Scripps Research Institute, The

NIH Research Projects · FY 2025 · 2025-08

Project Title: Design of single-shot sequential immunization regimens for HIV using atomic layer deposition technology Project Summary/Abstract 30 lines or less: Preclinical studies and early stage human trials evaluating passively transferred broadly neutralizing antibodies (bnAbs) suggest that a vaccine capable of eliciting bnAbs would provide effective protection from HIV infection. However, bnAb induction through vaccination is a major challenge. We have developed an immunogen series targeting the CD4 binding site bnAb epitope on HIV Env using germline targeting to prime appropriate B cell precursors, and then shepherd the BCR mutations of these recruited B cells through a series of booster vaccinations, where each engineered immunogen promotes key mutations along the path to bnAb development. In a rigorous humanized mouse model, a near-complete vaccine regimen has been demonstrated, leading to epitope-specific mAbs capable of binding to heterologous wildtype HIV Env trimers. However, this regimen involves up to 5 or 6 shots, which would be challenging to implement in global vaccination campaigns. To overcome this hurdle, we have developed a vaccine formulation strategy that can deliver multiple boosts over time from a single injection. Atomic layer deposition (ALD) is used to “cap” spray-dried microparticle vaccine formulations with a thin layer of alumina. On injection, the vaccine undergoes a rapid release from the ALD particle once the alumina coating dissolves, and the timing of vaccine release can be precisely determined by the thickness of the ALD coating. By injecting ALD particles containing a series of booster immunogens capped by alumina coatings of distinct thickness, a series of immunogen (and adjuvant) exposures can be pre- programmed from a single immunization. Here we propose to carry out systematic studies to apply this technology to sequential immunization regimens targeting the development of bnAbs against the CD4 binding site, establish the limits of such single-shot formulations, and develop a mechanistic understanding of immune responses elicited by ALD vaccine formulations. Our specific aims are to (1) Characterize key process parameters governing ALD vaccine formulation function, (2) Apply ALD technology for single-shot sequential immunizations in a humanized mouse model targeting the CD4bs, and (3) Optimize ALD technology for sequential delivery of mRNA vaccines. These studies will provide important insights into the immunology and practical potential of ALD vaccines for enabling sequential immunization regimens that may be critical for a successful HIV vaccine. This technology is being commercially developed for cGMP vaccine manufacturing, and these studies will provide important preclinical data to support translation to human HIV vaccine trials.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract Over the past three decades, the Blackmond laboratory has pioneered research in kinetic-assisted mechanistic analysis of organic catalytic reactions. The data-rich methodology of Reaction Progress Kinetic Analysis (RPKA), employing in-situ reaction monitoring and kinetic modeling of temporal reaction profiles, has proven to be an innovative tool in organic synthesis and catalysis. Our work has helped to streamline pharmaceutical reaction process understanding as well as to provide fundamental mechanistic insights that contribute to catalyst design and development. Looking forward at the future landscape for research in synthetic organic chemistry, the significant potential for data-rich science focuses on artificial intelligence and machine learning (AI/ML) methods as an important theme in both academic and industrial research, fueling the promise of accelerated discovery. The experience and accomplishments of the Blackmond laboratory positions this group to make significant advances over the next five years in the study of complex catalytic networks, sometimes referred to as “systems chemistry.” Coupled catalytic cycles operating together may exhibit emergent behavior that cannot be predicted by a reductive approach studying single reaction steps in isolation. Key to our proposal is that we offer an approach that is orthogonal to current data science work in organic synthesis. Most investigations of organic catalytic reactions extract a single piece of information from each reaction – an endpoint yield or selectivity – which may be sufficient to characterize simple catalytic cycles; however, structural and electronic molecular descriptors applied to catalyst systems of higher complexity may by themselves fail to produce accurate predictive models of the network behavior. To address this challenge, we plan to incorporate dynamic information about complex reaction networks by incorporating images of kinetic profiles as inputs into AI/ML models. Capturing this comprehensive temporal information – the “narrative” of an entire reaction sequence – in AI/ML models may provide mechanistic insights that will uncover and exploit emergent chemical behavior and aid in the identification of new reaction and catalyst combinations. Two general classes of reaction networks will be developed as proof of concept of this systems-based approach: i) asymmetric catalytic cascade reaction networks involving sequential catalytic cycles, in which the products of one cycle become the reactants in the next, much like metabolic cycles in biology; and ii) synergistic multi-catalyst networks incorporating several catalytic cycles that are interconnected as cogs in a process, where intrinsic reactivity of each catalyst must be balanced with the other cycles in the network. We seek to implement predictive designs of novel reaction sequences by developing kinetics-based markers using the temporal reaction profile as a design tool. A key goal is to broaden the chemical space accessed by these models.

NIH Research Projects · FY 2025 · 2025-08

Endometriosis is characterized by the extraneous presence of endometrial cells outside the uterine organ. The molecular mechanisms governing the migration of endometrial cells and the corresponding regulators of endometriosis are yet to be known, leaving critical gaps in the search for targets that can be used to treat endometriosis. We have recently found that an N-linked glycoprotein called basigin contributes to endometriosis. Here, we will apply proximity labeling technologies to define the interactome of basigin in cell culture models of endometriosis. Given the density of glycan post-translational modifications on basigin, we also reason that N-linked glycosylation can contribute to its interactome. The resulting interactomes will be used to define how basigin is regulating endometriosis and also open new potential targets for intervention.

