University Of California-Irvine

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY/ABSTRACT Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm diagnosed in about 5,000 Americans each year, characterized by the presence of the t(9;22) Philadelphia chromosome and its protein product, the BCR-ABL1 tyrosine kinase, in the leukemic cells. Current therapy for CML is centered on tyrosine kinase inhibitors (TKIs) such as imatinib mesylate, which can induce cytogenetic and molecular remissions in most patients, who then enjoy normal age-adjusted life expectancy. This clinical success will lead to an estimated prevalence of ~200,000 CML patients in the U.S. by the year 2050, with attendant drug costs of >$10 billion that can include burdensome out-of-pocket payments for patients. In addition, TKIs can have substantial side effects, some of which are potentially life-threatening. Accordingly, recent efforts have been made to stop TKI therapy in CML patients who have achieved molecular remission. About half of such patients experience progressive molecular relapse following TKI stopping, but the other half either remain molecularly undetectable or experience low-level recurrence that does not progress (collectively termed treatment-free remission or TFR), suggesting that there are biological mechanisms that limit the ability of small numbers of leukemic stem cells to expand and cause disease. These mechanisms are not understood, and represent a major unmet need in current CML research, as we do not have validated approaches to increase the proportion of CML patients who are eligible to stop their TKI nor to increase the proportion of patients who can maintain TFR. This application seeks to address these unmet needs by exploiting a newly developed CML mouse model of TFR. In this model, hematopoietic stem cells (HSCs) from an existing conditional double transgenic (dTg) mouse model of CML are transplanted into recipient congenic B6 mice without the use of conditioning radiation. The resulting bone marrow (BM) chimeras contain clones of dTg HSC in a background of normal BM, representing a physiological model of early CML. Mice bearing large (>10%) clones of dTg HSC uniformly develop CML-like leukemia when BCR-ABL1 expression is induced, but mice with smaller (<2%) dTg clones do not develop CML, but instead exhibit fluctuating low levels of dTg granulocytes in peripheral blood that mimics TFR. The proposed project will test whether two distinct processes, oncogene-induced replicative stress and the BM microenvironment/niche, are involved in the ability of the host to control the malignancy. Aim 1 will test whether oncogene-induced replicative stress is involved by a incorporating loss-of-function mutation in the p19Arf gene in the dTg donor cells. Aim 2 will test whether elements of the BM niche, including immune cells and cytokines, are required for disease control. Aim 3 will translate these findings to human CML BM samples using the spatial mass cytometry to define the topography of the CML niche and correlate this with TFR outcomes. These results will yield important new knowledge about the pathophysiology of TFR that should motivate novel therapeutic approaches to increase the frequency and durability of TFR in CML patients.

NIH Research Projects · FY 2025 · 2024-05

The overall goal of the All of Us Southern California Consortium, led by the University of California, Irvine, is to engage, recruit, and retain participants from the Southern California population with the goal to participate in the scientific mission of the All of Us Research Program, including participation in Partnered Research Studies (PRS) such as the Eyes on Health ocular imaging study. We have assembled a multidisciplinary team with significant scientific strength, experience, and motivation to be one of the most effective and efficient All of Us consortia nationwide. AoUSCC strives to promote access to health data and tools for participants, citizen scientists, and researchers to make queries and obtain impactful results using the All of Us research data in a privacy-preserving manner for the advancement of science in disease etiology and progression, health data research, data access, breakthroughs in artificial intelligence and machine learning, and precision medicine. We continue our work in promoting the data from the All of Us Research Hub to train future biomedical scientists. The AoUSCC goals for Year 2 guided by national All of Us priorities include: 1) Maintain regulatory requirements and develop processes and timelines for completion. 2) Achieve All of Us adult enrollment goals in direct support of PRS enrollment and expectations, including those for the Eyes on Health. 3) Ensure facilitated participation of existing potential and existing AoU participants for enrollment and retention. 4) Achieve electronic health record expectations, metrics, and provide twice-yearly electronic health records data transfers to the Data Research Center from UC Irvine. 5) Achieve performance metrics for sample quality related to biospecimens. AoUSCC will work with the Program to advance the National Institutes of Health’s mission to deliver results that matter to the American public. AoUSCC will continue to work with the national All of Us leadership to focus on scientifically valid and measurable health outcomes.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY/ABSTRACT Age-related macular degeneration (AMD) is a leading cause of visual disability worldwide, resulting in a significant medical and social burden. While the pathogenesis of AMD is multifactorial, dysfunction of the retinal pigment epithelium (RPE) contributes early to the progression of the disease. The RPE is a post-mitotic epithelial monolayer that is essential in maintaining the health and proper function of the adjacent photoreceptors. The RPE performs several functions, which include nutrient delivery, regeneration of the visual chromophore 11-cis-retinal for phototransduction, and phagocytosis of shed photoreceptor outer segments (POS). In fact, the RPE is the most actively phagocytic cell in the human body, engulfing and processing up to 10% of spent POS every day to avoid accumulation of harmful photooxidative products. Therefore, it is critical to understand age-related changes in RPE physiology; however, the role of lipid metabolism in regulating these changes has yet to be fully understood. It is becoming increasingly clear that alterations in lipid metabolism occur during aging across several tissues. In particular, the eye is highly enriched in docosahexanoic acid (DHA) and very long-chain polyunsaturated fatty acids (VLC-PUFAs), which play key roles in maintaining cellular membrane homeostasis. Recent research has correlated decreased levels of DHA and VLC-PUFAs with advanced age, and this decrease was further amplified in AMD eyes. A separate study has also linked a decline in RPE phagocytic function during aging, which also declined even further in AMD eyes. Thus, this proposal will investigate the mechanistic basis for age-related changes in RPE lipid metabolism and their influence on cell function. To pursue these objectives, we have generated Elovl2C234W mice, which lack Elovl2 enzymatic activity and exhibit decreased levels of DHA and VLC-PUFAs. Elovl2C234W mice also show accumulation of sub-RPE deposits with similar composition to drusen, one of the hallmarks of non-neovascular, or dry, AMD. The retinal structure, visual function, visual cycle activity, and phagocytic ability of mutant mice will be assessed at several ages. Changes in gene expression resulting from lack of Elovl2 activity will be analyzed by bulk and single cell RNA sequencing in RPE and retina. Lastly, we will correlate findings from mouse RPE to results from human RPE through the culture of RPE cells derived from human induced pluripotent stem cells. This proposal will be completed under the mentorship of Dorota Skowronska-Krawczyk, PhD and co-mentorship of Krzysztof Palczewsk, PhD in the Center for Translational Vision Research at the University of California, Irvine. The scientific training will also be supported by the Department of Physiololgy & Biophysics, the Medical Scientist Training Program, and collaborators and mentors from external institutions. The training plan details specific goals under this proposal, which include technical skills, such as measurements of mouse visual physiology and human induced pluripotent stem cell culture, analytical skills, including bioinformatic approaches, and professional skills, such as scientific communication and mentorship.

