistic simulation, and mesoscale modeling, and each cycle will refine DRAGONS, fostering stronger links between processing descriptors and microstructure features. The broader impacts of this work span the potential to reshape engineered alloy development and to foster collaborations with NIST scientists. Furthermore, educational programs targeted at developing a diverse, skilled workforce in materials engineering underscore the project's commitment to society. 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 2025 · 2025-04

Generative AI systems are increasingly used to create text, images, and other media. These systems raise technical and usability issues around ways to better-integrate AI-based tools into creative practice while respecting the needs of creative professionals whose content is used to train the models. These issues include questions about the nature of, ownership of, and responsibility for creativity and the creative content generated by these tools. To inform research addressing these issues, the Workshop on Creativity and Generative AI will bring together learning researchers and creative professionals. By bringing together the people who build these tools and the people who use them and are impacted by them, the workshop will identify important directions for research and tool development around generative AI. This award will support the participation of creative professionals in the workshop. The Workshop on Creativity and Generative AI will be held in conjunction with the Neural Information Processing Systems (NeurIPS) conference, one of the world’s leading research conferences on AI. NeurIPS is a home conference for machine learning researchers, so it is comparatively easier for them to attend the workshop than creative professionals. Supporting creative professionals to attend the workshop is important for achieving its goals. The participation of these professionals will inform the evolution of generative AI, while also bringing in a wider range of backgrounds and perspectives to the NeurIPS research community. 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 · 2025-04

Project Summary/Abstract Magnetic resonance (MR) neuroimaging is an essential tool for clinical diagnosis, monitoring, and management and for research on the pathophysiology, progression, and treatment efficacy of many neurological diseases. Because MR hardware and software can be different between sites and can change over time as technology improves, it has been extremely difficult to standardize the appearance of MR neuroimages. As a result, establishing consistent, reliable postprocessing for quantitative analysis of these images has been problematic, and there is evidence that radiologists’ assessments are also affected by this variability. Although many research protocols have been able to use standardized acquisitions, clinical acquisition protocols continue to be highly variable because of differences in hardware and software and from local preferences. To reduce costs, for example, although research protocols strive to acquire images using three-dimensional (3D) protocols, clinical protocols commonly acquire many scans using multi-slice, two- dimensional (2D) protocols which have thick slices and sometimes slice gaps. Also, different imaging centers may acquire different sets of tissue contrasts (e.g., T1-weighted and T2-weighted contrasts) with a different set of 3D versus multi-slice 2D acquisitions and may sometimes omit certain tissue contrasts entirely. Modern medical image analysis algorithms have been primarily designed for research protocols—with standardized, high-quality images—and they prove to be highly inconsistent when applied to clinical-quality images. There is a dire need to find a way to use modern AI algorithms on clinical images. This will do two things: first, it will permit translation of existing algorithms to the clinic; and second, it will open the vast catalog of clinical images to be used in training new algorithms. This research program proposes the Resolution Enhancement And Contrast Harmonization (REACH) algorithm which super-resolves multi-slice 2D MRI and adjusts the contrast of both multi-slice 2D and 3D MRI for use in both downstream processing and clinical diagnosis. Specifically, we will: 1) Develop and extensively train an interpretable deep learning algorithm called HACA3+ for harmonization, restoration, and imputation; 2) Develop SMORE+, a super-resolution method that incorporates high-resolution reference images and is computationally fast; 3) Develop and evaluate REACH for resolution enhancement and contrast harmonization; 4) Carry out a radiologist observer study using REACH. REACH addresses several aspects that have not been previously addressed. Most importantly, it will be specifically trained and tested on and for clinical-quality data, addressing issues such as images with thick slices and slice gaps, missing tissue contrasts, and harmonization that is optimized for specific downstream processing methods. We will further demonstrate the potential for REACH harmonization to be used by radiologists for clinical diagnosis. REACH will be made freely available to researchers upon its publication.