NIH Research Projects · FY 2025 · 2025-08

Project Summary Highly selective and diverse C(sp3)–H and C(sp2)–H functionalizations could greatly facilitate and impact the development and synthesis of therapeutics for human health and probes for chemical biology in three key aspects: the discovery of expedient new synthetic disconnections, the application of novel catalytic asymmetric methods for chiral synthesis, and molecular editing for late-stage diversification. The impact of our C–H activation reactions thus far is demonstrated by syntheses from over 20 laboratories and numerous successful drug discovery programs in pharma, ranging from Nav 1.8 (Vertex), KRAS12D (Eli Lilly), PD-1 (BMS), to WRN Helicase (Vividion). Realizing our ultimate vision of C–H functionalization requires addressing two key challenges: regio-/stereo-selectivity (activating the targeted C–H bonds with high precision) and functionalization diversity (installing diverse C–C, C–O, C–X, and C–N bonds). We first aim to develop next-generation ligands capable of the enantio- and site-selective C(sp3)–H activation of aliphatic carboxylic acid substrates. Through extensive bifunctional ligand development, we have achieved the challenging Pd-catalyzed C(sp3)–H activation reactivity of aliphatic carboxylic acids. Moving forward, we seek to develop enantioselective C(sp3)–H activation reactions at the β-, γ-, and δ-methylene C–H bonds relative to the carboxylic acid, with concomitant high site-selectivity. We will also use our newly developed ligand to broaden functionalization scope to olefination, alkylations, and valuable C–O/N/X bond formations with sustainable oxidants (molecular oxygen, peroxides). We also will develop enantio- and site-selective ring forming C–H functionalizations in which multiple C–H bonds are transformed in a single step to provide a new formal cycloaddition strategy for rapid carbocycle construction. Second, we aim to achieve enantioselective C(sp3)–H activation reactions of other weakly coordinating aliphatic substrates, specifically alcohols, ketones, and neutral amides. We have recently developed several strategies to improve Pd recruitment, including the use of non-covalent interactions to enhance catalyst-substrate affinity, ligand tuning of Pd binding affinity, and the formation of transient assemblies with the substrate (TDG strategy). We propose the enantioselective C(sp3)–H activation reactions of these substrates using next-generation chiral ligands and the complementary chiral tridentate TDG strategy. Finally, we propose the development of new and general template strategies for remote site-selective C(sp2)–H activation reactions of extended hetero(arenes), with an emphasis on ligand-enabled C–O/N bond formations with sustainable oxidants.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT Mitochondria are dynamic organelles, with the ability to rapidly change their morphology in response to metabolic or environmental stimuli. These dynamics are particularly important for neuronal function, as mitochondria must maintain a robust capacity to respond to the physiological and pathological stresses associated with the high metabolic demands of these cells. Imbalances in mitochondrial morphology that result in excessive mitochondrial fission (fragmentation) are associated with a wide range of neurological and neurodegenerative diseases, and mitochondrial fragmentation is a hallmark of ischemia/reperfusion-associated neuronal death. However, we lack a molecular description of the complex signaling pathways responsible for the rampant fragmentation associated with disease states and neuronal death. Morphological rearrangements that occur in response to events such as DNA damage involve communication from the mitochondrial interior to the exterior for recruitment of the endoplasmic reticulum, we don’t know how these external interactions are communicated. We hypothesize that the mitochondrial AAA+ protein ATAD3A, which has been shown to play a critical role in regulating mitochondrial dynamics, serves as an inter-organelle signaling conduit, recognizing mitochondrial DNA damage to cytosolic proteins as a mediator of mitochondrial DNA stress response. The C-terminal AAA+ domain of ATAD3A is located within the mitochondrial interior, while its N-terminus is located at the mitochondrial surface, enabling ATAD3A to establish bilateral interactions with mitochondrial and cytosolic fission/fusion cofactors. Our hypothesis is further supported by the observation that ATAD3A has been shown to accumulate at mitochondrion-ER junction sites. Notably, variants of the ATAD3A gene have been identified in patients exhibiting optic atrophies, fatal congenital pontocerebellar hypoplasia, encephalopathy with cerebellar atrophy, ataxia, dystonia, and other neurodevelopmental delays and axonal neuropathies, although how these mutations perturb ATAD3A function or associated interactions is unknown. These studies will provide foundational insights into how ATAD3A functions as a cross-membrane communication complex, transferring molecular cues across the outer mitochondrial membrane (OMM) to coordinate mitochondrial fission. We will combine biochemical, cellular, and structural approaches to confirm the role of ATAD3A in regulating mitochondrial morphology and dynamics through two aims: In Aim 1 we will characterize the interactions between ATAD3A and mitochondrial DNA to understand the rules of engagement. Aim 2 will use structure-based experiments to define the specific molecular mechanisms by which ATAD3A interacts with DNA and allosterically signals DNA damage events to the cytosol. These studies will provide key insights into the role that ATAD3A plays in dictating morphological rearrangements, laying the groundwork for a further investigation of how genetic mutations perturb ATAD3A function and the interactions that drive the mitochondrial fragmentation.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT Developing an HIV vaccine capable of eliciting a durable broadly neutralizing antibody (bnAb) response is needed for ending the HIV/AIDS epidemic. Inducing bnAbs will likely require a sequential vaccination approach with perhaps 5 to 6 immunizations. High and sustained bnAb titers should be elicited only after preceding immunizations drive affinity maturation of bnAb lineages. Inducing high antibody titers at earlier stages of the vaccine regimen could interfere with the subsequent steps of bnAb affinity maturation. Thus, learning how to induce a durable bnAb response would best be accomplished in the context of a vaccine regimen that is capable of inducing affinity matured bnAb lineages. This proposal leverages a novel 6-shot germline-targeting HIV vaccine regimen that has been validated to elicit a specific genetic-class (BG18) of cross-clade neutralizing antibody in non-human primates. Investigating the last step of the sequential regimen will allow us to probe the durability of the BG18-class long-lived plasma cells that have undergone the necessary affinity maturation. We will systematically investigate four key concepts: (1) assessing the inherent durability of a 6-shot sequential vaccine regimen that induces BG18-class cross-neutralizing antibodies in non-human primates; (2) evaluating the impact of a yearly maintenance shot on durability and whether deflecting competitor antibody responses during these boosts is necessary; (3) evaluating nanoparticle or fractionated escalating dose trimer delivery for the last immunization to improve durability; (4) investigating whether an mRNA sequential regimen with a last boost of adjuvanted protein, generates a durable bnAb response. To address these concepts, we will probe key immunological outputs such as quantification of B cell populations, including memory B cells in PBMCs, germinal center B cells in lymph nodes and long-lived plasma cells (LLPCs) in bone marrow. Additionally, monoclonal antibody and serum responses will be characterized for immunodominance, binding and neutralization capacity. By focusing on the final stage of a multi-step HIV vaccine regimen, that induces cross-neutralizing BG18-class responses, this project will explore durability in the phase of HIV vaccine development that was previously inaccessible to detailed investigation; post-elicitation of matured bnAb lineages. Identifying the immune outputs that most closely correlate with bnAb durability will be a central goal, providing invaluable insights for optimizing the design of an effective HIV vaccine.