NIH Research Projects · FY 2026 · 2024-05

Project Summary / Abstract Pancreatic ductal adenocarcinoma (PDA) is a devastating disease lacking effective treatment options. PDA is characterized by a dense and fibrotic tumor microenvironment deposited by extensive and diverse fibroblast and immune cell populations within this niche. The diversity of cell types within PDA tumors also extends to cancer cells themselves, as heterogenous subpopulations of cancer cells are capable of symbiotic behaviors that support resistance to therapy. Accordingly, targeting crosstalk interactions can remove barriers to allow more effective clinical treatment. Investigating clonal PDA behaviors, we have identified two metabolic subpopulations differentiated by their sensitivity to mitochondrial inhibition. Metabolic exchange between these populations confers resistance mediated by asparagine that is overproduced and released through a constitutively active integrated stress response in the insensitive clones. Further, we observed that degradation of asparagine functions to sensitize PDA to mitochondrial inhibitors. Targeting mitochondrial metabolism in PDA cells functions to lower intercellular nucleotide pools that compete with standard of care chemotherapy, pyrimidine anti-metabolites. Further, targeting mitochondrial metabolism also functions to reduce the anti- inflammatory polarization of tumor-associated macrophages that provide non-cell autonomous chemoresistance. This research proposal will target factors underpinning the programming of PDA cells that produce and release asparagine (Aim 1). We have identified oncogenic and stress pathways that can be targeted to impair the survival of asparagine producing cells and disrupt metabolic crosstalk. Further, we have identified that asparagine producing PDA cells have hypermethylated histones that correlate with a mesenchymal state. Accordingly, we will leverage metabolic approaches to normalize the histone methylation and reprogram these cells to desensitize them to mitochondrial inhibition. In parallel, we will combine treatment of mitochondrial inhibitors potentiated through asparagine degradation and with standard of care chemotherapy (Aim 2). Both systemic and local asparagine levels will be targeted and compared for efficacy in enhancing mitochondrial inhibitors. These experiments will be performed in multiple human and murine tumor models, and analyzed through a combination of techniques that will allow for in vivo assessment of PDA metabolic subtype response to therapy. Finally, we will characterize the remodeling of the immune and stromal compartments of PDA tumors in response to mitochondrial inhibitors potentiated by asparagine degradation to identify new immune targeting approaches. Together, these data will provide important insights into mechanisms that maintain cancer cell heterogeneity and generate important pre-clinical data examining the impact of targeting metabolic crosstalk pathways to enhance PDA response to therapy.

NIH Research Projects · FY 2026 · 2024-04

This project will: 1) Create an educational curriculum that examines the following components to optimize the health of women and their families; 2) Pilot test the educational curriculum to iterate and refine course content and supplementary instructional materials; 3) Develop and implement a fellowship training program to train two cohorts (N=40) of women’s health scholars. Over the course of the four-year project period, we will engage in a two-year formative development phase followed by a two-year implementation phase. During the formative development phase, we will engage in course design and engage pilot participants in the piloting of course material, syllabi, and supplemental materials. During the implementation phase, we will implement a summer fellowship training program to train two cohorts of community and population health scholars. Trainees will be assessed in their knowledge, skills, and application of key concepts and topics. Our pedagogy will bridge research and practice, using real-world examples and case-studies to train our scholars on practical solutions. All courses will involve guest presenters and lectures from experts engaged in the field on the front lines.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY/ABSTRACT Pregnancy is a physiological state of continuous and significant adaptation to changing maternal and fetal nutritional needs ensuring successful completion of pregnancy at term. To this end, as pregnancy progresses, the placenta produces multiple hormones that participate in modifying maternal metabolism to meet the metabolic needs of both fetus and mother. Of the placental hormones, circulating kisspeptin1 (Kiss1) levels progressively increase by several-hundred-fold during pregnancy. Although certain metabolic actions have been assigned to Kiss1, little is known about how Kiss1 contributes to the metabolic adaptations of pregnancy. In addition to developing insulin resistance, maternal hepatic glucose output (rate of appearance) increases as does the propensity to developing hypoglycemia and ketosis even after short periods of fasting. The mechanism underlying the tendency of the pregnant female to develop ketosis remains unknown. Further, insufficient glucose and nutrient supply to the fetus poses a significant health risk for the developing child. Based on our preliminary studies, we hypothesize that during gestation placenta-derived circulating Kiss1, activates its cognate G-protein coupled receptor Kiss1R on hepatocytes and signals via Gaq-inositol triphosphate receptors (IP3R) to activate AMPK (adenosine-monophosphate dependent kinase), lipolysis and ketogenesis. Absence of Kiss1R in hepatocytes of female mice during pregnancy leads to excessive lipid accumulation in maternal hepatocytes and to increased risk of hypoglycemia in the third trimester. Furthermore, our preliminary studies indicate that the pancreatic hormone glucagon stimulates hepatic Kiss1 production, whereby Kiss1 acts in the liver in an autocrine manner. Absent liver Kiss1R, glucagon-induced IP3 production as well as hepatic glucose output are blunted in fasting mice, suggesting that kisspeptin induction is an integral part of glucagon action in hepatocytes. These observations reveal a novel regulatory interplay between glucagon and Kiss1 in regulating hepatic metabolic pathways. We now seek to expand our novel and exciting findings specifically a) to understand the molecular mechanisms that shape maternal liver metabolism in gestation; b) to understand different Kiss1R-IP3R signaling pathways in regulating liver metabolism, and c) to understand the role of glucagon-stimulated kisspeptin production by the liver in modulating liver metabolism during gluconeogenesis. We will use complementary in vivo and in vitro approaches to elucidate these important signaling pathways in hepatocytes using newly generated unique mouse models as well as in vitro in human hepatocyte cell lines. Our studies will yield important insights into kisspeptin’s role in liver metabolism during eutherian pregnancy and into how kisspeptin and glucagon signaling interplay in hepatocytes to regulate metabolism. Further, our studies will dissect signaling pathways as potential therapeutic targets in metabolic liver disease and diabetes mellitus.

