Northwestern University

NSF Awards · FY 2025 · 2025-08

This award provides funding for U.S. researchers to attend two summer schools and two workshops during the special semester "Analysis and Geometry on Complex Manifolds" in Budapest, Hungary, scheduled for August-September 2025. Hosted by the Alfréd Rényi Institute of Mathematics, these events aim to connect renowned experts with junior researchers, providing an introduction to current topics in the field, sharing recent advancements, and encouraging collaborative research. Funding priority is given to U.S. based participants without alternative sources of support, with a special emphasis on applications from early-career mathematicians and members of underrepresented groups in the discipline. The first summer school will cover introductory topics in Kähler geometry, while the second will focus on non-Kählerian aspects. The workshops will address both classical Kählerian and non-Kählerian topics as well. On the Kählerian side, discussions will explore non-Archimedean aspects of the SYZ conjecture, pluripotential-theoretic approaches to singular Kähler-Einstein metrics, and Calabi-Yau metrics on non-compact manifolds. In the non-Kählerian realm, topics will include cohomological properties of complex and symplectic manifolds, analytic techniques in non-Kähler geometry, almost-complex and symplectic structures, deformations of complex objects, topological aspects of complex and symplectic manifolds, and Hodge theory on almost-Hermitian manifolds. Further details can be found on the special semester’s website: https://erdoscenter.renyi.hu/articles/complex-manifolds. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-08

SUMMARY | Pathogenic variants in KCNQ2 are among the most commonly discovered genetic etiologies of neonatal and infantile onset epilepsy. KCNQ2 encodes the voltage-gated potassium (KV) channel KV7.2, which forms hetero-tetrameric complexes with the related channel KV7.3 to generate M-current, a voltage-gated, slowly activating and deactivating current widely distributed in central and peripheral neurons. Activation of M-current at subthreshold membrane potentials opposes cell depolarization by incoming stimuli and dampens neuronal excitability. The clinical spectrum of KCNQ2-related disorders ranges from self-limited familial neonatal epilepsy (SLFNE) to sporadic cases of severe developmental and epileptic encephalopathy (DEE). It is not known why DEE patients suffer long-lasting intellectual and developmental disabilities, while SLFNE patients have normal neurodevelopment. This gap in knowledge hinders deployment and timing of optimal therapies. Current thinking posits that SLFNE patients harbor mutations that cause loss-of-function and haploinsufficiency, whereas DEE patients harbor mutations that exert dominant-negative effects or rarely gain-of-function. However, this inference does not fully explain the heterogenity in clinical outcomes. This is likely because this it is based on work in heterologous systems solely examining the effects of Kv7.2 mutations on channel function without considering the impact on trafficking, localization, and differential assembly of KV7.2 channels with other KV7 subunits in neurons. The objective of this proposal is to determine how KCNQ2 mutations impair the assembly and physiology of neuronal KV7 ion channels. We will utilize our multidisciplinary expertise and established toolbox of high throughput technologies and orthogonal cell models, including unique patient-specific induced pluripotent stem cell (iPSC) derived neurons and unique mouse models, to advance understanding of pathophysiological mechanisms that drive divergent phenotype severity in KCNQ2-related disorders. In Aim 1, we will employ our unique, large collection of patient-specific iPSC lines with heterozygous pathogenic KCNQ2 variants to determine drivers of phenotype divergence in this disorder, to assess trafficking and localization of mutant KV7.2, and to determine the subunit composition of KV7 channels in human neurons. In Aim 2, we will extend our investigations of channel composition in vivo using an existing portfolio of genetically engineered mice that express epitope-tagged endogenous KV7 channels subunits in brain. We will determine if pathogenic KV7.2 variants disrupt the normal time, region and cell type dependent formation of KV7 channel complexes. Finally in Aim 3, we will investigate the functional and pharmacological properties of pathogenic KCNQ2 variants when co-expressed with KV7.5, and determine if KCNQ2-DEE variants differ from KCNQ2-SLFNE variants in their responses to intracellular PIP2, a major regulator of neuronal M-current. Collectively, our work will fill fundamental gaps in our understanding of Kv7 channel diversity and the impact of pathogenic variants, and inform therapeutic strategies that seek to modify KCNQ2 patient outcomes.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Dizziness is a common problem affecting nearly 37 million U.S. individuals annually and accounting for 2 million emergency department (ED) visits per year. Dizziness presents a substantial diagnostic challenge for clinicians because of its broad differential spanning both benign and serious diagnoses; dizziness-related language is also frequently used by patients to describe symptoms from non-balance related conditions. Thus, ED visits for dizziness commonly result in low value diagnostic testing (e.g., computed tomography, magnetic resonance imaging) and unnecessary hospital admission, which in turn contributes to escalating healthcare costs. Patients suffering from dizziness report reduced quality of life, anxiety, and depression, in addition to a substantial number of lost working days and time spent seeking healthcare. Fortunately, vestibular rehabilitation therapy delivered by physical therapists in the outpatient setting has been shown to improve dizziness symptoms for a number of balanced-related conditions. Whether vestibular rehabilitation therapy can be delivered by physical therapists in the emergency care setting – where patients have received little to no prior medical evaluation – is currently unknown but represents vast potential for benefit. This multi-site feasibility trial will evaluate the feasibility of emergency department vestibular rehabilitation therapy for patients with undifferentiated dizziness in two diverse health systems in Chicago, IL and Salt Lake City, UT. We will also gather qualitative data on contextual implementation determinants and preferred implementation strategies among stakeholders at multiple levels in preparation for a future multi-site hybrid effectiveness- implementation trial.