NIH Research Projects · FY 2026 · 2025-04

Project Summary/Abstract Growth and neurodevelopment are fundamental to child health and have an epigenetic basis that remains poorly understood, posing a barrier to therapeutic development. Mendelian disorders of the epigenetic machin- ery (MDEMs) are monogenic syndromes characterized molecularly by altered epigenomes and phenotypically by disrupted growth and neurodevelopment. They can thus inform the epigenetic basis of growth and neurode- velopment. Weaver and Sotos syndromes are MDEMs caused by disruption of distinct histone writers that ex- hibit highly similar phenotypes of pathological overgrowth and intellectual disability (ID). The current proposal uses these disorders to elucidate epigenetic mechanisms of overgrowth and ID and to test a targeted treat- ment. The central hypothesis is that genetic disruption of the Weaver histone writer causes overgrowth and ID by altering cell type-specific chromatin and transcriptional pathways responsible for normal growth and neuro- development, which converge with disrupted Sotos pathways, and both are ultimately correctable by pharma- cological manipulation of a shared histone mark. Our rationale is that elucidating chromatin and gene expres- sion changes that cause skeletal overgrowth and ID in two rare diseases will inform our understanding of these central regulators of epigenetic marks and especially how they regulate normal growth and neurodevelopment and may reveal a common drug target. The central hypothesis will be tested by pursuing three specific aims: 1. Establish the neurological phenotype and causal mechanisms in our Weaver mouse model; 2. Elucidate epige- netic mechanisms of skeletal overgrowth and evaluate treatment in Weaver mice; and 3. Determine human disease mechanisms and therapeutic responses in Weaver iPSC models and compare to Sotos. In aim 1, data establishing skeletal overgrowth due to excess osteogenesis in a Weaver syndrome mouse model are present- ed. Studies to elucidate the neurobehavioral phenotype and its basis are proposed. In aim 2, preliminary data show an epigenetic drug (GSKJ4) reverses excess osteogenesis and the altered transcriptome in vitro in Wea- ver mouse osteoblasts. Preclinical trials with GSKJ4 in Weaver mice alongside transcriptomic and epigenomic profiling are proposed. In aim3, data from human Sotos cells show altered transcription of pathways shared with Weaver. Cross-disorder comparison of epigenetic mechanisms, phenotypes, and drug responses in pa- tient iPSC-based models are proposed. This research is innovative because it uses a cross-species, state-of- the-art multi-omics approach on models from two related disorders and tests an epigenetic drug’s ability to re- verse skeletal overgrowth and neurobehavioral phenotypes. The proposed research is significant because it establishes both human organoid and mouse disease models for testing targeted, mechanism-based therapies for currently untreatable phenotypes. Moreover, this work advances knowledge of fundamental epigenetic mechanisms controlling growth and neurodevelopment and has the potential to uncover new epigenetic para- digms, including treatments for MDEMs and more common lifelong neurological and growth disorders.

NIH Research Projects · FY 2026 · 2025-04

In hearing, our ability to rapidly and effortlessly recognize newly presented auditory input in a complex sensory environment, referred to as implicit learning, is one of the key processes that enables efficient auditory perception. This process would require the encoding of new auditory patterns at the neural level. However, little is known about underlying neural mechanisms and circuits that enable implicit learning. To draw a comprehensive neural circuit for implicit learning, investigating neural mechanisms for auditory processing is required. This project focuses on investigating neural dynamics and mapping relevant neural circuits in the auditory cortex (AC) during auditory implicit learning. To study this, we first investigate neuronal responses of awake mice in AC. First, in the passive listening condition, we use two-photon Ca+2 imaging to identify neural dynamics of different cell types by manipulating neural activity on a subset of neurons at a single-cell resolution using holographic optogenetic stimulation. To study neural processes for implicit learning, we present a series of randomly generated tone sequences while a specific target sound re-occurs at random trials. We define distinct neuronal responses that are developed only for the re-occurring target sound as an index of implicit learning. We expect distinctive neuronal characteristics for implicit learning to emerge for each cell type of inhibitory interneurons. A specific cell type that directly modulates the activity of excitatory neurons will be further identified. Upon thorough investigation