NIH Research Projects · FY 2026 · 2024-04

Project Summary/Abstract This project addresses a topic of critical significance in advancing research on speech communication in children and adults: the adaptive mechanisms that enable listeners to navigate cross-talker variability in human speech. Talkers’ pronunciations of segments, syllables, and words—and thus ultimately meaning—can differ substantially depending on physiology, social identity, and language background. Scientific breakthroughs over the last four decades have determined that listeners accommodate these differences by adapting their interpretation of incoming speech for different talkers. However, what perceptual, linguistic, and cognitive mechanisms achieve these adaptive changes has remained unclear. This status quo is recognized as a major roadblock in advancing the field, limiting effective knowledge transfer to clinical and physiological research. To address this question, we capitalize on two recent innovations from our team: a comprehensive computational framework of adaptive speech perception (ASP) and a model-guided approach to high- powered contrastive experiment design. ASP—for the first time—implements competing hypotheses about how changes in perception, linguistic representations, and decision-making might jointly or separately contribute to spoken language understanding. The model-guided design approach allows contrastive tests of these hypotheses against human behavior. We use this approach to investigate one of the most complex adaptive feats of human speech perception: adaptation to unfamiliar non-native accents. In 16 large-scale web-based experiments (total N > 2,880 listeners), we investigate what combinations of mechanisms best explain such adaptation, and how the engagement of different mechanisms depends on 1) specific acoustic-phonetic properties of the accent, 2) the duration and amount of input, ranging from the first utterances to repeated exposure over up to 12 months, and 3) cognitive demands and contextual affordances. Independent of these primary goals, the proposed experiments make significant empirical, methodological, and theoretical contributions to research on the perception of accents. This includes a new production database of Mandarin- accented speech (the 2nd most commonly heard non-native accent in the US, incl. in healthcare contexts), new insights on the perceptual and cognitive factors supporting accent adaptation; and new comparisons of adaptation to different segmental and prosodic properties, some of which may require more exposure than others. Our longitudinal testing extending over 12 months will be the critical first step towards understanding how rapid adaptive changes in the first few minutes of exposure could lead to the well-known, long-lasting benefits of talker and accent familiarity in speech perception. Finally, our data and computational models—both shared without embargo in the form of open-access R libraries—will serve as a key resource for future experimental and computational research, supporting effective and rigorous hypothesis testing.

NIH Research Projects · FY 2026 · 2024-04

Poor oral health during pregnancy may have long term implications for the oral and overall health of expectant mothers and their children. For example, children of mothers with high levels of tooth decay have three times the odds of developing caries before their sixth birthday. Tooth decay is the most common chronic disease of childhood and particularly acute for non-Hispanic Black and Hispanic children who experience more than twice the rate of untreated decay compared with non-Hispanic white children. While pregnancy increases susceptibility to oral health problems, pregnant women are less likely to visit the dentist (44%) than reproductive-aged women who are not pregnant (65%). The objective of this application is to use quasi-experimental methods to estimate the effects of Medicaid pregnancy dental benefits on dental care use among pregnant women and subsequent outcomes among their children. Our central hypothesis is that pregnancy dental benefits will increase the use of all service types among pregnant women and increase preventive care but reduce the need for restorative treatment among young children by delaying or preventing the onset of dental caries. The central hypothesis will be tested by pursuing three specific aims: 1) to examine the effects of Medicaid pregnancy dental benefits on reported dental visits and claims-based measures of the use of preventive and restorative dental services among pregnant women; 2) to examine the effects of Medicaid pregnancy dental benefits on later dental care use among children ages 2-11 who were exposed to the policy while in utero, including reported dental visits, claims-based measures of the use of preventive and restorative dental services, out-of-pocket spending on dental care, and unmet needs for dental care due to cost; and 3) to evaluate the effects of Medicaid pregnancy dental benefits by race and ethnicity and by county-level measures of access barriers and facilitators including dentist supply, federally-qualified community health center supply and investment, and area-level social determinants of health (e.g., area deprivation index). The research proposed in this application is innovative because it will be among the first to examine how children’s exposure to Medicaid dental benefits while in utero affects their later dental care utilization, it will link mothers and their children in a subset of our analyses, and we will apply newly developed methods to address variation in the timing of state policy changes. The proposed research is significant because pregnant women and children underutilize recommended dental services, untreated dental caries among children may interfere with their development, and there are persistent disparities in dental visit rates and oral health by race and ethnicity. The public health impact of this research will be to provide critical new evidence on whether pregnancy dental benefits have long-lasting impacts on children who were exposed to the policies while in utero and to assist policymakers in assessing the full scope of the benefits and costs of these policies.

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY/ABSTRACT Integrative approaches, including nutrition, to address pain suffer from a paucity of mechanistic understanding, which often disproportionately impacts vulnerable populations. Affective modulation of pain in chronic disease remains an unmet need, however personalized, accessible approaches utilizing diet may provide alternative approaches for difficult-to-treat pain. Sickle cell disease (SCD) is the most commonly inherited blood disorder, primarily afflicting individuals of African and Latin American descent in the United States. Pain is a major comorbidity of SCD that can start during infancy and persist throughout life. Affective modulation in SCD is associated with social stigma, discrimination, limited resources, poor nutrition, and social isolation. Experience of pain is an outcome of somatosensory nociceptive inputs, as well as affective and cognitive state. These factors may contribute to pain by attenuating the brain’s top-down spinothalamic descending inhibitory pain pathway (DIPP) and may even interfere with response to therapy. Currently, high dose opioids are used for sickle pain. We discovered that nutrition-based approaches using nutrient- and ω-3 fatty acid-enriched “sickle diet” (SD) to target chronic pain ameliorate chronic sensory hypersensitivity and enhance spinothalamic pain inhibition. Dietary manipulation is a potent modulator of endogenous cannabinoids, such as anandamide (AEA), which has potent analgesic properties in the DIPP via dopamine (DA). DA plays a key role in the DIPP by signaling via brain regions that directly inhibit ascending pain signals in the spinal cord dorsal horn. We hypothesize that nutritionally enriched sickle diet as an early-life intervention will stimulate dopaminergic activity and ameliorate hyperalgesia in sickle mice with multigenerational benefits. In this MOSAIC K99/R00 (PAR-21- 271-010) I propose to evaluate dietary intervention as an integrative approach to address the issue of resource and nutrient limitation as factors contributing to pain in SCD. I propose the evaluation of translational endpoints as follows: K99-SA#1. Year 1-2. Use PET neuroimaging and spatial transcriptomics to evaluate the effect of SD- intervention on functional AEA and DA activity in the brain and sensory hypersensitivity of sickle mice. Milestone 1. Stratify cell type distribution in SCD DIPP with nutritional enrichment intervention. R00-SA#2. Year 3-5. Determine effects of dietary enrichment on offspring DIPP function and gene expression. Milestone 2. Establish mouse breeding colony to continue independent studies and apply techniques from K99 phase. R00-SA#3. Year 3-5 Determine teratogenicity of perinatal cannabinoid exposure in SCD offspring mice. Milestone 3. Determine associations between cannabinoid exposure and adverse outcomes and establish collaboration for epigenomic evaluation. These findings will inform the development of nutrition-based clinical approaches and will form the basis for R01 grant applications to study dietary roles in SCD pain as prospective clinical study. Deliverables. Identification of SD as a potentially effective therapy for chronic pain in SCD and evaluation of the multigenerational effects of cannabinoid exposure.