NIH Research Projects · FY 2025 · 2025-07

Project Summary/Abstract. Xylazine has been reported as an adulterant in an increasing number of illicit drug mixtures; tragically, it has also been detected in a growing number of overdose deaths. Adulterants are substances typically added to illicit drugs that are intended to increase the value, increase the content, and modulate the activity of the drug while increasing its desirability. Adulterants can come from a wide range of pharmacological categories; however, due to its impact on the opioid crisis, xylazine is the first adulterant declared as an emerging threat by the White House’s Office of National Drug Control Policy. From a pharmacological standpoint, xylazine is a strong agonist of alpha-2 adrenergic receptors that decreases the release of norepinephrine and dopamine from the brain and thus forms a sedative effect. Xylazine is typically used in veterinary medicine, yet is readily available for purchase on internet sites, often with no association to the veterinary profession nor requirements to prove legitimate need. Indeed, xylazine powder can be purchased online with common prices ranging from $6-$20 US dollars per kilogram. At this low price, its use as an adulterant increases the profit for illicit drug traffickers, as its psychoactive effects allow them to reduce the amount of synthetic opioid used in a mixture. It also attracts customers seeking a longer “high”, since xylazine has many of the same effects for users as opioids but with a longer-lasting effect than the opioid alone. Complicating xylazine’s non-opiate sedative/analgesic effects, xylazine appears to cause severe skin ulcers developing mostly on extremities both at and away from drug injection sites, often within hours or days of exposure, that can quickly progress into large, complex, chronic wounds. Moreover, xylazine-associated wounds and xylazine withdrawal reportedly act as significant barriers to care, including addiction treatment. There is currently no antidote for xylazine poisoning other than supportive care, underscoring the need for effective measures to treat acute toxicity caused by xylazine. Moreover, the diverse and complex physiological processes involving the alpha-2 adrenergic receptors convolutes the use of a simple receptor antagonist to target the CNS site of action. As a starting point to neutralize xylazine’s pharmacologic effects, our overarching goal will be to generate a humanized monoclonal antibody with high affinity and specificity for xylazine. To meet this objective, we have proposed three specific aims that follow in a logical fashion including: (1) Isolation and production of monoclonal antibodies targeting xylazine. (2) Determination of the behavioral effects of the selected monoclonal antibodies on drug pharmacodynamics. (3) Humanization of the chosen lead anti-xylazine monoclonal antibody. A key aspect of the proposal is that it will provide a therapeutic for immediate changes in both the amount and the rate of xylazine entry into medically critical sites of action in the CNS while its preparation in a multi-manifold antibody format will engender the ability to prepare the first bispecific antibody against xylazine adulterated clandestine drugs.

NIH Research Projects · FY 2025 · 2025-07

Project Summary/Abstract Viral infections pose a major public health concern, affecting millions and contributing significantly to global mortality, as evidenced by the COVID-19 pandemic, which cut short over 7 million lives worldwide. The success of mRNA vaccines during this pandemic showcased the power of nucleic acid therapeutics in combating emerging viral threats. However, vaccines rely on the adaptive immune response, requiring time to mount protection and unable to treat ongoing infections. Small interfering RNAs (siRNAs) represent a promising class of nucleic acid therapeutics with the potential to overcome these limitations. siRNAs induce gene silencing by directly degrading targeted RNAs, offering rapid action and adaptability to emerging viral strains. These properties make siRNAs attractive for treating viral infections, with positive indications in models for many viruses on NIAID’s priority list, including Dengue Fever, Ebola, Hepatitis, Herpes, Human Papillomavirus, Influenza, Respiratory Syncytial Virus (RSV), Smallpox, West Nile Virus, and Zika Virus. Despite demonstrated efficacy in tissue culture and model systems, clinical translation of siRNAs is hampered by challenges in efficient delivery to target tissues. While the development of GalNAc-siRNA conjugates has led to FDA-approved liver-targeted therapies, scalable methods for screening siRNA delivery strategies in tissues beyond the liver are lacking. This proposal aims to address these limitations by developing high-throughput technologies for generating and screening siRNA-peptide conjugates—a novel approach to improving delivery efficiency and overcoming key bottlenecks of cellular uptake, endosomal escape, and siRNA activation. In Aim 1, we will adapt mRNA display, an established method for creating diverse mRNA-protein libraries, to synthesize compact siRNA-peptide conjugates. By encoding each peptide's amino acid sequence within its conjugated siRNA nucleotide sequence, we will create libraries with millions of variants, enabling high-throughput functional screening. In Aim 2, we will evaluate the functionality of these siRNA-peptide conjugates using biochemistry and small RNA sequencing (sRNA-seq) to identify those that successfully load into Argonaute 2 (Ago2), the enzyme that mediates silencing directed by siRNAs. This method allows for a direct, highly sensitive assessment of delivery efficiency and quantitative identification of the most promising siRNA conjugates for further development. Completion of this project will establish new technologies for high-throughput siRNA conjugate screening, facilitating the discovery of efficient delivery strategies for siRNA-based antiviral therapeutics across diverse biological contexts. This will significantly impact the treatment of viral infections, providing a pathway toward developing siRNA therapies that can rapidly respond to emerging viral threats, treat chronic infections, and protect vulnerable populations such as immunocompromised individuals. This work aligns with NIAID’s mission to combat infectious diseases through innovative therapeutics and the development of broadly applicable antiviral treatments.

NIH Research Projects · FY 2025 · 2025-07

The envelope (Env) glycoprotein of HIV is the only viral protein on the surface of virions, making it the sole target of B cell-based HIV vaccines. While Env is natively a transmembrane protein, most vaccine development relies on soluble versions of the trimer. These versions lack the membrane-proximal external region (MPER) epitope, the native bilayer environment, and the transmembrane (TM) and C-terminal (CT) domains. Broadly neutralizing antibodies (bnAbs) targeting MPER have remarkable breadth, reaching near- complete coverage of all circulating HIV strains, thus making MPER an attractive target for vaccine development. Recent progress in MPER-targeted vaccine development has been notable on two fronts. First, in the HVTN133 clinical trial, MPER peptide presented in a liposome formulation induced a B cell lineage for bnAbs and their precursors and reached 15 % neutralization breadth of a global tier 2 panel. Second, two studies described the development of a germline targeting immunogen for 10E8-class MPER bnAb, and affinity maturation process of the primed antibodies in pre-clinical mouse models. While mRNA technology can now deliver membrane-bound Env immunogens with a complete MPER, circumventing the need to produce recombinant transmembrane Env, the characterization of new immunogen candidates and the MPER-targeting responses they elicit will still require biophysical and structural analysis. As a result, challenges in handling Env as a recombinant transmembrane protein persist. This project incorporates engineered transmembrane Env vaccine candidates into stable lipid nanodiscs using membrane scaffold proteins and a selection of lipid molecules. This solution enables scalable and reproducible in vitro characterization and optimization of engineered transmembrane Env-based immunogens and evaluation of in vivo responses from MPER-targeting immunizations. Env nanodiscs allow using transmembrane Envs under identical conditions that have been established for soluble Envs in commonly used iterative vaccine development methods. In the first specific aim of this proposal, Env nanodisc structures are solved in complex with MPER-targeting antibodies to give guideposts for vaccine development. In the second, nanodiscs are assembled with controlled lipid compositions to elucidate the contribution of the bilayer surface to MPER antibody binding. Lastly, the third specific aim establishes conditions for utilizing Env nanodiscs in electron microscopy-based polyclonal epitope mapping (EMPEM). All aims will collectively contribute to improved nanodisc assembly pipeline that can be scaled to serve multiple HIV MPER targeting vaccine development projects. This pipeline can also serve the development of any transmembrane Env immunogen that targets other epitopes, and which will be administered as mRNA- LNPs. Ultimately, the tools will be made available for other virus glycoprotein vaccine development projects beyond HIV.