NIH Research Projects · FY 2025 · 2025-08

Project Summary Muscular Dystrophies are often rare, genetic disorders that typically result in progressive loss of muscle strength effecting the ability to stand, walk, and breathe. Sarcoglycanopathies are an inherited form of Limb Girdle Muscular Dystrophy (LGMD) caused by the loss of a, b, d, or g sarcoglycan proteins, rendering the muscle membrane highly susceptible to injury. LGMD 2C is a severe subtype of LGMD resulting from loss of g- sarcoglycan, with onset generally in the first decade of life. LGMD 2C is also known as R5. LGMD 2C is clinically similar to the more common Duchenne Muscular Dystrophy (DMD) caused by the loss of dystrophin. This similarity arises from sarcoglycan and dystrophin together contributing to the essential membrane stabilizing dystrophin-glycoprotein complex (DGC). Currently, there are limited therapies available to correct or delay LGMD 2C disease progression. Using an unbiased genomewide screen in LGMD 2C mice, Latent TGF- b Binding Protein 4 (LTBP4) was discovered as a genetic modifier of muscle disease specifically modulating muscle membrane stability and fibrosis. LTBP4 localizes to the exterior of the myofiber and extracellular matrix where it binds and sequesters all three forms of TGF-b. LTBP4’s hinge can be proteolytically cleaved promoting release of latent TGF-b, which is then activated triggering the downstream fibrotic cascade. Excess TGF-b activation is a pathological finding in many forms of muscular dystrophy, especially LGMDs and DMD, and excess TGF-b is linked to fibrotic accumulation in muscle and impaired muscle regeneration. In mice, the genetic protective form of LTBP4 is less susceptible to protease cleavage, correlating with decreased TGF- b activity and delayed muscle disease progression. Importantly, a similar protective genetic effect of LTBP4 was shown to modify disease progression in humans with DMD, reducing TGF-b release, correlating with longer ambulation and improved heart function in three independent DMD cohorts. Combined, these data provided the rationale to develop antibodies that stabilize the LTBP4 hinge and limit latent TGF-b release as a therapeutic to treat muscular dystrophy. We demonstrated in the mdx mouse model of DMD that anti-LTBP4 antibodies directed at the hinge region are effective at mitigating disease progression. Anti-LTBP4 hinge region antibodies protected against LTBP4 cleavage, reduced fibrosis formation, enhanced muscle performance, and improved recovery after muscle injury. This proposal outlines a preclinical plan for testing a 2nd generation antibody for the treatment of LGMD 2C. This lead candidate has already been affinity and sequence optimized. The milestones are designed to evaluate the PK PD relationship of this lead anti-LTBP4 antibody and assess in vivo efficacy in a validated mouse model of LGMD 2C. Completion of this award will position the program to secure external funding from strategic investors and partners, which will aid in advancing the anti-LTBP4 biologic therapy into the clinic.

NSF Awards · FY 2025 · 2025-08

In this project funded by the Chemical Mechanism, Function, and Properties Program of the Chemistry Division, Professors Biwu Ma, Bin Ouyang of Florida State University and Professor Lin X. Chen of Northwestern University will investigate how light-induced structural changes in hybrid materials affect their optical and electronic behaviors. By combining material design, ultrafast optical and X-ray techniques, and theoretical modeling, the team will study an emerging class of organic-inorganic hybrid materials, organic metal halide hybrids (OMHHs), with deformable lattices. The project will provide insights to guide the development of next-generation light-responsive materials and devices. Participating graduate and undergraduate students will receive interdisciplinary training in synthesis, spectroscopy, and theory. The project’s findings will also support science education through outreach activities such as summer programs and public exhibitions. This project addresses fundamental questions about the coupling between electronic and atomic motions in photoactive materials, focusing on OMHHs with controllable 0D, 1D, and 2D structures. These low-dimensional systems offer an ideal platform to explore how structural reorganization under light excitation influences exciton dynamics and carrier transport. The research will combine three major strategies: (i) ultrafast optical spectroscopy to track charge carrier and exciton localization and dynamics on femtosecond timescales, (ii) ultrafast X-ray absorption and scattering techniques to reveal structural reorganizations at the atomic level, and (iii) density functional theory (DFT) calculations to model excited-state properties and structure–function relationships. The findings will advance fundamental knowledge of light-matter interactions and inform the rational design of next-generation hybrid materials with tunable optical and electronic properties. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Membrane contact sites (MCSs) play critical roles in spatially organizing cells and facilitating the transfer of biological materials between organelles. MCSs are defined as sites of close apposition between membranes that are physically tethered by protein-protein or protein-lipid interactions and perform specific biological functions. These sites of contact are a ubiquitous mechanism used by cells to facilitate communication between organelles and are associated with a wide array of cellular functions. Given their importance in maintaining cellular homeostasis, it is not surprising that MCSs have been implicated in a wide range of diseases, including neurological diseases, cancer, and pathogen-induced diseases. Our plan for the next five years is to build on the successes we have had studying mitochondrial MCSs and address fundamental unanswered questions that are widely applicable to MCS biology. Our work will be primarily grounded in the yeast system. The simple organelle architecture of budding yeast has proven to be an excellent model for studying MCS form, function, and regulation in mechanistic detail. Our studies in yeast over the past five years have opened avenues of scientific exploration that have broadened the scope of our research program beyond a limited view of a single MCS. Our research program will follow three independent yet complementary directions, each of which will address a critical unanswered question in MCS biology. We will continue our studies on a tripartite membrane contact site between the mitochondria, endoplasmic reticulum, and plasma membrane to elucidate how and why three distinct membranes are brought into functional close contact. We will explore the fundamental mechanisms by which MCSs are coordinately regulated at two different length scales— within a shared space and across the MCS network. We will also examine the role of lipids as critical structural, functional, and regulatory components of MCSs. Our prior accomplishments and plans for the next five years will place us in a strong position to initiate studies in mammalian systems, in which we will examine how the fundamental principles of MCS formation, function, and regulation we uncover in yeast are utilized in more complex cellular settings. Our goal is to uncover fundamental mechanisms used by cells to form and regulate interorganelle contacts and deepen our understanding of MCS physiology. In doing so, we anticipate this work will provide insight into novel therapeutic strategies for a range of human disease conditions in which the manipulation of MCSs can be used to positively influence cellular health and homeostasis.