NIH Research Projects · FY 2025 · 2024-03

PROJECT SUMMARY/ABSTRACT The gut microbiota produces a myriad of metabolites that have been shown to have wide effects on host biology. Specifically, peptidoglycan (PG) fragments are well established immunomodulators in many health issues including inflammatory diseases, microbial infections, and cancers and have been shown to be translationally relevant in immune cell differentiation, insulin processing, and the efficacy of checkpoint inhibitor immunotherapies. Although the microbiota’s ability to produce PG fragments may provide an underlying mechanism for host-microbial interactions, it remains difficult to selectively modulate the amount of host-available PG. Therefore, the development of new tools to upregulate PG fragments in circulation for gain of function studies are needed to understand certain fundamental host biologies. Previous efforts to decipher these signaling pathways have focused the phylogenetic relationships of correlated microbes rather than their shared metabolic outputs; however, these genomic data do not provide information on protein secretion levels, stability, or activity. Unlike previous work, this proposal will directly assay microbial enzymes through a chemoproteomic platform to uncover functional PG-degrading enzymes for the development of functionalized probiotics to control metabolite output in host systems. It is hypothesized that increased hydrolytic activity in the gut will selectively control PG fragment levels in circulation. The proposal’s main goals are to identify highly active, secreted, and stable PG-degrading enzymes (Aim 1) and to genetically engineer tools to upregulate PG metabolites in circulation (Aim 2). This research will allow for the discovery of high performing microbial enzymes to rationally control circulating glycan metabolites through gut colonization with engineered tool organisms. The potential discoveries in this proposal could be translationally applied to alter microbe-human dynamics through the utilization of mechanistically-defined probiotics. The Sponsor, Co-Sponsor and PI have developed a fellowship training plan that will enable the PI’s future goal of becoming an independent researcher through enhancing both her scientific expertise and professional skills. To accomplish the experimental aims as proposed, the PI will receive training in proteomics, probiotic genomic engineering, and animal handling. In addition, the training plan outlines key professional development events that will improve the PI’s scientific communication and writing abilities, which will enable a successful career trajectory for her. This research plan will ultimately develop the PI’s scientific and professional proficiencies so that she may obtain a post-doctoral research position, which will lead her toward becoming an independent scientist. The expertise that will be gained through her experimental work on this proposal as well as her participation in the didactic and career development activities planned will enable the PI to accrue the tools needed to have a successful career as a future independent researcher.

NIH Research Projects · FY 2025 · 2024-03

PROJECT SUMMARY A number of hormones in the body follow periodic patterns, with concentrations cycling up and down every hour or so. These cyclic patterns are important for functions including growth, reproduction, glucose control, excitation, and rest. However, these dynamic processes are rarely reproduced in cell culture, meaning that we often study cells out of their natural environment. Thus, the biology that we observe in the laboratory can be incomplete or different from in our bodies. This severely handicaps our understanding of disease and our search for effective therapies. This project aims to build a cheap and easy to use cell culture device that reproduces the hormonal cycles present in our bodies. Furthermore, the system monitors the response of cells to these hormonal pulses, sampling rapidly to capture quickly changing behavior. The system is built to resemble a conventional cell culture plate, making it familiar to all biologists. However, inside the plate are hidden pumps, channels, and even simple computing circuits that allow culture media to be automatically cycled between different formulations, or sampled out into collection wells. If this project is successful, these affordable and simple to use tools will become broadly accessible to the biomedical community, transforming the study of a number of diseases as well as the search for cures.

NIH Research Projects · FY 2025 · 2024-03

RESEARCH SUMMARY The proposal will study the unusual phenotype of a 69-year-old woman who displays exceptionally accelerated skin wound healing with minimal scarring. Genome sequencing revealed that her phenotype is caused by an ~8 kb deletion downstream of the fatty acid aldehyde hydrolase (FAAH) gene that results in the loss of a long noncoding RNA (lncRNA) gene named FAAH OUT. The goal of this proposal is to understand how the FAAH OUT deletion results in accelerated wound healing. In the United States, the annual medical burden of chronic wounds exceeds $25 billion and continues to rise with the aging population. There is a critical need to improve understanding of the biological processes underlying skin wound healing and to innovate new therapies. In the first aim, we will study normal and wounded skin tissue from the study subject using spatial transcriptomics, in situ hybridization, and xenograft skin repair models to understand how the FAAH OUT locus regulates wound healing. In the second aim, we will elucidate the FAAH OUT genetic interactome to gain insight to its molecular mechanisms. By studying a rare genetic allele of an individual with markedly enhanced wound healing, this proposal aims to generate novel insight to the role of lncRNAs in wound repair and discover new human-validated targets to treat cutaneous wounds.

NIH Research Projects · FY 2026 · 2024-03

PROJECT SUMMARY Our laboratory is interested in studying artificial assembly of natural products with promising biological activities and developing new reactions. Securing short, scalable, and flexible synthetic routes tests the limitations of chemical methods and provides access to unnatural analogs that would otherwise be beyond the reach. This approach often necessitates development of new transformations and synthetic strategies that streamline the assembly of the desired scaffolds. Therefore, vertical advancements in the fields of chemistry and related areas of biology can be anticipated. Over the past several years, we succeeded in developing new synthetic routes to several families of natural products, including indoloterpenoids, anthraquinone-xanthone heterodimers, labdane diterpenes, quassinoids, and mutilins. We demonstrated a new radical-polar crossover polycyclization that allowed for concise assembly of the tricyclic core found in indoloterpenoids and led to the synthesis of emindole SB, the simplest member of the family. As a corollary to these studies, we also developed a catalytic intermolecular formal ene reaction between ketone-derived silyl enol ethers and alkynes, which exhibited high selectivity for generation of quaternary centers. We subsequently completed the synthesis of nodulisporic acid C, a potent parasiticidal agent, where we employed a diverse set of tactics to assemble disparate polycyclic motifs and a sensitive indole moiety. In a continuation of these studies, we developed a powerful annulation reaction, which allowed for direct assembly of complex terpenoid motifs and led to the synthesis of forskolin, a densely functionalized labdane diterpenoid. Further studies of the annulation spanned a broader range of polycyclic scaffolds and ultimately resulted in short syntheses of quassin and pleuoromutilin. In another effort, we developed a short synthesis of acremoxanthone A, an anthraquinone-xanthone heterodimer with antibacterial activity. Driven by these investigations, we also developed hydrogen atom transfer (HAT)-initiated semipinacol rearrangements of tertiary allylic alcohols where the outcome of the reaction was under strong catalyst control. Based on our findings, we proposed that these transformations involve catalysis by alkylcobalt complexes and developed the first asymmetric HAT-initiated hydrofunctionalization, which allowed for cyclization of dialkyl(vinyl)carbinols to the corresponding enantioenriched epoxides. A significant component of our future efforts will focus on identification of new ways to control reactivity in HAT- initiated process, which remains a significant challenge. These studies will capitalize on our previous discoveries to uncover new transformations for assembly of complex structural motifs and will also employ natural product synthesis as a way to interrogate the limitations of our methods. Overall, new chemical reactions and new synthetic strategies are expected to result.