NIH Research Projects · FY 2025 · 2025-07

SUMMARY/ABSTRACT During the past five years, major breakthroughs have occurred in discovery biologyy, computational “big data” science, and translation to drug discovery that have not yet impacted the training of preclinical addiction researchers. To address this gap, the present new predoctoral training grant uses a mentor mosaic model of scientific training in the unique transdisciplinary, open culture of Scripps Research to develop a new generation of leaders equipped with the new technical skills and expertise with team science needed to translate targets to treatment. The training program is set in the historically successful addiction research environment at Scripps and combines a core of expert mentors in the neuropsychopharmacology of addiction with pioneering partner mentors in 4 other domains: a) discovery biology, b) computational and medicinal chemistry, c) advanced data science and artificial intelligence, and d) translational medical science for drug discovery. An experienced Project Director will be supported by impactful co-Directors in Biology and Chemistry, educational leaders from the graduate school and other campus training grants, and a distinguished External Advisory Board of scientific and mentoring experts dedicated to diversity. The mosaic scientific mentoring is supported by synergy with addiction and translational training grants at Scripps for more senior career stages, new translational curricula in advanced data science at Scripps and UC-San Diego, distinguished seminar series in each key discipline, reverse mentoring through SANDI summer internships, peer-to-peer mentoring for career development, and both didactic and experiential opportunities to enhance leadership, writing and grantspersonship, oral communication, ethical science, and rigor and reproducibility. A recruitment plan is detailed to attract diverse young scientists to apply to work with the 30 experienced, well-funded mentors at all career stages. The training plan has the potential to yield a new type of addiction researcher – skilled in team science and with transdisciplinary fluency not only in neurobiology, but also big data science and leading-edge approaches in discovery biology and chemistry.

NIH Research Projects · FY 2026 · 2025-06

PROJECT SUMMARY Human coronaviruses have caused devastating global pandemics and epidemics and continue to threaten global public health. Coronaviruses are highly variable, which has led evasion of most neutralizing antibodies and reduction in vaccine effectiveness. Many potent antibodies to coronaviruses have very limited breadth, while some of the broadest neutralizing antibodies described to date exhibit notably lower neutralization potency. Thus, the exigency to capitalize on what we have learned during the SARS-CoV-2 pandemic to find novel epitopes that elicit broad and potent antibodies against the coronavirus family and enhance pandemic preparedness. We have developed a highly integrated platform for identification of B cell epitopes against coronaviruses. Our previous studies revealed over ten B cell epitopes on the SARS-CoV-2 spike, through comprehensive characterization and high-resolution structure determination. This project aims to identify novel B cell epitopes on SARS-CoV-2 and other human coronaviruses, focusing on conserved and cryptic epitopes that elicit broadly neutralizing antibodies. Specifically, we will (1) identify unexplored epitopes on the SARS-CoV-2 spike protein, (2) uncover cryptic epitopes that have been largely understudied, and (3) identify pan-sarbecovirus, pan- betacoronavirus, and pan-coronavirus epitopes. Collectively, utilizing diverse donor samples, state-of-the-art multi-bait B cell isolation strategies, and high-throughput structural biology, this research aims to uncover novel B cell epitopes that inform on the design of next-generation vaccines and therapeutics, enhancing our preparedness for future coronavirus pandemics.

NIH Research Projects · FY 2026 · 2025-06

Project Summary/Abstract Fundamentally, a major bottleneck in the drug discovery process across all medical indications is the difficulty of synthesizing topologically complex small molecules for initial biological evaluation and ultimately for large-scale production. This, in turn, points back to limitations in the synthetic toolkit, specifically the paucity of reactions that can be deployed to rapidly and efficiently synthesize families of structurally intricate compounds from simple starting materials. In line with the goals of NIHGMS, our research laboratory seeks to address this problem by developing novel transformations to expedite organic synthesis. Central to our approach is the use of transition metal catalysts that enable otherwise impossible modes of bond construction and that facilitate sustainable synthesis consistent with goals of green chemistry. Since our laboratory’s inception, we have been motivated by the goal of achieving “universal functionalization” of carbon–carbon π-bonds, namely the introduction of any two functional groups desired by an end-user with complete control of regio-, stereo-, and chemoselectivity. In this way, we endeavor to unlock alkenes, alkynes, and related functional groups as general progenitors for all functional group combinations needed in synthesis. Our efforts to date have resulted in the discovery of numerous historically challenging transformations; the invention of new catalysts, reagents, and ligands that have been subsequently commercialized; and the development of novel strategies for reaction development that have been widely adopted within the field. In the current proposal we seek to continue this positive momentum. The described projects build on our established platform for reaction development, wherein gaps in synthetic methodology for π-bond functionalization are targeted, catalyst design principles and mechanistic insights are extracted, and practical utility and scope are iteratively improved. In the next five years, we will generate chemical knowledge that that advances the field of π-bond functionalization and transcends it. First, we will refine and leverage an auxiliary-directed approach to unlock novel reactivity modes with earth-abundant first-row metal catalysts. Second, we will develop strategies that obviate auxiliary installation and removal by relying on interactions with native functional groups. Third, through innovations in ligand design, we will invent non-directed methods that integrate α-olefins and other unsaturated feedstocks.