on the role of different cell types in the passive listening condition, we move on to the active listening condition. In the active listening condition where a listening task is given to trained animals, we expect similar neuronal characteristics to the passive condition from a different subgroup of cells. We further manipulate activities of selected neurons of different cell types, both excitatory and inhibitory neurons, and compute behavioral change between pre- and post-stimulation to map neural circuits during implicit learning. We expect to identify a causal link between neuronal characteristics and implicit learning and draw the complete neural circuit. Altogether, this project will provide a complete overview of neural mechanisms for implicit learning.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY / ABSTRACT The emergence of clinical photon-counting CT shows much promise for new clinical diagnostics owing to its noise advantages, improved material discrimination, and small detector pixels. The latter element has the po- tential to have particular impact on the overall spatial resolution of the system. Recently available high-resolution systems have demonstrated particular advantage in cardiothoracic imaging and pulmonary imaging in particular, where good visualization of the fine structure of the lung can have significant impact on diagnostics. These x-ray detector developments have, in some ways, outpaced x-ray source developments; and, with these new systems the x-ray now tends to be the limiting factor for high-resolution capability. The fundamental issue is that smaller detector voxels require a smaller x-ray focal spot – which tends to limit fluence and increase overall noise. This compounds with the general need for more fluence when image voxels are made smaller (higher resolution) to keep from increasing noise. In x-ray tube design there is an inherent trade-off where smaller focal spots have lower capacity for generating fluence. Thus, much of the capability of high-resolution CT with photon-counting detectors is unrealized. We proposed a novel data acquisition strategy that uses multiple focal spots. That is multiple, structured spots that change the balance of focal spot size and fluence – e.g. performing a data acqui- sition with both a large and small focal spot to get both high-resolution information but sufficient fluence to reduce noise. Combined with state-of-the-art model-based and deep learning approaches, we will develop a new para- digm for ultra-high-spatial resolution CT (UHR-CT). We seek to accomplish that development through the follow- ing specific aims: Aim 1: Develop system models and reconstruction approaches for data acquisition with multiple focal spots, in which high-fidelity model form a framework for both simulation and joint data processing of the multiresolution data associated with the multiple focal spot technique. Aim 2: Investigate and evaluate different multiple focal spot strategies for UHR-CT, wherein we study a range of system designs from current technology to more complex focal spot designs, and evaluate optimized strategies in simulated and physical systems. Aim 3: Assessment of UHR-CT in clinical PCCT on lifelike phantoms and an in-vivo animal model, where we translate the multiple focal spot method to a clinical PCCT for immediate impact. Successful completion of these aims will demonstrate the underlying technology, validate the methods, and characterize the potential for high-resolution performance improvements using both current and emerging x-ray source technol- ogies. The availability of the ultra-high-resolution capability opens the doors to a wide range of potential clinical diagnostic as smaller and smaller features can be resolved.

NIH Research Projects · FY 2025 · 2025-04

PROJECT SUMMARY Approximately 100,000 Americans, primarily of African descent, live with sickle cell disease (SCD), a genetic red blood cell (RBC) disorder characterized by a mutated hemoglobin (HbS). HbS-containing RBCs sickle when exposed to low oxygen or hypertonic environments, precipitating acute, excruciatingly painful episodes of vascular obstruction. Vaso-occlusive episodes (VOEs) account for a 7 to 30-fold higher hospitalization rate and a 2- to 6-fold higher rate of emergency department visits, compared to age-specific rates for Black Americans without SCD, and adversely impact quality of life and survival. Current disease-modifying treatments for SCD such as hydroxyurea, voxelotor, and crizanlizumab only reduce hospitalizations for VOE by 50% at most. Thus, prevention of VOE by other means in combination with existing treatments remains crucial. Chronic dehydration is a quantifiable and potentially actionable biomarker, which may predict morbidity and mortality in patients with SCD. In emergency room settings, VOE is frequently accompanied by acute