NIH Research Projects · FY 2026 · 2024-03

Abstract: Microglia are the primary immune cells of the brain. These resident macrophages play critical roles not only in immunity, but also in brain development and homeostasis. In the adult brain, microglia constantly extend and retract their processes to survey the local environment and clear any pathological insults/injury. In the Alzheimer's disease (AD) brain, studies have identified activated microglia that surround amyloid-β plaques, one of the central and hallmark pathologies of the disease, and transcriptional profiling of these cells has identified a unique signature – termed disease-associated microglia (DAMs). However, it remains unclear whether this microglial response to plaques is beneficial or harmful to disease. To address this question, we have developed a novel inducible reporter mouse that allows for specific targeting of DAMs. This novel reporter mouse produces destabilized Cre (ddCre) at the Cst7, a gene that highly and specifically upregulated in DAMs, locus allowing us to effectively label or knockout Cst7 expression by the administration of trimethoprim (TMP). TMP is non-toxic and avoids the caveats associated with CreERT2 system-dependent tamoxifen. Here, we will use our Cst7ddCre line to evaluate the roles of TREM2, NLRP3, and CST7 in disease progression, and their distinct function at different ages/disease stages, as well as the fate of DAM's following Ab immunotherapy. We will assess behavior, cognition, glia, amyloid, tau, synapses, neurons, dystrophic neurites, NfL, as well as explore gene expression changes (via bulk tissue RNAseq) and spatial transcriptomics (via MERFISH) utilizing floxed Trem2, Nlrp3, or Cst7 KO mice crossed to 5xFAD or 5xFAD/hTau mice. These findings will elucidate the distinct functions of DAMs during disease and provide insights into new therapeutic approaches for AD.

NIH Research Projects · FY 2026 · 2024-03

Project Summary To date, no therapy exists to restore vision to the over 64 million people worldwide who are legally blind from diseases that damage the optic nerve. Neuro-protective strategies aimed at preventing damaged retinal ganglion cells (RGCs) from degenerating and neuro-regenerative strategies aimed at promoting axon growth confer modest gains in vision after optic nerve crush injury when applied alone. Moreover, these approaches appear to be lacking in guidance cues as regenerating RGC axons have been reported to have circuitous projections, with 10-20% of axons exhibiting premature branching and 40% of axons having regenerated aberrantly, making u-turns and extending back towards the eye or growing into the opposite optic nerve. We have shown that exogenously applied electric fields (EFs) not only promote RGC axon growth but appear to also be able to control the direction of axon growth. This suggests that EFs may be exploited to not only “drive” axon growth but also “steer” axons to grow towards intended targets. Indeed, in vivo stimulation with asymmetric waveforms was found to be effective at directing full-length optic nerve regeneration, without evidence of aberrant targeting, and restoring partial visual function (local field potential recordings in the superior colliculus and pattern electroretinogram) after crush injury. Given this, we hypothesized that combining EF stimulation with other neuro-regenerative strategies would have synergistic effects on promoting optic nerve regeneration. More targeted regeneration could confer increased gains in visual function. Our multi-disciplinary consortium between neuro-ophthalmologists, developmental biologists, neuro-anatomists, neurosurgeons, electrophysiologists, and electrical engineers proposes to test the efficacy of combining neuro-protective and neuro- regenerative strategies with EF application to direct RGC axon regeneration and restore visual function to adult rats after optic nerve crush injury. Additionally, we will map and characterize the morphology and trajectory of regenerated axons in whole rat brains using 3D light sheet microscopy and SHIELD tissue clearing histology and assess whether EFs direct target specific regeneration.

NIH Research Projects · FY 2025 · 2024-03

PROJECT SUMMARY / ABSTRACT As the leading preventable cause of death, tobacco smoking causes nearly 8 million deaths globally each year. Nearly 70% of U.S. adults who smoke want to quit, but only 7.5% manage to quit for 6 months or more. Cigarette craving, induced or exacerbated by exposure to smoking-related cues, is a major factor in lapses in abstinence. The goal of this project is to evaluate whether a cognitive technique for reducing negative affect, called Affect Labeling, can be adapted into a new strategy for reducing craving in people who smoke. Affect Labeling refers to the act of naming an emotional experience or an emotion-inducing stimulus. Affect Labeling reduces self-reported distress and activity in the amygdala, a key brain region linked to emotional experience and response. Given that negative affect and craving may share neural and psychological underpinnings, interventions that downregulate negative affect (e.g., Affect Labeling) may be effective in downregulating craving. To examine this possibility, the Cue Labeling task was developed as a tool to regulate craving and tested on 47 adults (Pittsburgh study) and 19 emerging adults (LA study) who smoked daily. The objective of this proposal is to analyze these two datasets, in order to: 1) Examine the overlap in the neural substrates of cue-elicited negative affect and craving; 2) Examine the effect of Cue Labeling on self-report and neural markers of craving; 3) Identify the neural mechanism of Cue Labeling; and 4) Compare the neural pathways of Cue Labeling and Cue Reappraisal, another cognitive technique for regulating craving. Participants completed the Cue Labeling and Cue Reappraisal tasks during fMRI after overnight abstinence from smoking. In the Cue Labeling task, participants viewed either neutral picture cues (e.g., a man holding a cup) or cigarette picture cues (e.g., a man holding a cigarette), and they selected one of two words (labeling condition) or one of two pictures (matching condition) that fit the cue. In the Reappraisal task, participants reinterpreted a cigarette cue in a way that made it less enticing, or they passively viewed neutral, negative, or cigarette cues. During Cue Labeling, participants in the Pittsburgh study provided ratings of their craving following each cue. During Reappraisal, all participants provided craving ratings following each cue. Primary analyses of activation will focus on data extracted from pre-defined ROIs in the salience network and other regions associated with craving, such as the striatum. Positive findings would provide the first evidence that Affect Labeling can be adapted for regulating craving. If confirmed in trials, the potential clinical impact of this finding could parallel that of Affect Labeling. In the same way that Affect Labeling has been identified as a method for enhancing exposure therapy for phobia, this project may identify Cue Labeling as a method for enhancing standard therapies for addiction. Part of the appeal of the Labeling technique is its simplicity and low cognitive demand, important advantages in substance use disorder and particularly during withdrawal, when cognitive function may be compromised.