NIH Research Projects · FY 2026 · 2025-08

The mission of the Northwestern Center for Reproductive Science Predoctoral Training Program in Reproductive Science, Medicine, and Technology (CRS Training Program) is to train future leaders in the reproductive sciences, while simultaneously improving human health. The CRS Training Program is embedded in the CRS, which has a four-decade history of keeping reproductive science and medicine visible, viable, and valuable. The CRS infrastructure provides a physical space for our trainees and an intellectual hub of data clubs, seminars, workshops, and summits. Over the first five-year duration of the program, our trainees have co-authored fifteen papers, including eight first author papers, presented at conferences and meetings in both oral and poster formats, received independent research grants, and received awards and recognitions for their outstanding predoctoral work. In the next funding cycle, we will continue to train predoctoral graduate students from five of Northwestern’s top graduate programs in the life sciences, bioengineering, and medicine. We will expand our course offerings, and we will enhance training outcomes by improving our training for mentors and continually adapting our program based on improved program evaluation mechanisms and trainee focus groups. Renewed funding of this program is critical as our freshly minted doctorates will enter the professional arena at an unusual time for science – one marked by low funding and fierce job competition. As such, our comprehensive educational program was designed with a focus on cutting edge and emerging technologies so we can develop successful leaders in reproductive science and across multiple disciplines in this lean, face-paced environment. Our trainees receive well-rounded training in reproductive science and medicine through coursework spanning didactics on basic and clinical reproductive physiology, reproductive technologies laboratory skills, research proposals and scientific communication, and responsible conduct of research. Our 21 Faculty Mentors come from 13 departments and study reproductive science and medicine from basic, translational, and clinical perspectives. Trainee coursework and laboratory training is bolstered by unique CRS Training Program experiences which focus on professional and career development experiences. All trainees participate in Academic Accelerator Partnerships, which are extended laboratory and core facility exchanges, or externships designed to expose students to team science and the latest technologies related to their research. Trainees also receive formalized professional and career development upskilling through our Career Catalyst Series which exposes our trainees to diverse career opportunities and prime them with career skills, including written, oral, and visual communication, self-assessment, networking, teamwork, and outreach. Ultimately, the CRS Training Program provides trainees with the most comprehensive formal training in our field.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY The BCR-ABL1 tyrosine kinase inhibitor (TKI) nilotinib (Tasigna, Novartis) is the most commonly prescribed treatment for chronic myelogenous leukemia (CML). The 10-year analysis of the ENESTnd clinical trial (2021) showed that nilotinib is more effective than its closest competitor imatinib, with 97.3% of patients achieving freedom from progression to acute/blast phase. Despite this success in effectively curing this once fatal blood cancer, the ENESTnd trial has also clarified the well-known vascular side-effects of nilotinib, demonstrating that 23.5% of patients experienced some form of artery disease, which in some cases is severe enough to require amputation. This nilotinib-induced artery disease (NIAD) occurs even in patients with no pre-existing cardiovascular risk factors. Currently, no tools exist to elucidate the mechanisms of NIAD or predict which patients are predisposed to this adverse effect. Susceptible patients are therefore only identified after they have developed irreversible complications. We hypothesize that an individual’s predisposition to NIAD is due to variance in their endothelial cell (EC) response to kinase inhibition by nilotinib. Our recent publication has already eliminated vascular smooth muscle cells as part of this NIAD phenotype. We have also identified that it is not on-target ABL1 kinase inhibition that is responsible for the EC phenotype (Pinheiro et al., 2024). We have previously demonstrated that human induced pluripotent stem cells (hiPSCs) are a uniquely powerful tool with which to discover the genomic basis of adverse drug reactions. In this study, we shall first recruit 100 nilotinib- treated patients, 50 with artery disease or reduced ankle brachial index (ABI) and 50 without. We will then generate hiPSC from all 100 patients and complete whole genome sequencing. Each hiPSC line will be differentiated to ECs and their response to nilotinib will be functionally characterized using RNA-seq and a battery of six phenotypic and biochemical assays we have already developed and validated. This work will confirm the in vitro patient-specific predisposition to NIAD and confirm its genomic nature. The dose-response changes in gene expression after nilotinib exposure will then be correlated with the patients’ whole genome data to identify differential expression quantitative trait loci (deQTL). We will recruit a 200-patient DNA-only replication cohort and complete SNP array genotyping to corroborate findings. Novel NIAD-associated SNPs discovered will then be corrected/introduced using CRISPR-based genome editing to functionally validate their role in NIAD. This validated variant data will identify candidate mechanisms and pathways that we will then pharmacologically target to assess suitability in preventing NIAD. This study will provide 1, functionally validated predictive SNPs that can be used to inform clinicians on the most appropriate CML therapy, 2, mechanistic understanding on the mechanisms of NIAD, and 3, candidate protective adjuvant therapeutics discovered in a human model suitable for clinical trial. Together, these tools will advance the use of precision medicine in oncology and allow for proactive prevention of NIAD.

NSF Awards · FY 2025 · 2025-08

This project will study equations which arise from the study of mathematical structures called arithmetic groups. These play a central role in many branches of modern mathematics, from Number Theory, to Geometry, to Mathematical Physics. There are infinitely many equations in this class and the goal is to understand which of those have solutions that are integral numbers. The primary goal of this project is to prove a conjectural criterion for the solvability of an equation in this class. Proving this conjectural criterion will answer several important questions about the algebraic, logical, and geometric properties of arithmetic groups. A secondary goal of the project is to count the number of such solutions when they exist. This part is more analytic in nature and will study a new and unexplored statistical-mechanics model of random matrices. A good example of an equation in this project is the following: given two elements g,h in an arithmetic group G and a positive integer m, write h as a product of m conjugates of g. The conjugating matrices are the variables in this equation. The main conjecture is a kind of local-to-global criterion saying that, for higher-rank arithmetic groups, if a solution exists in every completion of G, then a solution exists in G itself, except that one may need to increase the number m. This conjecture has consequences for many other problems, including: the Congruence Subgroup Problem; bounded generation for isotropic arithmetic groups; model theory of higher rank lattices; and conjugation-invariant norms on higher rank arithmetic groups. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-08