dehydration, which is managed by fluid replacement. However, the prevalence of chronic dehydration during “steady-state” conditions (i.e., non- crisis) is unknown, and it is uncertain whether mild, chronic dehydration predicts increased risk of SCD-related morbidity or mortality. Age-associated hyposthenuria (i.e., the inability to concentrate urine), is common in SCD, and could plausibly contribute to chronic dehydration. Although SCD is thought to induce compensatory polydipsia (i.e., increased thirst), conflicting reports also note impaired thirst regulation, which may be sex or age dependent. Of note, all large examinations of steady-state dehydration have been limited to infants and very young children, excluding adolescents or adults who may be more susceptible to chronic dehydration due to progressive renal dysfunction. Our hypothesis is that chronic dehydration is predictive of VOE, hospitalizations, and death, and of relevance, may be suitable for monitoring to prevent VOE. To analyze the relationship between chronic dehydration and subsequent VOE we will 1). Conduct an epidemiologic investigation, using data and specimens available from the Cooperative Study of Sickle Cell Disease (CSSCD) and the more contemporary Multicenter Study of Hydroxyurea (MSH), and 2). Conduct a prospective, clinical study enrolling 50 participants with SCD. The CSSCD and MSH are open BioLINCC studies with rich phenotyping, lengthy prospective follow up, and adjudicated clinical events. We will use available serum specimens from these cohorts to assay serum osmolality, a marker of dehydration. Our observations from the epidemiologic investigation will be complemented by the prospective clinical study, which will include more granular data collection and state-of-the-art measurements of dehydration. The knowledge to be gained from this project will establish whether chronic dehydration during steady-state conditions is predictive of morbidity and mortality in patients with SCD and has the potential to influence patient behavior and recommendations for care, such as at-home hydration monitoring to encourage fluid intake for VOE prevention.

NIH Research Projects · FY 2026 · 2025-04

Cachexia induced by pancreatic ductal adenocarcinoma (PDAC) results in significant morbidity, mortality, and poor response to treatment including immune therapy. We intend to apply our molecular and functional imaging capabilities, and our experience in developing theranostic nanoparticles (NPs) that deliver small interfering RNA (siRNA), to focus on reversing PDAC-induced cachexia. We found that a cachexia inducing PDAC xenograft induced profound changes in brain, plasma and tumor interstitial fluid glutamine levels that led us to focus on the glutamine/glutamate axis and disruption of glutamine metabolism in Aims 1 and 2 of this application. Our preliminary data with human plasma and human PDAC tissue further support targeting the glutamine/glutamate axis. Of all the visceral organs, the spleen showed the highest number of metabolic changes and the largest weight loss with cachexia. Downregulating the glutamine transporter, SLC1A5, significantly reduced body weight loss compared to empty vector or wild type tumors of similar volumes, and normalized spleen weights to those of normal non-tumor bearing mice or mice with non-cachexia inducing tumors. Since the spleen is a major reservoir of immune cells, the splenic weight loss and metabolic alterations have prompted us to focus on the spleen and tumor immune environments with cachexia, and following disruption of glutamine metabolism, in Aim 3. In Aim 1 we will focus on the glutamine/glutamate axis, studying preclinical PDAC models in immune suppressed as well as immune competent mice with SLC1A5 and glutaminase 1 and 2 (GLS1/2) downregulated. These studies will expand our understanding of the effects of downregulating these target genes on cachexia, and on tumor and organ metabolism using 1H magnetic resonance spectroscopy (MRS), transcriptomics, and molecular characterization. In Aim 2, we will downregulate these target genes in established wild type tumors using biocompatible dextran siRNA NPs that can be imaged to detect tumor delivery and biodistribution. We will also evaluate a pharmacological inhibitor of SLC1A5, V-9302, and of GLS, CB-839, and determine the effects of treatment with siRNA NPs and of pharmacological inhibitors on cachexia and on tumor and organ metabolism using 1H MRS. CB-839 is already in clinical trials for solid cancers, presenting a more immediate strategy for reversing or reducing cachexia. In Aim 3 we will investigate changes in T-cell exhaustion and myeloid derived suppressor cells combined with metabolic changes in the spleen and tumor with or without glutamine disrupted. Mass spectrometry imaging will be used to relate spatial metabolic information to immunostaining. Studies in Aim 3 will include investigating paired spleen and tumor tissue from PDAC patients with or without weight loss and loss of muscle mass as identified in CT scans. The three aims are designed to advance understanding of the consequences of cachexia on organ metabolism and the immune microenvironments in the spleen and tumor, and the role of glutamine metabolism disruption on reversing or reducing these consequences.