NIH Research Projects · FY 2025 · 2025-06

eDyNAmiC (extrachromosomal DNA in Cancer) Human genes are arranged on 23 pairs of chromosomes, but in cancer, tumour-promoting genes can free themselves from chromosomes and relocate to circular, extrachromosomal pieces of DNA (ecDNA). These ecDNA do not follow the normal “rules” of chromosomal inheritance, enabling tumours to achieve far higher levels of cancer-causing oncogenes than would otherwise be possible, and licensing cancers with a way to evolve and change their genomes to evade treatments at rates that would be unthinkable for human cells. The altered circular architecture of ecDNAs also changes the way that the cancer-causing genes are regulated and expressed, further contributing to aggressive tumour growth. These unique features make ecDNA-containing cancers especially aggressive and difficult to treat. Cancer patients whose tumours harbour ecDNA have markedly shorter survival. Despite being first seen over fifty years ago, the critical importance of ecDNA has only recently come to light, and the scale of the problem is substantial. ecDNAs are present in nearly half of all human cancer types and potentially up-to a third of all cancer patients. The collective current understanding of how ecDNA form, how they function, how they move around the cell, how they evolve to resist treatment, how they impact the immune system, and how they can be effectively targeted are lacking. We bring together an internationally recognized, pioneering interdisciplinary team of cancer biologists, geneticists, computer scientists, evolutionary biologists, mathematicians, clinicians, and patient advocates to boldly create novel insights and resources and to provide transformative solutions to one of Cancer’s Grand Challenges. A core team of experienced and productive ecDNA investigators will work with new investigators in the ecDNA and cancer fields to bring completely new perspectives and approaches to this daunting challenge. By bridging cutting-edge and diverse approaches and insights from cancer genomics, yeast genetics, epigenomics, artificial genome synthesis, longitudinal patient tracking, combinatorial and machine learning algorithms, mathematical modelling, immunobiology, and innovative chemistry we will develop a new understanding of the role of ecDNA in cancer, and we will find new ways to drug the undruggable. This bold programme, which consists of 7 work packages and a committed international infrastructure, generates new and unusual collaborations that would simply be impossible under any other type of funding mechanism. Our programme endeavours to foster bold innovative solutions to one of the hardest problems in cancer and to one of the greatest challenges facing cancer patients.

NIH Research Projects · FY 2026 · 2025-06

Project Summary/Abstract: Correcting gene dosage is crucial for addressing neurodevelopmental disorders (NDDs) linked to haploinsufficient genes, where the loss of one allele disrupts normal gene function. This research focuses on developing a cutting-edge platform to identify and manipulate microRNA (miRNA)-mediated repression of haploinsufficient genes, a strategy that has been underexplored due to technical limitations. Our approach integrates advanced tools to map miRNA-target interactions (MTIs), block these interactions, and measure the ability of blocking specific MTIs to restore levels of protein translation with high precision and at scale. We will utilize AGO2 eCLIPseq to map cell-type and human-specific MTIs in iPSC-derived cortical neurons, providing a comprehensive view of target sites on haploinsufficient genes where miRNAs repress translation. To address the challenge of blocking specific MTIs with high throughput, we will employ a novel CRISPR-based system using pooled barcoded guide RNAs (gRNAs) that target and inhibit specific MTIs. This method, demonstrated to be effective in preliminary tests, will be adapted for pooled screening. We will combine the above techniques with single-cell Ribo-STAMP technology to quantify translational changes in target proteins at single-cell resolution, a significant advancement over current methods. This platform will first be validated in mouse cortical neurons before transitioning to human iPSC-derived neurons, where we aim to discover and validate promising MTI targets with potential to rescue protein levels in human haploinsufficient genes. Our innovative approach aims to map, block, and validate MTIs that can be targeted to rescue protein levels in haploinsufficient NDD causing genes. By systematically identifying and blocking these MTIs, we seek to establish a robust screening platform that could lead to new therapeutic strategies for NDDs and other haploinsufficient disorders. The successful execution of this project will provide critical insights into miRNA-mediated regulation of gene expression and offer potential novel avenues for clinical intervention.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY. To date, biochemical tools to study secreted proteins’ origins and destinations leading to the discovery of new biomarkers associated with disease are underdeveloped. Deciphering interorgan communication pathways will provide insights into key modulators of obesity driven inflammation. Interorgan dysfunction from overconsumption, hence overstimulation of key metabolic pathways, has a significant impact on the development of metabolic diseases, such as Type II Diabetes, cardiovascular disease, liver disease, and cancer. Specifically, disrupting the interaction between the intestine and adipose tissue plays a crucial role in the development of complications of obesity. Therefore, uncovering intestinal secreted proteins trafficked to adipose tissue can in the future lead to the development of druggable targets that may attenuate the progression of obesity related metabolic diseases. The objective of this proposal is to utilize novel tools to study the interorgan communication pathway between the intestine and adipose tissue immune cells. We have developed a Cre-inducible endogenous biotin-ligase BirA*G3 affinity tracking system expressed in the mouse intestine, with the capability of biotin-tagging proteins sent through the endoplasmic reticulum of intestinal epithelial cells. After Cre-induction, the addition of free-biotin induces rapid labeling of the intestinal epithelium, and of all secreted proteins. Utilizing streptavidin affinity enrichment, we capture the proteins trafficked to our target organ and employ tandem mass- tag (TMT) quantitative mass spectrometry proteomics to identify the low-abundance trafficked proteins, as well as their origins and destinations. Using this approach, we identified PlexinB2 which is secreted from intestine to regulate subcutaneous white adipose tissue lipolysis and systemic metabolism. I hypothesize that the intestines regulate adipose tissue remodeling and inflammation by secreting signals including PlexinB2 to distinct immune cells populations in response to diet induced inflammation. Specifically, in Aim 1, I will elicit novel proteins trafficked from the intestines to adipose tissue immune cells, in mice. I will determine and validate the intestinally secreted proteins targeting adipose tissue immune cells during a high fat, fructose, and cholesterol diet which induces obesity. Then, in Aim 2, I will define the impact of enriched intestinal proteins on immune cell function. I will determine the effect of these identified secreted proteins, including PlexinB2, on macrophages, dendritic cells, T-cells and B-cells in vitro. Finally, I will demonstrate the biological significance of discovered proteins using in vivo models of overexpression as well as the effects our validated Plexin-B2 knock-out mouse has on immune cell function in vivo. Advised by Dr. Ilia Droujinine, co-advised by Dr. Enrique Saez, and in collaboration with Drs. Ben Cravatt, Lindsey Miles, and Howard Hang, my multidisciplinary training will enable me to advance proteomic tools to study organ-to-organ communication, and during its course to become an expert and an independent investigator in the field of metabolic disease.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY In response to a variety of stress and starvation cues, bacteria spend ATP to make a polymer, polyphosphate (polyP), consisting of long chains of phosphate groups. PolyP synthesis is important for fitness during stress and starvation, and promotes virulence in many human pathogens, including the opportunistic pathogen Pseudomonas aeruginosa. The molecular mechanisms by which polyP exerts its pleiotropic effects on bacterial physiology and virulence remain poorly understood, in part because of the difficulty in identifying bona fide protein interactions with this simple polyanion. While lacking specificity at the primary level of organization, polyP chains come together to form granular superstructures, membraneless condensates which are spatially organized in some species. In P. aeruginosa, polyP granules form in the nucleoid region and become evenly spaced on the cell’s long axis during nitrogen starvation. We recently discovered that the histone H1-like DNA binding protein AlgP facilitates polyP granule spacing in P. aeruginosa, and that DNA alone can modulate the biophysical properties of polyP condensates in vitro. Together with other observations, these findings lead us to propose our central hypothesis, that polyP granules remodel bacterial chromatin during stress in P. aeruginosa. We will test our central hypothesis through three aims: (1) Define the epistatic relationship between polyP and algP as regulators of gene expression and virulence under clinically relevant conditions, (2) Evaluate how polyP and polyP condensates affect interactions of AlgP with DNA in vitro, and (3) Determine how polyP condensates affect functional AlgP-chromosome interactions in cells. This proposal’s innovation lies in its integrative approach to explore an important emerging theme in the polyP field, that this polymer may be an important part of bacterial chromatin, in the context of a DNA-binding protein that may be under positive genetic selection in chronic infections. This proposal integrates detailed in vitro biophysical and quantitative cell biological studies of the disordered histone H1-like C-terminus of AlgP and its interactions with polyP and DNA with quantitative analysis of genetic variability of this domain in clinical isolates from chronic CF infections and in vivo cell and murine lung infection models. The expected outcome of this study is an understanding of how these two polyanions, polyP and DNA, work together during stress and starvation states, as well as establishing the functional significance of the genetically variable protein AlgP in the evolutionary trajectory of chronic infections. The significance of the proposed research is both in establishing the molecular function of polyP in stress responses and virulence, and contributing to our larger understanding of the role of phase separation in subcellular organization in bacteria, an emerging theme in bacterial cell biology.