ECR R21 – Project Summary The central auditory system modulates its responses to self-generated sounds that result from an individual’s movements. However, how the human auditory system balances two competing functions—coarse attenuation of self-generated sounds allowing us to remain vigilant to the external environment, and fine-grained accentuation of unexpected sounds to monitor for prediction errors—is not well-understood. We will use the frequency-following response (FFR)— which measures the fidelity of a sounds’ representation in the early auditory system—to assess the timing and location of auditory–motor interactions in the auditory system, whether subcortical or in primary auditory cortex. We will then uncover how early auditory processing of self-generated sounds is modulated when the auditory stimulus is unexpected and therefore does not align with sensory predictions. Separately, but in the same participants, we will use functional magnetic resonance imaging (fMRI) to identify cortical neural processing of auditory–motor interactions when hearing both expected and unexpected stimuli during active and passive sound presentation. Finally, we will directly compare early auditory FFR representations and later auditory cortical fMRI representations to map the neural processing of self-generated and expected sounds. By assaying auditory perception across self- vs. passive generation and expected vs. unexpected contexts, as well as by synthesizing non-invasive methods for imaging early and later auditory processing, this project will uncover fundamental information about how the human brain processes self-generated and passively perceived sounds, and how that processing changes when the sounds are unexpected vs. expected.

NSF Awards · FY 2025 · 2025-08

In this project, funded by the Chemical Mechanism, Function, and Properties Program of the Chemistry Division, Professor Michael R. Wasielewski of the Department of Chemistry at Northwestern University is developing molecular quantum bits (qubits) for quantum information applications that offer a variety of benefits compared to other physical qubits, such as structural reproducibility, atomic scale spatial control, and structural modularity. Molecular architectures provide unmatched flexibility for tailoring quantum properties using bottom-up synthetic strategies. The project will use light to generate unpaired electron spins in molecules that will serve as good qubits because their two spin states constitute the quintessential two-level quantum system, in which the two states can exist in a superposition. The project will also study the interaction of two or more spins resulting in quantum entanglement, a property essential to most quantum information science applications in computing, communications and sensing. In addition, this project will provide the advanced education for students necessary for workforce development in the rapidly expanding field of quantum information science. Photogenerated spin-correlated radical pairs (SCRPs) in organic molecules provide new molecular approaches to spin qubit pairs (SQPs) for QIS applications. This project addresses four goals essential for exploiting SCRPs as SQPs that target QIS applications. The investigators will 1) photo-generate SCRPs doped into crystalline hosts to produce oriented SQPs with well-defined initial quantum states that will be addressed and manipulated using microwave pulses to serve as two-qubit quantum gates using optically detected magnetic resonance (pulse-ODMR) readout; 2) teleport spin states between two sites, focusing on a new approach that employs long-lived excited states of stable radicals to promote longer distance teleportation in systems doped into crystalline hosts; 3) explore how the degree of molecular chirality influences coherent spin dynamics through the chirality-induced spin selectivity (CISS) effect; and 4) investigate how CISS influences spin teleportation, and in turn, how teleportation can inform on the magnitude of the CISS contribution to spin dynamics. In topics 3 and 4, in addition to small molecules, they will employ DNA hairpins, which will provide a scalable platform for the rapid synthesis of a wide variety of molecular QIS systems. They will perform time resolved electron paramagnetic resonance experiments using continuous as well as pulsed microwaves following laser excitation of the molecules to create the SQPs. They will also employ pulse-ODMR to explore how to reduce the size of the spin ensembles with the ultimate goal of achieving single molecule or near single molecule sensitivity to probe the spin states of these systems. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-08

Learning to innovate is crucial for preparing students to design and implement innovative solutions to social and technical problems upon graduation. However, students rarely receive opportunities to learn or practice the skills that drive innovation. Students need authentic project-based learning experiences, but also coaches who can help them develop regulation skills – namely, cognitive, metacognitive, motivational, emotional, and strategic behaviors for reaching desired goals and outcomes. Effective coaching can not only troubleshoot project issues, but help students understand and address underlying gaps in regulation skills that limit their effectiveness as innovators. However, even experienced coaches find it challenging to help students develop their regulation skills. This project aims to improve regulation skills in college students by advancing computational tools and techniques to create tailored practice opportunities for coaches and students. Students can struggle to understand and articulate the underlying causes beneath their project struggles, and coaches challenged by the need to elicit, model, and facilitate effective practices and provide tailored feedback to large numbers of students. This project aims to overcome these challenges by developing Situated Practice Systems, a new intelligent coaching tool that (1) computationally encodes learners’ regulation behaviors across coaching sessions; (2) uses Artificial Intelligence practice agents to provide learners with tailored reminders and feedback on regulation skills between coaching sessions; and (3) leverages Large Language Models, machine learning and case libraries to provide tailored practice support to students. This research uses a design-based research approach to generate empirically validated principles that advance our understanding of learning to innovate. This project is funded by the Research on Innovative Technologies for Enhanced Learning (RITEL) program that supports early-stage exploratory research in emerging technologies for teaching and learning. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-08