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY This project addresses technological challenges in personalized neoantigen immunotherapy for cancer treatment, focusing on developing a more precise and broadly applicable neoantigen prediction algorithm by integrating multiomic data. The research aims to innovate in algorithm and software development, enhancing the selection and validation of neoantigens for immunotherapy. Despite the potential of personalized neoantigen therapies in oncology, their clinical adoption is hindered by the time-consuming and costly process of neoantigen selection and validation. Current computational tools for neoantigen prediction have limited effectiveness due to several factors, including inadequate training on immunologically validated neoantigens, limited HLA allele coverage in current training datasets, and the absence of multiomic patient data in algorithm training. Our project leverages a multidisciplinary team and a rich dataset of matched tumor and normal specimens from patients treated at our institutions, focusing on HLA alleles with limited existing data available, and the highly sensitive Mutation-Associated Neoantigen Functional Expansion of Specific T Cells (MANAFEST) assay for T cell activation and expansion. We propose to generate the first public dataset of immunologically assessed neoantigens with patient-matched multiomic sequence data, enhancing the precision of neoantigen prediction through advanced algorithmic methods and the integration of comprehensive biological data. The research design includes the creation of a Multiomic Neoantigen Algorithm Training and Assessment Resource and the development of a novel deep learning-based neoantigen prediction algorithm that utilizes patient-specific multiomic data. This approach aims to improve the prediction and clinical utility of neoantigen-based therapies and to provide community resources through open data and open-source software, promoting wider application and innovation in the field. By addressing these challenges, the project expects to substantially enhance the precision and applicability of neoantigen prediction tools, paving the way for their effective use in clinical settings and improving outcomes in cancer immunotherapy.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY/ABSTRACT The United States (US) is experiencing dual public health crises in maternal mortality and incarceration. Both phenomena are characterized by negative structural determinants of health. Substance use and mental health conditions are exceedingly common among incarcerated women and are also substantial and increasing causes of pregnancy-associated deaths. However, the contribution of incarceration during pregnancy or postpartum to maternal mortality has not been studied. Yet, each year, tens of thousands of pregnant women are incarcerated. To date, research on drivers of maternal mortality has not included incarceration status of the mother. Likewise, studies on deaths in custody and post-release mortality have not reported whether the decedent was pregnant or postpartum. Similar social and structural risk factors exist for fetal and infant mortality among infants whose mothers were incarcerated. Nonetheless, we know little about the association and trends of maternal incarceration up to one year postpartum with incidence of fetal and infant mortality. The overall goal of this proposed R01 is to provide the first population-based estimates of incidence, causes, and disparities in pregnancy-associated death, stillbirth, and infant mortality among women who were incarcerated during pregnancy and/or up to one year postpartum; a further goal is to examine gaps and opportunities in how public health and correctional health agencies address risk factors for preventable mortality in this group of mothers and infants affected by numerous adverse systemic, social, and environmental conditions. Our first aim is to create databases in three states (Maryland, Minnesota, and Washington) of women who were incarcerated during pregnancy, delivery, and/or up to one year postpartum (“perinatal period”) between 2010-2024; we will accomplish this by linking prison admissions and release data from state Departments of Corrections with birth certificate and fetal death certificate data from state vital records. Our second aim is to calculate the incidence of pregnancy-associated, fetal, and infant death among mothers incarcerated during