NIH Research Projects · FY 2026 · 2024-02

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a neurodegenerative disease characterized by aggregation of Tau protein into paired helical filaments causing neurofibrillary tangles (NFT) in the brain. The goal of this study is to design, develop and evaluate the effectiveness of novel radioiodinated tracers for binding to Tau protein in postmortem human brains of AD and non-AD Taupathies and serve as in vivo imaging agents. These novel radioligands, such as IPPI, will be suitable for in vitro studies ([125I]IPPI), for extended positron emission tomography (PET) studies ([124I]IPPI) and for single photon emission computed tomography (SPECT) studies ([123I]IPPI). The radioligands will complement and support studies of several PET NFT imaging agents, such as [18F]MK-6240, currently being carried out in AD related disorders (ADRD). Phosphorylated Tau (pTau) is a reliable marker for NFT accumulation in AD beginning in the entorhinal cortex and hippocampus, spreading to the temporal cortex and subsequently to the neocortex. Preliminary studies using [125I]IPPI in human AD frontal cortex, anterior cingulate and hippocampus show excellent binding of [125I]IPPI to Tau consistent with total Tau (tTau) immunohistochemical (IHC) staining. However, variations in the degree of [125I]IPPI binding and sensitivity to distinguish Braak stages lower than IV needs to be understood. Several pTau species are known to be present in AD. Novel radiotracers that exhibit high binding affinity and selectivity for Tau (Ki<10 nM Tau; Ki>1 μM for Aβ) and optimal lipophilicity will be evaluated in AD, cognitively normal, progressive supranuclear palsy, Pick’s disease, corticobasal degeneration and Down’s syndrome subjects. Brain regions will be studied using radioiodinated tracers including [125/124/123I]IPPI and IHC. Methods of image analysis for detailed IHC and autoradiography will be used to correlate binding. Because of the interplay between A? plaques and NFT, autoradiographic images of Aβ plaques (using [18F]flotaza and [125I]IBETA) will also be acquired. Correlation of Aβ plaques and NFT autoradiography will be carried out in brain regions of the same subjects. The binding of radioiodinated tracers, [125/124/123I]IPPI will also be compared with [18F]MK-6240 and [18F]AV-1451. This will further demonstrate the potential translational utility of the radioiodinated ligands for human AD imaging studies. In vivo metabolic stability, brain penetration and clearance of the [124I] and [123I]radiotracers will be evaluated in rats, wild type and Tau transgenic mice using in vivo PET and SPECT, respectively. Based on the in vitro and in vivo parameters of Tau imaging, the optimal derivative will be chosen for whole-body radiation dosimetry and acute toxicity studies. An exploratory IND application will be filed with FDA for the selected imaging agent. Thus, the overall impact of this application will be the availability of novel radioiodinated Tau imaging agent for NFT imaging using SPECT and PET. Our promising preliminary work with [125I]IPPI and [125I]INFT is indicative of the likelihood of success for imaging human NFT in ADRD using these novel radioiodinated Tau imaging agents.

NIH Research Projects · FY 2026 · 2024-02

PROJECT SUMMARY/ABSTRACT Chromosomal translocations occur in nearly all human lymphoid neoplasms, many the result of aberrant repair of DNA double-stand breaks (DSBs) generated in pre-B cells during V(D)J recombination. In this pathological process, unrepaired V(D)J DSBs induced at the IgH locus join with a second, non-IgH DSB to generate the translocation. The non-IgH DSBs occur by an unknown mechanism, representing a serious knowledge gap. The rationale for this project arose from creation of a sequencing database composed of DNA translocation breakpoint junctions mapped from over 2,000 human patients covering most B cell malignancies. This analysis uncovered 6 non-IgH human fragile zones (HFZs) ranging in size from 20-600 bp where DSBs are enriched up to 1,000-fold compared to the surrounding DNA. HFZ DSBs account for half of all human B cell cancers and break in the pre-B cell stage of development concurrent with V(D)J recombination. Building on a foundation of previous work, the central hypothesis is that three factors are critical for HFZ DSBs in lymphoid cells: 1) Formation of single-stranded DNA (ssDNA) structures at HFZs resulting from torsional stress, 2) Expression of activation-induced cytidine deaminase (AID) that targets ssDNA to create mismatched DNA lesions, and 3) Presence of an activated form of the structure-specific Artemis endonuclease that cleaves these lesions to generate the HFZ DSBs. The overall objectives for this proposal are: (1) Utilize digital PCR (dPCR) and DNA sequencing assays to quantify DNA DSB formation at HFZs under conditions that will elucidate the HFZ DSB mechanism and (2) show how loss of topoisomerase function through pharmacologic or genetic ablation enhances HFZ DSB formation. The central hypothesis will be tested by pursuing three specific aims: 1) To determine how torsional stress stabilizes ssDNA structures at HFZs, 2) To determine the role of AID in HFZ DSBs, and 3) To delineate how Artemis induces HFZ DSBs. The innovative aspects of this research are that human patient data was used as a source to demonstrate that many B cell malignances are the result of non- random DSBs at discreet 20-600 bp HFZs, human pre-B cell lines and primary human cells are used in the analysis, and the genetic assays used can quantify indels resulting from DSB formation and repair in human pre- B cell lines and patient material. This work is significant as it defines a unified mechanism for many B cell malignances involving multiple steps, each of which can be affected by an individual’s genetics and lifestyle. Results from this proposal would represent a significant advancement towards predicting disease in high-risk populations and tailoring treatments to individuals. Furthermore, our assays can be applied in the clinic to quickly diagnose diseases with a genome instability component and monitor a patient’s response to treatment and potential for relapse. Overall, the results will lead to early detection of primary cancers, prevention of secondary cancers, and an overall reduction in mortality.