Project Summary/Abstract My research program investigates how the epitranscriptome regulates protein synthesis and how this interplay affects cell fate decisions under normal homeostasis and stress conditions. The epitranscriptome is the collection of more than 150 chemical modifications that occur on RNA molecules and influence all steps of gene expression. One such step is the translation of mRNAs - the process by which the information stored in DNA is converted into functional proteins. Though translation typically initiates at an optimal 'AUG' start codon, the 5' untranslated region (5'UTR) can harbor cryptic initiation sites. These cryptic sites result in upstream Open Reading Frames (uORFs) that generally regulate the expression of canonical proteins but can also produce new minipeptides with diverse biological functions. Importantly, these uORFs are not merely errors in translation but serve as regulatory mechanisms typically co-opted by cells when exposed to stress conditions. Hence, understanding how cells harness the noncanonical mechanisms of translation to their advantage remains a fundamental question in biology. My published and preliminary studies demonstrate that different RNA modifications and their cognate RNA- modifying enzyme dynamically regulate translation initiation. Under this MIRA award, my research program will integrate RNA biochemistry, chemical biology, transcriptomics, and cell biology to fill gaps in our understanding of how RNA modifications regulate uORF expression and the adaptability of eukaryotic cells to stress conditions. We will also investigate how genetic and physical interactions between RNA-modifying enzymes and translation factors influence the noncanonical mechanism of translation initiation. Lastly, we will implement synthetic biology strategies to modulate the expression of aberrant uORFs in transcript-specific manners. Overall, this research program will provide new insights on how the epitranscriptome is harnessed to diversify the coding potential of the genome. Our long-term goal is to pioneer conceptual leaps and technological innovations to comprehend and manipulate the epitranscriptome for the benefit of human health.

NIH Research Projects · FY 2026 · 2025-08

Project Summary/Abstract Ulcerative colitis (UC) is a complex disorder impacting millions of people worldwide resulting in significant costs, chronic debilitating symptoms, and complications such as colon cancer. Even with biologic therapies targeting immune signaling pathways, variability in patient responses is highly prevalent and remission rates remain low (~40%). Therefore, personalized biomarker development is an area of unmet clinical need. Macrophages have been identified as a crucial intermediary of pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes in UC. Due to the significant overlap between M1 and M2 signaling even in histologically identical tissues, biomarkers focused on transcriptomics alone are limited. Chromatin, the genome folded into 3-D, regulates how genes interact with transcription factors and polymerases to synthesize RNA. Since cytokine signaling converges on transcription-factor cascades, understanding chromatin structure in UC may serve as a rational framework for biomarker development. The goal of this proposal is to establish a cohesive framework that links transcriptomic states with chromatin structure for biomarker development in UC. Preliminary work shows that chromatin packing domains are the primary regulator of transcriptional reactions in cells. The stochastic returns-excluded volume (SR-EV) model can produce the structure of chromatin packing domains observed on electron microscopy at high-throughout (>100k independent configurations). We hypothesize that it’s possible model and predict macrophage transcriptomic behavior in UC by combining SR-EV with in situ transcriptomic and chromatin measurements. We test this hypothesis through three separate but inter-related aims. Aim 1 focuses on expanding the capabilities of SR-EV to predict domains associated with M1 and M2 macrophage transcriptomic patterns. Aim 2 studies the mechanisms governing packing domain formation in macrophages and the ability to manipulate expression by regulating domains. Aim 3 tests how packing domains are transformed UC patients before and after treatment. Collectively, this approach expands (1) the structure-function of chromatin in macrophage signaling, (2) develops new technologies for patient care, and (3) advances chromatin modeling to address heterogeneity in cellular states that can be applied to other diseases in the future. This application is for a K23 Career Development Award for Luay Almassalha, M.D., Ph.D., a fellow in Gastroenterology and Hepatology at Northwestern Memorial Hospital. Dr. Almassalha will commit the majority of his post-medical training to research studying chromatin packing domains and inflammatory signaling. The division of gastroenterology and hepatology has an unwavering commitment to his career development. This training program is tailored to enhance his background in chromatin modeling and imaging and by pairing it with training in immunology, spatial transcriptomics, and clinical investigation. The assembled team of Drs. Parambir Dulai (spatial transcriptomics, clinical trials, UC), Vadim Backman (chromatin organization, nanoscopic imaging) and Igal Szleifer (transcription, chromatin modeling) provides a mentorship team unique to Northwestern University.

NIH Research Projects · FY 2025 · 2025-07

Project Summary Understanding how stem cell attributes are controlled and how they evolve to generate diverse and novel cell types is essential to understanding how mis-regulation of these processes results in stem cell-linked pathologies. My research will focus on two key stem cell populations, pluripotent blastula stem cells and neural crest (NC) stem cells that both arose at the base of the vertebrates. NC cells give rise to many of the hallmark anatomical, physiological and behavioral traits of vertebrate animals—including humans—and defects in the development of these cells is linked to a broad set of birth defects and cancers. Previous work has shown that the gene regulatory networks (GRNs) deployed in NC cells and blastula stem cells are highly overlapping. The overall goal of this project is to use comparative studies in three organisms that represent key nodes in the chordate phylogeny to dissect the gene regulatory logic underlying the development and evolution of these important stem cell populations in vertebrates. Under the mentorship of my sponsoring scientist and career advisory board I will combine genomic and functional studies in a jawed vertebrate (Xenopus laevis), a basal jawless vertebrate, the sea lamprey (Petromyzon marinus), and an invertebrate chordate (Ciona intestinalis). My research will trace the developmental origins of “stemness” in vertebrates and provide novel insights into the molecular-genetic processes controlling how stem cells arise in the embryo and how aberrant execution of these processes leads to defects in the formation of these key stem cells that are essential for early embryonic development. My mentored training plan during the K99 phase of my research as a postdoctoral fellow will enable me to incorporate a new model system, Ciona, into my research program, develop new experimental techniques, and acquire expertise in cutting-edge, single-cell “multiomic” approaches and associated bioinformatic and computational analyses. During the R00 phase I will utilize this new expertise to provide novel insights into the molecular, cellular, and developmental mechanisms underlying the formation and maintenance of these stem cell populations at unprecedented single-cell resolution. My sponsor and advisory board members are outstanding scientists and mentors whose expertise will catalyze my transition to Principal Investigator of my own laboratory. My long-term career goal is to establish a productive independent research program that uses multiple model systems to make important discoveries about the gene regulatory control of stem cell attributes during development and evolution, and how mis-regulation of these processes leads to congenital defects and cancers.