NIH Research Projects · FY 2025 · 2025-03

ABSTRACT Pharmacological modulation of regulatory T cell numbers and function has significant potential in the context of autoimmune and inflammatory disease. However, the overlapping and pleotropic nature of immune-related signaling pathways associated with currently known methods to expand functional regulatory T cells makes it challenging to increase regulatory T cell populations, without having intolerable immunosuppressive or cytotoxic effects. Agents reported to date can result in the expansion of additional cell types that can hinder the effect of Tregs or produce nonfunctional Tregs. Here, we have conducted a high throughput flow cytometry screen to address this issue and have identified multiple Treg-inducing small molecules, including A205804, as novel inducers of FOXP3 expression. A205804 induces FOXP3 expression in human and mouse CD4+ T cells and Tregs induced to differentiate using this compound maintain suppressive activity. Mechanistic studies revealed that A204804’s ability to regulate Treg differentiation occurs independently of its reported impact on endothelial cells (i.e., functional inhibition of ICAM-1 expression) or NF-kB signaling and also functions independent of known mechanisms related to IL-2 or TGF- signaling. To achieve the overall objective of this proposal, the following three specific aims will be successfully completed: 1A. Identify the relevant biomolecular target and associated mechanism of action for A205804 in the context of its ability to induce functional human and mouse CD4 Treg differentiation. 1B. Optimize the pharmacokinetic properties of A205804. 2A. Determine selectivity, human activity and validate induction of suppressive Treg function for three novel mechanism of action small molecule scaffolds (SR0723, SR0767, SR0320). 2B. Determine potential cross-reactivity with identified target of A205804 and identify relevant biomolecular target(s) for small molecules demonstrated to function independently of the A205804 mechanism. 3. Determine the ability of A205804 and at least one novel MOA compound to selectively induce CD4 Treg differentiation, impact total CD4 Treg numbers and positively impact remyelination in the cuprizone demyelination/remyelination model. Successful completion of the research objectives described in this proposal will address a key knowledge gap in our understanding of the biology and application of naïve CD4 progenitor T cells, which is relevant to human biology and diverse human disease contexts. Specifically, by identifying actionable targets for the selective induction of Treg differentiation, results from the proposed research activities will facilitate future preclinical studies and efforts aimed at developing stem cell-based therapies with applications across diverse forms of inflammatory and auto-immune related human diseases.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY: Neurodegenerative diseases pose significant challenges to public health and our understanding of brain function. Central to these conditions is the pathological accumulation of protein aggregates, notably alpha-synuclein, beta- amyloid, and Tau. Specifically, Tau aggregates are expelled into the extracellular space as neurons degenerate, where they act as damage-associated molecular patterns (DAMPs) that are sensed by microglia. Microglial activation leads to inflammatory responses, which contribute to impaired neuronal function and cognitive decline in diseases like Alzheimer’s Disease (AD). Although various pattern recognition receptors (PRRs) have been reported to sense Tau, emerging evidence suggests that cyclic cGAMP synthase (cGAS), a DNA PRR, also plays a crucial role in promoting inflammatory responses. Recent reports suggest that Tau activates the cGAS pathway, and this would require an initial interaction with an adaptor, Polyglutamate Binding Protein 1 (PQBP1). In three separate studies, our group has shown a similar requirement for cGAS activation by HIV-1 infection. PQBP1 decorates HIV-1 capsids and recruits cGAS to the site of HIV-1 DNA synthesis. PQBP1 recruitment to the capsid is mediated by charge complementation, and its dimerization is required for cGAS activation. We hypothesize that PQBP1 binding to Tau is necessary for cGAS activation, which contributes to chronic neuroinflammation in AD and other tauopathies. Building on our experience and reagents from our HIV-1 studies on PQBP1 and cGAS, we propose to fill major gaps in knowledge regarding the structural requirements of PQBP1-Tau complex formation and its contribution to cGAS activation. In Aim 1, we will determine the regions of PQBP1 that are required for the recognition of Tau monomers and fibrils. Further, we will elucidate whether PQBP1 interacts with exogenous PQBP1 as well as PQBP1 expressed in microglia. In Aim 2, we will demonstrate that the cGAS pathway is active in human AD brain tissue and is associated with PQBP1 and Tau. Cellular models will be used to directly show cGAS activation by PQBP1 and Tau. The combined support from Dr. Chanda and Dr. Timothy Huang will ensure the success of the proposed training plan. Whereas the Chanda Lab brings innate immunity expertise and reagents, the Huang Lab brings the requisite expertise and reagents in neurodegenerative disease. As an institute, Scripps Research provides an optimal training environment through its state-of-the-art doctoral program, core facilities, seminar series, and proximity to other major research institutes, including Sanford Burnham Prebys, where the Huang Lab is situated. This rich scientific environment will enable the completion of the proposed studies, which will support the identification of novel therapeutic modalities to mitigate inflammatory responses and neurodegeneration in humans.