NIH Research Projects · FY 2025 · 2024-02

Project Summary Title: Larval Ecology of Invasive Anopheles stephensi in Ethiopia The invasion and rapid expansion of Anopheles stephensi in Africa have created major challenges to effective malaria control and elimination in Africa, triggering calls for urgent action to stop its spread. Since its first detection in Djibouti in 2012, An. stephensi has spread to Ethiopia, Sudan, Kenya, and Somalia in Eastern Africa and to Nigeria in Western Africa. Modelling studies have found that most cities in sub-Saharan Africa are highly suitable for An. stephensi invasion. Unlike native African malaria vectors, such as An. gambiae, An. Arabiensis, and An. funestus, which reside predominantly in rural areas, An. stephensi mosquitoes thrive in urban environments. Furthermore, the invasion of An. stephensi has already caused local malaria outbreaks in Djibouti and Ethiopia. Control of An. stephensi in Africa currently emphasizes larviciding. However, effective larval control requires addressing major knowledge gaps in the factors regulating An. stephensi populations as well as where and when to implement interventions. While mapping out all habitats through visual inspection is infeasible and impractical, machine learning techniques and models provide an effective approach for mapping An. stephensi larval habitats. The development of effective machine learning models for larval habitat prediction requires better understanding of the environmental and biological determinants of larval habitats. To accomplish these objectives, two aims are proposed: 1) To examine population dynamics and environmental regulation of An. stephensi, and 2) To develop and validate An. stephensi habitat models. Our proposed work will have broad implications for the development of larval biological control strategies to stop the spread of An. stephensi in Ethiopia, and our machine learning methods utilizing multiscale data is applicable for guiding mosquito-borne disease controls in urban areas in other countries.

NIH Research Projects · FY 2025 · 2024-02

Project Summary Serological Biomarkers for Monitoring Human-Vector Contact by Invasive Anopheles stephensi in Africa Anopheles stephensi was historically considered a major malaria vector in urban environments in Southeast Asia, the Middle East and the Arabian Peninsula. Since its first detection in Djibouti in 2012, the distribution of this vector species has expanded to Ethiopia, Sudan and Somalia in the Horn of Africa, and Nigeria in west Africa. Establishment and spread of An. stephensi in Africa pose major challenges for malaria control and elimination in fast-growing urban Africa because An. stephensi is a confirmed vector for local African Plasmodium falciparum and P. vivax strains and is resistant to multiple classes of synthetic insecticides. Accordingly, the World Health Organization recently established an initiative to take concerted actions to stop the spread of An. stephensi by improving surveillance and control of this species in Africa. However, the commonly- used mosquito surveillance methods such as CDC light traps, human landing catches and larval dipping methods lack the necessary sensitivity in urban settings due to environmental light pollution and low vector abundance. However, sensitive surveillance of An. stephensi is critical to its early detection and control. Recently, serological methods for monitoring human-vector contact by measuring antibody response to mosquito salivary proteins have been developed. However, the available serological method is based on well-conserved proteins and cannot be used to differentiate An. stephensi exposure from those of native Anopheles species. The objective of this R21 application is to develop serological biomarkers that can distinguish exposure to invasive An. stephensi from the native African malaria vector species using novel peptide microarray technology. Two aims are proposed: 1) identify salivary peptides that distinguish the exposure of invasive An. stephensi from the native African malaria vector species, An. arabiensis, using novel peptide microarray technology; and 2) evaluate candidate salivary peptides using human plasma from field sites with contrasting An. stephensi distribution in Ethiopia. The new tool from this project can be used to measure human-vector contact with the invasive An. stephensi, and thus help assess the role of An. stephensi in malaria transmission. Serological biomarkers have the potential to be utilized in domesticated animals, the main blood source for An. stephensi mosquitoes. This could enhance the detection sensitivity of invasive An. stephensi mosquitoes, thereby facilitating the surveillance and control of An. stephensi populations in Africa.

NIH Research Projects · FY 2026 · 2024-02

SUMMARY Congenital anomalies represent an increasing burden of disease worldwide, accounting for millions of birth defect-related disabilities with a disproportionate impact on Low to Middle Income Countries (LIMCs). Many harbor genetic etiologies, for which no confirmatory diagnosis can be made due to the dearth of diagnostic technologies in most LMICs. The inability to rapidly and accurately diagnose individuals that harbor a genetic syndrome increases the risk of mortality and morbidity (as a number of manageable congenital anomalies may be hidden, such as congenital heart defects or hearing infections) and prevents the accurate determination of prevalence rates, critical for public health surveillance and intervention programs. The first part (R21) of this project addresses these gaps using two synergistic mobile health intervention tools to screen for syndromic conditions and specifically demonstrate that a specific diagnostic of Down syndrome (expandable to all aneuploidies and those diseases resulting from copy number variants, point mutations and insertions/deletions) can be performed with minimal resources, in the Democratic Republic of the Congo (DRC). Aim 1 will be to train and validate AI-guided smartphone-based technology to screen for syndromic conditions, while Aim 2 will create low-cost, rapid initial genetic diagnostic capacity in the DRC. In the expansion part of the proposal (R33), we will test whether the implementation of a registry measuring health outcomes can be used as a scalable model for future newborn screening and health surveillance in a low-resource setting. To this effect, Aim 3 will build infrastructure for birth defects detection, genetic confirmation, competence building, and practice and outcomes surveillance in low-resource conditions with two parallel sub-aims: Aim 3a will assess the feasibility of the diagnostic capacity on a large population sample and provide a tool to measure specific health outcomes, while Aim 3b will establish a small-scale and functional database/registry of morphological, genetic, and health outcomes data. In limited resources settings, comprehensive systems to detect, refer, treat and surveil individuals with congenital anomalies are non-existent. Our innovative technologies will address this gap, build local capacity of diagnostic screening and of a data registry, allowing for early diagnosis and condition-specific care, likely to lower morbidity and mortality of children with non-communicable syndromic conditions.