NSF Awards · FY 2025 · 2025-07

Tilings are everywhere around us: brick walls, bee hives, chessboards, etc. The study of tilings is fascinating and has connections to numerous areas in mathematics as well as applications in many areas of science and engineering, such as in the design of materials, the study of quasicrystals and signal processing and in the construction of computer algorithms. This study goes back to ancient Greeks and has remained vibrant up to the present day. Recent works indicate a mysterious divide between “structured” tiling problems, in which the tilings are well behaved, to “wild” tiling problems, where almost anything can happen. One goal of this project is to develop tools to reveal the tiling mystery and, in turn, apply these tools to study related problems. Along with advancing the project’s research goals, the principal investigator also initiates events to the benefit of the community and contribute to synergistic activities related to the topics of this project, such as mentoring young researchers and organizing seminars, summer schools, conferences and workshops. This project investigates central structural problems and conjectures in the areas of discrete analysis, additive combinatorics and symbolic dynamics via exploring interrelationships among them and using tools from various mathematical fields. More specifically, the principal investigator continues to develop tools to advance the study of the structure of translational tilings. This includes the study of continuous and discrete translational tilings as well as multi-tilings in low dimensions. She then adapts these tools to study related problems, such as Nivat’s conjecture on the structure of low complexity configurations, colorings of a grid that have a sufficiently low number of different local patterns. In addition, building on her recent work in conjunction with Illiopoulou and Peluse, the principal investigator studies the structure of integer and rational distance sets in Euclidean space. This study is closely related to the celebrated Erdos–Ulam problem. 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 · 2025-07

Markov chains are an important family of stochastic processes used in many scientific fields, including sampling and optimization algorithms and physical modeling of thermodynamics. In recent decades, their mathematical study has been oriented around the time to converge to an equilibrium state from a worst-case initialization, known as the mixing time. Often, however, the worst-case mixing time is much larger than the convergence time from typical initializations. This project will develop the theory of convergence times from commonly encountered initializations when worst-case mixing times are slow. The research program will be complemented by educational activities, including a summer school for graduate students focused on the interplay between high-dimensional probability, data science, and machine learning. The project will also support the PI’s engagement with the broader scientific community around developing solid theoretical foundations to parallel the rapid acceleration of artificial intelligence capabilities. The project also provides research opportunities for graduate students. The research aims of the project are focused on developing mathematical tools for studying equilibration of Markov chains in high-dimensional spaces from nice initializations (e.g., random or high-temperature) when worst-case mixing times are exponentially slow in the dimension. Markov chains to be studied include families appearing in (1) Markov chain Monte Carlo sampling in computer science, (2) low-temperature Glauber dynamics in statistical physics, and (3) optimization algorithms on non-convex loss landscapes in machine learning. A core goal is to put the scientific understanding of simulated annealing, metastability, and the role of initialization in high dimensions on a more rigorous mathematical footing. 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 · 2025-07

Synchronous programming languages offer order-of-magnitude improvements in reliability and responsiveness in software systems. They have been used in safety-critical systems such as the virtual display systems of civilian and military aircraft at Dassault Aviation, the control software of the N4 nuclear power plants, and the Airbus A320 fly-by-wire system, among others. The success is largely due to the radically different way these programming languages work. As one example, built into these programming languages is the notion of a "reaction" that is completely isolated from the environment, which makes reasoning about the correctness of the program significantly easier than it is in conventional programming languages. Despite the significant success in these safety-critical domains, most programmers remain unaware of and unable to use these programming languages because the languages are deeply tied to specific environments, requiring specialized tools that do not work in every context. In this project, the investigators plan to bring the power of synchronous programming to general-purpose programming systems by solving technical challenges that currently limit the adoption of these important languages. The major technical challenge stems from the radically different semantics that synchronous languages have. This different semantics has led to an entirely different compiler and tool-chain for programs using these languages. The investigators have two different implementation strategies, specifically for Esterel-inspired programming languages that both offer the opportunity of a connection to conventional programming languages. These techniques allow reuse of the tool-chain and existing libraries in the conventional languages' ecosystem while still offering the advantages of the synchronous programming model. One implementation relies on existing ideas for compiling Esterel, but views Esterel programs as data structures in the conventional language, in a shallow embedding manner, invoking the Esterel compiler at the hosts’ runtime to interpret and execute Esterel code. The other implementation is novel and based on a deep embedding, relying on multi-shot continuations. The project's novelties are a new semantics for the continuation-based approach to Esterel as well as novel debugging techniques. The project's impacts are to bring Esterel to a modern generation of programmers, hopefully eventually leading to more reliable and robust software. 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 · 2025-06

The ability to trace errors through artificial neural networks was a revolutionary advance that laid the groundwork for “machine learning” in computer vision and language models. Research completed in association with this Faculty Early Career Development (CAREER) project will explore a similar opportunity for “machine evolution” in robots. While both robots and neural networks have existed since the 1940s, only the latter have been designed in a scalable manner using error tracing algorithms that automatically identify parts responsible for poor behavior and efficiently revise them to improve behavior. This project will work to generalize these efficient automatic optimization techniques to the design of robots and thereby attempt to realize novel robots with important new capabilities that are difficult or impossible to design by hand. In parallel, the project will develop a robot design game for education, outreach, and crowdsourcing designs. This research project will look to determine the extent to which freeform robot design can be encoded into a differentiable representation that smooths the search landscape—and when and how this produces robots that are better adapted to their environment than human-designed robots. This intends to show how backpropagated design gradients lead to innovative nonobvious body plans that advance the state-of-the-art in adaptive robots, focusing on terrestrial and arboreal task environments. Analysis of the resulting search landscapes will attempt to illuminate the conditions in which useful embodied gradients, or subgradients of certain body segments, can be computed in robots and other physical machines with moving parts. 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 · 2025-06