NIH Research Projects · FY 2026 · 2025-01

The development of a broad-spectrum influenza vaccine remains a significant challenge. One promising target for vaccine design is neuraminidase (NA), which is engaged by broadly neutralizing antibodies (bnAbs) that mimic the sialic acid receptor and bind to the conserved active site. These NA bnAbs use long heavy chain complementarity determining region 3 (HCDR3) loops to access the recessed active site. However, antibodies with long HCDR3s are rare in the naive human antibody repertoire, making it unlikely for them to be consistently elicited through standard vaccination strategies. To address this, a strategy called germline targeting vaccine design aims to prime the rare precursor B cells with the potential to develop into bnAbs by giving them an affinity advantage over more common strain-specific competitors. In this proposal, recently discovered NA bnAbs will be evaluated to assess their potential for germline targeting. Factors such as precursor frequency in the human antibody repertoire, somatic hypermutation levels, and structural characteristics will be considered. Once the most promising bnAb candidates have been identified, mammalian display directed evolution will be employed to design NA immunogens that can engage diverse bnAb precursors from those NA bnAb classes. This protein engineering effort will pave the way for future preclinical animal studies and other immunogen validation studies. If successful, a demonstration that NA germline targeting immunogens can engage diverse NA bnAb precursors would open up a new pathway towards a universal influenza vaccine.

NIH Research Projects · FY 2026 · 2025-01

The progress of type 1 diabetes research has been limited by the accessibility of the target organ, the pancreas. The recent progress in the design and manufacturing of microfluidic platform has allowed the development of vascularized micro-endocrine pancreas on a chip. However, neither primary islets, nor islet-like structures produced from embryonic stem cells or induced pluripotent stem cells (iPSC) have allowed to build a fully syngeneic system, yet. However, full histocompatibility is necessary to introduce in those devices immune cells and study the mechanisms of immune attack to the b cells. Thus, the primary goal of the UG3 phase of the proposal is to build the elements that will allow this histocompatibility and the introduction of immune cells from patients into the vascularized micro-organ. Towards this end, we will use a series of iPSC cell lines from 3 T1D patients and 3 control individuals to produce endocrine cells, blood vessels, tissue-resident macrophages, and fibroblasts. While large quantities of PBMCs are available from each donor, clonal populations of CD4 and CD8 T cells of known antigen specificity will be produced for each individual using Crispr/Cas9 editing and TCR viral transfer. The micro-organ and each cell type will be tested in vitro for functionality as well as their capacity at responding to inflammatory mediators. This analysis will combine functional tests such as GSIS for b cells and permeability for blood vessels, and phenotypic analysis by immunofluorescence microscopy (confocal and 2- photon confocal) and single cell transcriptome. The UH3 phase will integrate this platform into the understanding of b cell death and its mechanisms. The immunological interrogation will proceed in three steps: 1- What cells are presenting antigens to CD4 and CD8 T cells? 2- What are the target cells and effectors molecules of CD4 and CD8 T cells? 3- Can we show that CD4 are cytotoxic by bystander effects, and CD8 directly cytotoxic? To complement these mechanistic studies, a genome wide screen of b cell resistance to death will be performed to identify/confirm the pathways of killing. In addition, we will take advantage of our unique system to screen candidate compounds capable of protecting b cells from death. Finally, we will attempt to examine the behavior of the exocrine pancreas by testing organoids in the same inflammatory context than the one used for islets and T cells. Our path to success is built on the complementarity and congruency of the three experts leading this effort: Jeff Millman, a force in the world of iPSC differentiation and type 1 diabetes, Chris Hughes who designed and engineered the original microfluidic system and is a world leader in vascular biology, and Luc Teyton, an immunologist of type 1 diabetes.

NIH Research Projects · FY 2025 · 2025-01

Cancer cells often amplify signaling proteins, altering cell signaling networks and leading to protumor cellular behaviors. These signaling proteins can be copy-number amplified genetically via formation of circular extrachromosomal DNA (ecDNA). ecDNA is detected in a quarter of cancer samples and half of all cancer types, and is associated with poor patient outcomes. Despite the prevalence of ecDNA-mediated oncogene amplification in cancer, we have a limited understanding of how ecDNAs are maintained in cancer cells. While there have been extensive studies on how overexpression of these genes affects tumor growth and activities of signaling molecules, we have a poor understanding of how these genomic changes ultimately affect the logic of signaling that alter cellular behavior. The goal of this work is to elucidate the mechanism of retention of amplified genes encoding signaling proteins on ecDNA in cancer cells and to investigate the logic of biochemical and mechanical integration via amplified signaling proteins in cancer cell proliferation and migration. I hypothesize that specific genetic elements on ecDNA enable hitchhiking onto chromosomes in order to partition into daughter nuclei during cancer cell division. In Aim 1, I propose to identify DNA elements and protein mediators that enable retention of ecDNAs using a shotgun episome-based genetic screen, mitotic chromatin conformation capture, CRISPR screening and integration of epigenomic datasets. I also hypothesize that cancer cells with EGFR amplification integrate epidermal growth factor (EGF) signals and mechanical forces differently than wild-type-EGFR cells. In Aim 2, I propose to investigate the logic of biochemical and mechanical integration via amplified signaling proteins in cancer cell proliferation and migration. I will use Forster resonance energy transfer (FRET)-based biosensors, traction force microscopy, and fluorescence cell imaging to measure ERK signaling activity in EGFR-amplified cancer cells under mechanical stretch. I will also measure cell migration and cell fate changes of EGFR-amplified cells after ERK activation and cultured in substrate with various stiffness levels. Together, elucidating the mechanisms of extrachromosomal oncogene amplification and altered signaling logic due to oncogene amplification in cancer cells will reveal potential therapeutic opportunities. This work will also provide novel insights into how biochemical and mechanical signaling is altered in these oncogene-amplified cells to drive cancer cell behaviors.

NIH Research Projects · FY 2026 · 2024-12

Abstract The Translator project has made substantial progress in the area of biomedical data integration and question answering, evolving from a feasibility study to its current development phase. This proposal builds on prior progress made collaboratively between the Exploring Agent and Service Provider teams, and between those teams and the rest of the Translator Consortium. Our proposal, entitled "DOGSURF: Database Optimized for Graph Search Using Robust Federation" will further advance the project into the Performance Phase, focusing on architectural standardization and centralization, improved performance and result quality, and expanded functionality. The proposal is organized around three Specific Aims: 1. Expanding the BioPack Framework: This aim involves enhancing BioPack, a modular framework for querying the Translator Knowledge Graph (KG) and improving result scoring and organization. Collaboration with the DOGSLED team will focus on the Retriever and Shepherd components to boost performance and functionality. 2. Enhancing the BioThings SDK and BioThings Explorer: Leveraging BioPack, the project will extend the BioThings SDK and improve the BioThings Explorer. This includes enhancing answer quality, introducing new query types, and improving performance through integration with BioPack. 3. Building High-Performance Central Components: The final aim focuses on developing a unified backend infrastructure and access interface. This includes consolidating data ingestion backends, unifying services like Annotator and NodeNorm, and creating a centralized interface for efficient access across the Translator ecosystem. User engagement is central to the proposal, with a plan to collect feedback, prioritize features, and increase usage by the research community. Collaborations with external bioinformatics cores will further expand Translator's impact. The project plan provides detailed annual milestones for each Specific Aim for five years. Key abbreviations ARA: Autonomous Relay Agent – Translator components responsible for reasoning BSDK: BioThing SDK – a framework developed by our team to efficiently create high-performance APIs BTE: BioThings Explorer – an ARA developed by our team for reasoning on a federated KG DOGSLED: Data, Ontologies, and Graphs to Support Learning and Enhance Development – the name of another team with whom the BioPack vision and plan was developed DOGSURF: Database Optimized for Graph Search Using Robust Federation – the name of the project described in this proposal ITRB: Information Resources Technology Branch – the branch of NCATS responsible for provisioning computational resources KP: Knowledge Provider – Translator components responsible for providing access to information from knowledge sources KS: knowledge source – a generic term for a resource that provides useful and relevant data to Translator SDK: Software Development Kit – a set of programmatic tools and libraries to efficiently create and extend software applications