the perinatal period by integrating death certificate data with the linked dataset of perinatal incarceration that is created in Aim 1. Our third aim is to identify health care and incarceration system barriers and opportunities to reduce risk for maternal and infant mortality; we will accomplish this aim through qualitative interviews with national samples of practitioners in correctional health and child welfare and of review committee members for maternal and fetal/infant mortality. Together, results from these aims will identify key modifiable risk factors, especially related to incarceration. The proposed research will extend the current knowledge base on maternal and infant mortality to include incarceration, which carries numerous adverse health risks. Achieving our aims will enable clinical and policy interventions to optimize care that can prevent mortality.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY This research proposal aims to investigate the critical role of the placenta-brain axis in Down Syndrome (DS) development. DS or Trisomy 21 (T21) results from trisomy or partial translocation of human chromosome 21 (HSA21), impacting roughly 1 in 700 births. Both placental and brain alterations are well established in DS, yet underlying mechanisms and prenatal treatments for these abnormalities are lacking. A key unanswered question is whether placental abnormalities contribute to altered cortical development in individuals affected by DS. Here, I investigate the effects of HSA21 dosage and HSA21-linked genes APP and SOD1 on placental function, alterations in neuroactive compounds secreted from placental syncytiotrophoblast (STBs) and the resulting neurodevelopmental consequences. I hypothesize that increased dosage of HSA21, driven by HSA21-linked genes APP and SOD1, causes impaired STB formation and secretion of crucial neuroendocrine factors, which subsequently contributes to cell non- autonomous neurodevelopmental perturbations. I will test my hypothesis with two aims. First, I will determine perturbation in T21 STB function and secretome and test the involvement of SOD1, APP and oxidative stress. Second, I will investigate the contribution of an impaired STB secretome to neurodevelopmental perturbations in T21. Hypothesis testing will be done by using a novel model of the human placenta-brain axis using human induced pluripotent stem cell (hiPSC)-derived STBs and cerebral organoids. The research outcomes are expected to address a key unanswered question in the field: do placental abnormalities contribute to altered cortical development in humans affected by DS? Our approach will uncover the role of specific T21 genes on T21-induced oxidative stress on the placenta-brain axis in neurodevelopment, test dietary compounds that could improve T21 dysfunction and more broadly facilitate our understanding of the role of placental signals in fetal brain development. Our proposed research will contribute to identifying potential therapeutic targets for prenatal treatment and enable real-time assessment of T21. Furthermore, our innovative hiPSC based placenta-brain axis will be instrumental in comprehending how high-risk pregnancies, substance misuse, and environmental chemical exposure impact fetal brain development. I will be trained for a scientific career during this proposal by my mentor Dr. Erwin, co-mentor Dr. Mueller, collaborators Dr. Burd, Dr. Rasmussen and Dr. Paquola, and lab members Dr. Sawada, Dr. Wang, and Ms. McCord.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY Chronic respiratory diseases (CRDs) remain the third leading cause of death worldwide and their incidence is increasing. In 2019, it was estimated that 455 million people worldwide live with a CRD such as asthma, COPD, and chronic bronchitis. CRDs are responsible for 4 million deaths and 103.5 million disability-adjusted life years lost each year. The development and severity of CRDs is attributed to both environmental exposures and infectious causes. Individuals who live in densely populated cities in low- and middle-income countries (LMICs) are disproportionately affected by high levels of ambient particulate matter, indoor exposure to allergens, dust and tobacco smoke, and a high incidence of viral and bacterial infections. Therefore, to have a meaningful impact on the incidence and severity of CRDs, and prevent further lung function decline, a multi- component evidence-based intervention targeting multiple risk factors is needed. We seek to test the implementation and effectiveness of a tailored multi-component evidence-based intervention following a community health worker (CHW)-driven chronic care delivery model to protect lung health over a 40-month period using a Type I hybrid implementation-effectiveness randomized controlled trial in Bhaktapur, Nepal. The multi-component intervention will consist of: reducing