NIH Research Projects · FY 2026 · 2024-02

Project Summary/Abstract The goal of this application is to support the candidate in developing advanced and specialized skills necessary to build an independent program of research, with a focus on improving the implementation of culturally relevant pain assessment and management for language-diverse patients and families who use interpretation services in pediatric medical settings. The F32 candidate will be a Postdoctoral Research Fellow at the University of California-Irvine Center on Stress and Health (UCI-CSH) which is currently funded by 5-NIH awards (including a K-23) and has an excellent history with mentorship of early career faculty. This application proposes a mixed methods design study to identify sociocultural factors that influence pain communication and evaluate the concordance of pain understanding among multiple stakeholders (caregivers, children, interpreters, and clinicians) in a linguistically and ethnically diverse sample of children 1-6 years old who present to the emergency department (ED) with pain-related complaints. Indeed, millions of children present to the ED setting each year in pain and although current guidelines emphasize the need to address such pain, inadequate pain assessment and management remains prevalent. Latinx children are at a particularly high risk for experiencing pain disparities and Spanish-speaking families are at particularly high risk because of additional linguistic barriers. The first aim of the application calls for a quantitative approach to identify the congruence of pain reporting across all stakeholders (child-parent-interpreter-clinician). The second aim is focused on a qualitative approach to understand the perspective of the stakeholders regarding communication of pain using interpreters. With enthusiastic and material support from UCI-CSH and Children’s Hospital of Orange County (CHOD) ED senior leadership, the project will be conducted in a high-volume pediatric department where a large proportion of patients are Spanish-speaking Latinx and are part of an innovative population health program. The candidate’s training plan capitalizes on the expertise of a highly experienced multidisciplinary mentorship team, integrating key training in pain in the ED, NIMHD Minority Health and Health Disparities Research Frameworks, sociocultural factors in pediatric pain and healthcare disparities, mixed methods research, and professional development. The training plan will incorporate didactic coursework, one-on-one mentoring, and seminars focused on career development, training evaluation and research ethics. UCI-CSH is a highly productive, well-established research environment that incorporates a unique multidisciplinary approach to training and clinical research. UCI-CSH is embedded within CHOC, where the study will be implemented. Collectively, this will provide an exceptional training and research environment to characterize sociocultural contributors to pain in a population at-risk for experiencing care disparities and provide a strong foundation for a Career Development Award focused on developing and piloting an intervention to train diverse stakeholders to improve cross-cultural and cross-linguistic pain communication during interpreted medical encounters.

NIH Research Projects · FY 2025 · 2024-01

Project Summary/Abstract Obstructive sleep apnea (OSA) affects a significant portion of the middle-aged population in the US and has been associated with a number of health concerns including cardiovascular disease and cognitive dys- function. The development and progression of these health consequences is believed to be related to the severity of OSA. However, current clinical indicators of OSA severity, which include an intermittent hypoxia pattern at the tissues and the apnea-hypopnea index (AHI), fail to capture the impact of the consequences associated with the disease. The intermittent hypoxia exposure pattern at the tissue-level, a qualitative indicator of OSA severity, relies on pulse oximetry for measurement, which has limitations including inaccu- racies in recording and only a generalized representation of systemic arterial oxygen hemoglobin saturation. In addition, the AHI, a quantitative measure of OSA severity, has not been shown to be strongly correlated to disease development in previous clinical studies. Accordingly, there is a large volume of OSA sleep study data that needs to be re-analyzed. Therefore, to better understand the development of OSA-related con- sequences, there is a need to assess OSA severity with a method that avoids the aforementioned clinical limitations. This can be achieved with mathematical modeling and, in this project, we propose to develop a model for a more detailed clinical representation of OSA. In Aim 1, the model will be constructed using fundamental mass transfer equations to track the transport of oxygen and carbon dioxide throughout the body. Considering the lack of patient-specific approaches in current OSA modeling literature, our model will have the ability to use respiratory and heart rate data from polysomnography studies and will be feasible for clinical application. Therefore, to address the limitations of current measures of intermittent hypoxia expo- sure, the result of Aim 1 will be a presentation of blood gas concentration profiles at the arterial and venous ends of various target tissues, which will allow for a quantification of hypoxia burden. In Aim 2, the model from Aim 1 will be used with clinical data to run a correlation analysis between predicted oxygen decreases and patient daytime sleepiness, a potential indicator of OSA presentation, which could provide an alternative to the AHI. Therefore, the two primary outcomes of this project will be a clinically deployable mathematical model for OSA severity assessment and a large pool of data obtained from simulated cases of OSA and a re-analysis of existing sleep studies, which will play an important role in improving patient care.

NIH Research Projects · FY 2025 · 2024-01

Project Summary The vertebrate eye lens is made up of concentrated, highly refractive proteins called crystallins, which enable it to form images by focusing light on the retina. Most studies of crystallins focus on their ability to remain stable and soluble for decades in the absence of protein turnover in the lens. Refractivity is equally important to crystallin functionality, but is less well understood. This project seeks to elucidate how crystallins provide focusing power both as individual proteins and as a network of intermolecular interactions in the crowded environment of the lens. Our preliminary work has shown that amino acid composition alone does not determine crystallin refractiv- ity: three-dimensional structure and interactions with water on the protein surface are also critical. We will build on this work by measuring the refractive index increment for lens crystallins from humans and model organisms and relating the results to spatial interactions among polarizable side-chain moieties. In particular, we propose to investigate cataract-related and engineered crystallin variants in order to test hypotheses about how structure impacts refractivity. We will measure refractivity first in concentrated solutions mimicking the crowded cellular milieu, and then in whole lenses from model organisms in order to set the stage for future studies on human lenses. This will enhance the current model of protein refractivity, which is mostly based on measurements in dilute solution. On the level of the whole lens, we will develop novel methodologies to specifically visualize the refractive index distribution in space. The long-term goal of this research is to bridge the gap between interactions of light with individual crystallin molecules and the spatial arrangement of proteins that generates the refractive index gradient of the vertebrate lens. In the future, the knowledge gained will provide insight into healthy lens function and guide the design of improved artificial lens materials.

NIH Research Projects · FY 2026 · 2024-01

PROJECT SUMMARY In the 21st century it has become clear that many of the major problems facing humanity will need to be addressed by biologists carrying out biomedical research. In order for the US biomedical research community to succeed in combating the major challenges facing our world, scientists will have to operate with high efficiency and develop solutions to many different unique problems. A broad number of studies have now concluded that teams and organizations that are diverse and inclusive are more successful at these endeavors. Moreover, if public funding is to be used to support biomedical research, in order for it to be equitable, it should allow access to students from all backgrounds and represent the diversity in the US population. Success as a scientist requires more than just skill at a lab bench and there are special barriers facing students from underrepresented groups. Therefore, our comprehensive approach will implement (1) enhanced educational and research outreach to minority-serving institutions, (2) recruitment activities to help students transition to our university, (3) advanced start activities to help students transition readily to the next stage in their training, (4) coursework and activities that are relevant to their underserved communities and themselves, (5) faculty- AND peer-mentoring support, coupled with culturally-aware mentor training, (6) UCI research and collaboration visit opportunities for their prior undergraduate mentors who likely inspired them to enter graduate school, (7) funding to support an annual ”reconnection” visit to their alumni institution and community, (8) funding for them to attend conferences, such as SACNAS, ABRCMS and SfN, and (9) training in oral and written communication and leadership skills. Taken together, these opportunities will prepare students for careers inside and outside academia and will advance the NIH goals of enhancing biomedical research in the context of health and human services as a whole.