NIH Research Projects · FY 2026 · 2024-12

Prionopathies are rare human neurodegenerative diseases (ND) characterized by spongiform change, gliosis, and the deposition of misfolded prion protein (PrP) aggregates in and outside neurons across the brain. While cellular mechanisms remain largely undefined, evidence points toward a particular vulnerability of axons to the formation of misfolded PrP aggregates, and their accumulation inside lysosome-like compartments that contain incompletely digested material suggestive of defective lysosomal degradative pathways. These enlarged organelles are also an early pathological feature in brains of patients with Alzheimer’s Disease and Alzheimer’s Disease related dementias. Indeed, abnormal autophagic activity has been observed in brains of Alzheimer’s Disease, Alzheimer’s Disease Related Dementia, and prion disease patients, and activation of autophagy restores impaired lysosomal flux and reduces protein aggregates in cellular and ND animal models. Compelling evidence shows that PrP aggregates in axons impair neuronal function by driving the accumulation of organelles/vesicles and poisoning axonal transport. Thus, pharmacological targeting of toxic axonal aggregates via activation of autophagy could be a key strategy for preventing or ameliorating neuronal dysfunction in the proteinopathies. This application builds on our previous findings that identified an endolysosomal pathway unique to axons that promotes the initial stages of formation of misfolded mutant PrP aggregates inside enlarged endolysosome structures called ’endoggresomes’, that hyper-acidify and thus fail to degrade mutant PrP from axons, indicating impaired lysosomal degradation. This pathway is called axonal rapid endosomal sorting and transport-dependent aggregation (ARESTA), and genetic reduction of ARESTA genes efficiently inhibits mutant PrP endoggresome formation in axons, and restores neuronal function. In this application, we outline a therapeutic strategy to treat prionopathies. It is based on a small molecule A5, that we identified in a screen for lysosomal flux activators, and that activates macroautophagy via nuclear translocation of the transcription factor EB (TFEB), which controls transcription of lysosome and autophagosome biogenesis. A5 clears neurotoxic mutant PrP endoggresomes in axons of primary neurons, normalizing completely axonal transport impairments in cultured neurons expressing mutant PrP. Notably, A5 treatment reduces brain pathology in a mouse model of inherited prion disease. A5 degrades PrP aggregates at concentrations in the lower nanomolar range, shows no overt signs of toxicity in mice, and has brain penetrance. The proposed aims will test the efficacy of A5 in neuronal and mouse models of familial and infectious prion disease. We will also identify the mechanisms of action (MoA) of A5 by identifying interaction partners and characterizing the role of TFEB. Our findings reveal a therapeutic strategy to treat prionopathies by pharmacological activation of macroautophagy. As lysosomal clearance is commonly impaired in Alzheimer’s Disease and in Alzheimer’s Disease related dementias, our findings are also expected to be relevant to treating these disorders.

NIH Research Projects · FY 2025 · 2024-12

ABSTRACT The 2024 SoCal Genome Stability Symposium is a one-day conference that will be held at The Scripps Research Institute, La Jolla, CA. The conference will focus on the topics of genomic instability, DNA damage signaling, mechanisms of DNA repair, DNA mutagenesis, environmental mutagens, cancer etiology and cancer treatment. Understanding the mechanisms in these areas will not only shed light on the fundamental processes governing the maintenance of genome stability but will also pave the way for developing new effective cancer treatment. We aim to bring a rigorous scientific program that fosters the exchange of new research findings and innovative ideas on the interplay between DNA repair and cancer treatment. We will invite graduate students and postdoctoral fellows from diverse research laboratories to present cutting-edge unpublished research. One unique aspect of this conference is that we dedicate the entire program to the trainees, allowing only graduate students and postdoctoral fellows to give oral and poster presentations. This creates invaluable opportunities for trainees to gain experience in formal research presentations in a real conference setting. Additionally, this conference will provide networking and mentoring opportunities for the career development of young scientists. This conference is free of charge for all participants, ensuring that every student or postdoctoral fellow from Southern California has equal access to participate. The goals and objectives of the conference are: 1) to expose students and postdocs to the new frontiers of a rapidly progressing research area; 2) to provide a formal platform for presentations to trainees, and an opportunity to receive feedback on their research progress; 3) to stimulate new collaborations between laboratories across different research institutions; 4) to catalyze opportunities for young scientists to network with a diverse group of scientists, including by receiving formal and informal mentoring and by opening future postdoctoral or faculty position opportunities; 5) to provide an atmosphere of inclusion and rigor for the trainees participating in the symposium. The symposium will enhance interactions among students and postdoctoral fellows from all genders, backgrounds, and origins, including historically marginalized groups such as those from underrepresented racial and ethnic groups, individuals with disabilities, individuals with different sexual orientations, and individuals from socioeconomically disadvantaged backgrounds.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY Key metabolites from intestinal microbiota can modulate host immune responses, but their mechanisms of action are unclear and limit the development of new therapeutic approaches in human health and disease. To determine the mechanism(s) of action of prominent microbiota metabolites (short chain fatty acids, aromatic amino acids, bile acids and others), multi-disciplinary approaches are needed to biochemically identify metabolite-protein targets in mammalian cells and characterize their activity on host immunity in vivo. For this grant application, our laboratories will focus on microbiota-associated bile acids and employ innovative methods in chemical biology and proteomics to identify their protein targets in mammalian cells and characterize their mechanism(s) of action on host immunity in vitro, ex vivo and in mouse models in vivo. A better understanding of how these microbiota metabolites affects host immunity should reveal potential therapeutic targets and facilitate the development of therapeutic approaches against infection and cancer in animals and humans.