environmental risk factors by targeting tobacco smoking through CHW-delivered messaging and education on smoking prevention and smoking cessation, and targeting indoor and ambient air pollution exposures by providing households with HEPA-indoor air purifiers and vacuum cleaners and encourage masking outdoors with N95 respirators when e-notified about days with high ambient air pollution; reducing infectious risks through an CHW-led vaccine campaign for annual influenza, COVID and pneumococcal vaccine in all eligible participants and household members; encouraging use of surgical masks in indoor public spaces during the peak winter season or at home when there are sick household contacts; and, improving physiologic health by encouraging physical activity through CHW- monitored pedometer goals. Aligned with the Consolidated Framework for Implementation Research, we will first conduct human-centered design workshops with community members and healthcare practitioners to tailor the multi-component intervention. We will then screen and identify 800 index participants aged ≥ 9 years (with a pre-bronchodilator FEV1/FVC Z-score ≤ 10th percentile and chronic cough or wheeze (i.e., at-risk participants). We will enroll index participants and household members and assign half of the households to the adapted intervention. Controls will be asked to continue usual care practices. We will evaluate the effect of the intervention on pre-bronchodilator FEV1 Z-score (primary outcome), respiratory symptoms, and evaluate implementation outcomes. We seek to facilitate scale-up of a multi-component intervention that responds to the real-world implementation context to protect lung health in Nepal and other LMICs.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY- Triglyceride (TG)-rich ApoB-containing lipoproteins (BLP) are micelle-like particles that enable efficient transport of lipids through the bloodstream, but also promote atherosclerotic cardiovascular disease (CVD), the leading cause of death worldwide. Although the lipid content of BLP is known to be a strong determinant of CVD risk, very little is known about how ER lipids are loaded onto nascent BLP prior to entering the secretory pathway. Whereas invertebrate lipoproteins predominantly transport cholesterol and are quite small, vertebrate lipoproteins evolved the additional capacity to transport TGs in much larger BLP. Neither the mechanistic basis nor the physiological implications of TG incorporation into vertebrate lipoproteins have been well defined. In this Multi-PI proposal, we leverage our most recent findings that identify Phospholipase A2 Group XIIB (PLA2G12B), a catalytically inactive phospholipase gene with no known function, as a vertebrate-specific protein responsible for channeling TG to nascent BLP. Our preliminary data indicates that PLA2G12B interacts with ApoB and recruits microsomal triglyceride transfer protein (MTP) to the lumenal face of the ER membrane. We show that PLA2G12B deficiency selectively disrupts TG transfer to BLP, and in a mouse model of CVD, leads to significant reductions in plasma lipid levels and atherosclerosis. We find corresponding BLP phenotypes in cultured human liver and intestinal cells deficient in PLA2G12B, providing direct relevance of our findings to human physiology. These data suggest that incorporation of TG into BLP via PLA2G12B and MTP is a key driver of delayed lipoprotein turnover and hypercholesterolemia in vertebrate animals. We have developed a suite of novel tools to measure digestive organ lipid uptake, transport, and storage in zebrafish. These include in vivo reporter lines to quantify BLP size, numbers, and turnover, as well as lipid droplet protein dynamics. In Aim 1, we will use these new tools along with genetic epistasis analyses to define the position of PLA2G12B along the BLP assembly pathway. We specifically are focusing on proteins that are implicated in BLP synthesis and/or interact with PLA2G12B (e.g., TM6SF2, ERLIN1/2, and OIT3/LZP). We will also define the PLA2G12B interactome and create zebrafish knockouts of these interacting proteins and explore the degree to which they alter ApoB and MTP binding. In Aim 2, we will (a) address the role of intestinal and hepatic PLA2G12B in driving proatherogenic phenotypes; (b) explore the cellular response to loss of PLA2G12B and how this alters ApoB degradation; and (c) explain the role of polymorphisms in the promoter of human PLA2G12B and the role of some transcription factors in regulating PLA2G12B expression and plasma lipid levels. The experiments proposed leverage a long-standing partnership between two field-leading labs to shed new light on the poorly understood process of BLP expansion, ascribe function to the previously uncharacterized gene PLA2G12B, and reveal a potentially promising new strategy to remodel serum lipoproteins to prevent disease.