Recent improvements in the capabilities and real-world applications of AI have highlighted the need for researchers working at the intersection of AI, security, and privacy. This project will promote scientific progress by training undergraduate students to conduct research connecting these three fields. This project will advance national prosperity and welfare by investigating the security and privacy challenges of AI methods, and by developing new AI methods that can improve security and privacy. Students will work on individual research projects while developing a broader understanding of the technical and social issues that connect AI, security, and privacy. This project will introduce undergraduate students to a rigorous research environment in which they will develop the competence and confidence to conduct computer science research. Students will work with faculty mentors to choose their research projects, review literature, design and conduct experiments and/or theoretical analyses, and present their work orally and in writing. The structure of summer activities will help students develop autonomy and an understanding of research directions outside their specific project. An introductory overview on the foundations of AI, security, and privacy research will ensure that all participants share a common baseline across all topics. Students will attend talks that highlight research ethics and the diversity of research careers. The eight-week summer program will be hosted at Northwestern University; students will join a supportive research environment at an institute that highly values undergraduate research. All students will receive on-campus housing and meal plans as well as a weekly stipend. 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 · 2025-06

PROJECT SUMMARY Nearly two-thirds of all Alzheimer’s disease (AD) cases are in females, suggesting sex differences in both prevalence and presentation. Yet, the mechanisms underlying sex disparities in AD remain unknown. The hypothalamus plays a key role in regulating numerous physiological processes that are disrupted in AD, such as sleep-wake cycle, appetite, and sex-hormone production. The hypothalamus is also uniquely positioned as a hub for peripheral signals in the brain due to its leaky blood-cerebrospinal fluid-barrier (BCSFB), central position in the neuroendocrine axis, and bi-directional neuronal circuits. Recent evidence suggests tanycytes, specialized ependymal cells that comprise the hypothalamic BCSFB, transport tau out of the cerebrospinal fluid (CSF) and may be dysfunctional in AD. However, hypothalamic involvement and mechanisms of immune cell infiltration in this region remain critically understudied in AD. Thus, interrogating the link between peripheral immune infiltration and hypothalamic pathology is essential to understanding clinical symptoms underlying sex disparities in AD. Preliminary data indicates uniquely altered populations of clonally expanded CD8 T cells exist in both the blood and CSF of AD patients. Notably, these altered T cell populations could have increased access to the hypothalamus due to the leaky BCSFB in AD patients. This led to the hypothesis that BCSFB dysfunction in the hypothalamus results in increased peripheral immune infiltration and subsequent neuroinflammation in AD. Therefore, the goals of this project are to investigate sex-specific transcriptomic alterations in the AD hypothalamus (Aims 1 and 2) and explore how altered hormonal signaling may influence neuroinflammation in the brain (Aim 3). Specific Aim 1 will utilize single-cell fixed RNA profiling to identify and evaluate cell-specific transcriptomic alterations in AD hypothalamus, according to sex and disease severity. Specific Aim 2 will use spatial transcriptomics to elucidate the spatial relationship between BCSFB dysfunction, neuroinflammation, and AD pathology in the hypothalamus. Specific Aim 3 will use human induced pluripotent stem cells, phagocytosis assays, flow cytometry, and qRT-PCR to delineate the effect of hormones on microglia. The proposed studies will work towards establishing a mechanistic link between peripheral immunity and AD pathobiology in the hypothalamus. They work to aid therapeutic approaches by providing deeper understanding about how BCSFB function may exacerbate neuroinflammation and promote sex disparities in AD.

NSF Awards · FY 2025 · 2025-05

Carbon isotopes serve as important tracers of metabolism in both the biological and earth sciences. Earth scientists have long used subtle variations in the natural abundance of the stable isotope carbon-13 in biomolecules to draw inferences about organismal or biochemical origins, and metabolic carbon fluxes. In systems biology, the metabolomics approach employs the addition of carbon-13 tracers to cultures, followed by monitoring of labeled metabolites to quantify carbon fluxes through metabolic pathways. However, a key drawback is that this approach is only feasible for organisms cultivated in the lab, where relatively high levels of isotope tracer can be achieved. Similar information is potentially available in the natural-abundance distribution of carbon isotopes, as they are modulated by kinetic isotope effects that accompany most metabolic reactions. Retrieving this information requires a specialized style of mass spectrometry that is already available in isotope geochemistry labs; as well as new metabolic models that account for all of the relevant fluxes and isotope effects. The latter is tractable but as-yet unproven. This project will leverage the unique collaboration between an isotope geochemist (at Caltech) and a systems biologist (at Northwestern) to combine these two approaches to develop and validate a new algorithm for measuring rates and types of metabolism in organisms, based on natural abundances of the carbon-13 isotope. The goal of this project is to build and validate the newly developed algorithm for aerobic and anaerobic heterotrophic bacteria, using both conventional (13C-tracer) and natural-abundance measurements as constraints. The success of this project would greatly expand our ability to quantify metabolic fluxes in organisms collected from the environment, as well as to predict their stable isotope signatures. This new ability could have many important applications, including improved understanding of how many microbes function in the environment, as well as marine and soil food webs, fisheries, and the carbon cycle. The project will provide training of graduate students at Caltech and Northwestern, and involve the partnerships of respective institutions with educational activities with local middle-school and high-school students. . 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