NIH Research Projects · FY 2025 · 2025-03

Project Summary Although the World Health Organization recommends using postpartum family planning (PPFP) to promote healthy birth spacing to improve maternal and newborn outcomes, approximately 60% of postpartum women in low- and middle- income countries (LMICs) do not use contraception. Understanding demographic and temporal variation in the biological and behavioral determinants of postpartum pregnancy risk can help identify or strengthen family planning interventions during a critical reproductive window, yet research on this topic has been limited by data and methodological constraints. The goal of this research is to identify when women are at risk of short birth intervals during the postpartum period and the dynamic behaviors that increase or reduce such risk in Ethiopia. The proposed project will use two cohorts of longitudinal, population-based survey data following pregnant and postpartum women for 12 months after birth, with a total sample of approximately 5,209 Ethiopian women to achieve two specific aims. First, we aim to establish common postpartum pregnancy risk trajectories of women in a setting with low PPFP use and high risk for adverse maternal and newborn outcomes associated with short birth intervals. Using monthly data in the 12-month postpartum period on contraceptive use dynamics, sexual activity, and return of menses, we will use sequence and cluster analyses to identify and understand risk profiles for short birth intervals. Second, we will identify individual, interpersonal, and health system factors that predict postpartum pregnancy risk trajectories. We will use multivariable logistic regression to determine if and how individual (e.g., sociodemographic); interpersonal (e.g., intimate partner violence); and health system (e.g., PPFP counseling over the continuum of care) factors are related to postpartum pregnancy risk trajectories. By identifying risk profiles of women as they relate to short birth intervals, particularly women at sustained high risk for unintended pregnancies, the findings will inform and better tailor ongoing efforts and interventions in Ethiopia by revealing potentially modifiable risk factors. Results can also inform future research in similar LMIC contexts, as both a proof of concept for the methodology’s applicability to the postpartum period, as well as related to the specific findings.

NIH Research Projects · FY 2026 · 2025-03

Abstract This application focuses on understanding the genetic basis of a recently recognized cancer-prone syndrome caused by long telomere length. It is driven by extended cellular longevity, a mechanism that is distinct from tumor suppressor- and oncogene-mediated familial cancer syndromes. Telomere length is constrained in the human population to a relatively narrow range and telomerase elongation is tightly regulated. Recent studies, from multiple lines of evidence from our group and others, have uncovered that genetically-determined short telomere length, at certain thresholds, is protective against most age-related malignancies. Exceptions include squamous cancers that arise in the setting of T cell immune exhaustion, and myelodysplastic syndrome and acute myeloid leukemia that arise in the setting of hematopoietic stem cell failure. These cancers occur at significantly higher rates among individuals with Mendelian short telomere syndromes. The relatively lower risk of other age-related malignancies in the short telomere syndromes has deep mechanistic underpinnings as short telomere length mediates cellular senescence and apoptosis, thus limiting cancer evolution in nearly all tumor-prone animal models. By contrast, there is emerging evidence that long telomere length is associated with significantly increased cancer risk in the human population with common variants in telomere genes increasing the risk for more than 28 malignancies. Our group recently reported on an autosomal dominant long telomere syndrome caused by heterozygous mutations in POT1. Haploinsufficiency of POT1 enhances telomerase elongation in vitro, and we found mediates ultra-long telomere length. POT1 mutation carriers with long telomeres had high cancer penetrance, near 100% by age 60, and were prone to multiple malignancies including melanoma, thyroid cancer, sarcoma, epithelial and hematologic malignancies. Alongside, they shared a predilection to high rates of clonal hematopoiesis, which we phylogenetically inferred arose in the first decade of life and was sustained by the longer telomere length. In more recent work, we found two other mutant telomere genes phenocopy the long telomere syndrome phenotype supporting wide locus heterogeneity. This application aims to advance this new and timely area. We will identify additional novel mechanisms for the long telomere syndrome with the goal of identifying high risk groups who would benefit from screening and surveillance. The proposed studies will define the role of these variants in familial cancer predisposition, and examine how they disrupt normal telomere length regulation in relevant genetic models and in human cancer-prone families. Building on our recently published data, and leveraging unique resources in our group, we will also examine how the long telomere background influences cancer somatic landscapes. The proposed application promises to identify novel large effect size cancer-predisposing variants in children and adults and define their underlying mechanisms of pathogenicity in relevant models, while establishing approaches that will advance patient care through early detection and prevention protocols.