Project Summary: Examination of genetic risk factors for Parkinson’s disease (PD) has allowed for the identification of key mechanisms contributing to the pathogenesis of this disorder. Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial PD and pathogenic LRRK2 mutations are also found in approximately 1% of idiopathic PD cases. Multiple lines of evidence point towards LRRK2 as playing an important role in immune system regulation, including the finding that LRRK2 is highly expressed in both peripheral macrophages as well as microglia, the resident immune cells of the central nervous system (CNS). Furthermore, evaluation of PD-specific risk variants in LRRK2 has demonstrated that these variants are associated with microglia-specific changes in LRRK2 expression. The pathogenic LRRK2 G2019S mutation has been shown to lead to lysosomal dysfunction in dopaminergic neurons through multiple mechanisms, including modulation of the lysosomal enzyme glucocererbrosidase (GCase) which is encoded by GBA1, another PD risk gene. Induced pluripotent stem cells (iPSCs) derived from PD patients with known genetic mutations provide an ideal platform to define specific mechanisms by which PD-associated genes contribute to microglial dysfunction. Our preliminary data shows that iPSC-derived microglia with the LRRK2 G2019S mutation exhibit reduced lysosomal uptake of multiple substrates as well as impaired lysosomal protease activity. I hypothesize that the LRRK2 G2019S mutation leads to lysosomal dysfunction in microglia at least in part through modulation of lysosomal GCase and that lysosomal stress in microglia alters downstream inflammatory signaling. I additionally hypothesize that inflammatory factors produced by LRRK2 mutant microglia contribute to lysosomal dysfunction and oxidative stress in dopaminergic neurons. In Aim 1, I will investigate how LRRK2 and GBA1 interact to regulate lysosomal function and phagocytosis of alpha-synuclein and myelin in iPSC-derived human microglia. I will then evaluate the impact of mutations in these genes on cytokine secretion profiles and transcriptional states of iPSC-derived microglia in response to exposure to CNS substrates. In Aim 2 I will co-culture iPSC-derived microglia and dopaminergic neurons to assess whether factors produced by LRRK2 mutant microglia contribute to lysosomal dysfunction and oxidative stress in dopaminergic neurons and define specific mediators of dopaminergic neuron vulnerability. The overarching goal of this project is to identify signaling pathways downstream of LRRK2 that could serve as potential targets for the development of therapies designed to slow PD progression. The proposed research strategy and career development plan will provide me with critical tools to launch my career as an independent physician scientist, including developing expertise in iPSC technologies, transcriptomics, and neuroimmunology. This award will ultimately provide me a platform to cultivate a research program studying the complex interplay between genetics and neuroinflammation in PD and other degenerative movement disorders.

NIH Research Projects · FY 2025 · 2025-05

Colorectal cancer (CRC) is the second leading cause of cancer deaths in the U.S. despite being eminently preventable by colonoscopy. Colonoscopy is the gold standard of CRC screening. Its goal is to identify and remove premalignant adenomatous polyps with the advanced adenoma being the primary target. According to guidelines, colonoscopy is recommended for all patients over the age of 45 (roughly 100 million Americans). However, it is practically impossible to screen this entire eligible population with colonoscopy due to noncompliance, cost, and insufficient resources. As a result, less than half of the population receives colonoscopies as appropriate. The goal of this project is to develop a screening test to identify the subset of patients who harbor advanced adenomas and should undergo colonoscopy. The test must be accurate, low- cost, and can be carried out in the primary care setting. Despite significant interest in CRC screening, none of the existing or emerging tests has clinically practical sensitivity for advanced adenomas. We propose an alternate approach that bridges CRC field carcinogenesis as the biomarker source, dysregulation of chromatin conformation at the nanoscale as an etiological biomarker, and a new, AI-enhanced optical spectroscopic statistical nanosensing technology, which is uniquely positioned to enable detection of these subdiffractional and microscopically undetectable chromatin alterations. Our preliminary data show the feasibility of identifying patients who harbor advanced adenomas anywhere in the colon by the nanosensing of chromatin conformation alterations in colonocytes swabbed from the rectal mucosa. Our target is to achieve a negative predictive value of 99.5% with 95% sensitivity and 80% specificity for advanced adenomas, which would constitute a very high accuracy for a CRC screening test. The goal of the proposed project is to finalize the technology development, test it in a prospective clinical study, and bring it to the point where it is ready for definitive clinical validation. First, we will optimize optical nanosensing of chromatin, develop new methods of analysis of 3D chromatin scanning transmission electron tomography, deploy multi-label spectroscopic single molecule photolocalization nanoscopy for molecular nanoimaging of chromatin structure, and leverage computational electrodynamics and molecular dynamics simulations to link chromatin conformation alterations with transcriptional plasticity regulation in carcinogenesis and test the ability of spectroscopic nanosensing to identify these alterations. The technology will then be validated in a prospective clinical study. As our overarching goal, we envision that this screening test can be performed on any average-risk patient over the age of 45 as a first-line screening to identify patients who would benefit from colonoscopy. The test can be administered during a regular annual visit by a PCP. After a simple rectal swab with a cytology brush, the cells will be preserved and shipped to a centralized laboratory for chromatin nanosensing. This will increase the uptake of CRC screening with the goal of catchment of the entire eligible population while reducing unnecessary colonoscopies.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY Among the 5 classes of neurons in the mouse retina (photoreceptors, horizontal cells, bipolar cells, amacrine cells, and retinal ganglion cells), our field has achieved complete or nearly complete classifications of all but the amacrine cells. One goal of this project is to fill part of this gap in knowledge by establishing a multimodal classification of displaced amacrine cells (dACs). However, unlike many other types of neurons, amacrine cells (ACs) either have no axons or they have multiple axons that may transmit different information to different locations. Thus, a second goal of this project is to go beyond somatic recordings to measure the subcellular compartmentalization critical to revealing the role amacrine cells play in retinal circuits. We have measured light responses, intrinsic electrical properties, and morphology from over 100 dACs and clustered them into 21 types. In Aim 1, we will align these morpho-electric types to transcriptomic clusters from the published single-cell RNA-seq databases. In Aims 2 and 3, we will use two-photon calcium imaging to measure functional compartmentalization within dAC neurites. The successful completion and publication of this project will have major impacts on retinal neuroscience. As we did for RGCs at rgctypes.org, we will create a website to disseminate our multimodal dAC classification data, providing a common foundation for future work across labs. Our biophysical and functional measurements of compartmentalization in dACs will combine with existing and emerging connectomic data, leading to a more complete understanding of their roles in many circuits. In Aim 3, we will use orientation selectivity as a model for a computation that may take place at the level of neurites rather than at the level of an integrated signal in the soma. Ultimately, revealing the roles of amacrine cells in retinal computation will help us understand their dysfunction in disease. The high degree of conservation of these cells from mice to humans suggests that some of the circuits we discover may translate to new interventions for blinding diseases in patients.