Trustees Of Indiana University

NIH Research Projects · FY 2025 · 2025-05

Aggression is a complex, adaptive suite of behaviors conserved across mammals that has evolved to allow individuals to compete for limited resources and is critical for survival. Pathological aggression and violence, however, are associated with several psychiatric disorders, including mood disorders, anxiety, post-traumatic stress disorder, autism, and attention deficit hyperactivity disorder. We lack a fundamental understanding of the mechanisms underlying pathological aggression because we lack a full understanding of the complex mechanisms regulating variation in typical aggressive behavior. This knowledge is relevant to the NIH’s mission of understanding the biobehavioral and neurobiological mechanisms underlying aggressive behavior. This grant proposes to use an integrative approach, drawing upon environmental biology, neuroendocrinology, pharmacology, and molecular neuroscience to understand how the pineal hormone melatonin orchestrates increased aggressive behavior in males and females through actions on adrenal DHEA, its conversion to bioactive steroids, and direct actions on aggression circuits within the brain. It is widely accepted that there is a robust relationship between gonadal testosterone and aggression. This notion is based on studies of male-male aggression in highly domesticated species. These correlations are weak or absent in other species, including humans. Our data support our hypothesis of a “seasonal switch” from gonadal to adrenal and melatonin regulation of aggression. This is a novel alternative endocrine mechanism regulating aggressive behaviors. Siberian hamsters are an ideal model to address our hypothesis because males and females display high levels of aggression independent of reproduction, allowing the relationship between gonadal steroids and aggression to be uncoupled. Likewise, growing evidence exists for a strong direct relationship between high DHEA and aggressive or violent behaviors in humans. Thus, the similarities between hamsters and human adrenals make hamsters an excellent model system to experimentally test the link between DHEA and human aggression. By employing neuroendocrine and molecular genetic approaches, we will test the hypothesis that melatonin acts directly on the adrenals to regulate DHEA synthesis, conversion to active metabolites, and ultimately aggressive behavior (Specific Aim 1). We will also test the hypothesis that melatonin acts directly within the canonical aggression circuit in the brain at the level of the periaqueductal gray regulating aggression through the conversion of testosterone to estradiol and on estrogen receptor expression (Specific Aim 2). The proposed studies address this key gap in the literature and will determine how melatonin orchestrates aggression in males and females. This is critically important, especially in females, because they are rarely examined for aggression; thus, we are well-positioned to elucidate novel mechanisms controlling aggression. Furthermore, these findings will provide unique insights into violent human behavior that is associated with mental illness.

NIH Research Projects · FY 2026 · 2025-03

Summary This project leverages the unique resources of three different institutions to assess offspring respiratory health impacts caused by in utero exposures to Electronic Nicotine Delivery Systems (ENDS) products. ENDS are a diverse class of products such as electronic cigarettes (e-cigs), vaporizers, vape pens, and pods. In this study, we focus on e-cigs as they are the most adopted ENDS devices in recent years. Over 9 million American adults, including women of childbearing age, are current e-cig users. Little, however, is known about the effects of fetal exposures to e- cig aerosols on lung development in the offspring. We propose the “ENDS aerosol particle deposition, in utero exposures and children’s respiratory health effects (ENDURE)” consortium to investigate ENDS aerosol particle deposition in the lungs of mothers who used ENDS products (vaping) or were exposed to household ENDS aerosols and examine the resulting effects on the offspring’s respiratory health. The ViCTER mechanism provides an exceptional opportunity to enhance cross-disciplinary and translational research to study in utero exposure to tobacco products from maternal or environmental sources and its effects on the trajectory of lung health. We hypothesize that constituents of ENDS aerosols with the highest maternal lung deposition will result in the dysregulation of lung inflammatory genes in the offspring, particularly IL-10, leading to asthma susceptibility. To test our hypothesis, we will investigate the deposited dose of harmful substances from ENDS aerosols in human airways and estimate associated health risks (Aim 1). This aim will provide critical information on the deposited dose of ENDS-related harmful substances in the alveolar region through active and passive vaping and associated health risks. Informed by preliminary studies, we will use ENDS products whose aerosols significantly deposit in the lower airways (Vuse and NJOY) and assess the role of Il-10 gene regulation on pulmonary function, inflammation, and lung epigenome in utero ENDS-exposed mouse offspring (Aim 2). For this aim, we will use wild-type (WT) and Il-10 knockout (KO) mouse models with and without house-dust mite (HDM) treatment, to investigate the role of Il-10 in adversely altering airway resistance, inflammation, and the lung epigenome of in utero ENDS exposed offspring in early life. Finally, we will determine the impact of parental ENDS use on infant recurrent wheeze and asthma-like symptoms, and buccal DNA methylation in a cohort of children from Indiana (Aim 3). This project will help bridge the knowledge gap of which ENDS aerosols enter the fetal-maternal circulation and trigger dysregulation of genes associated with the offspring’s lung function and lung development.

NIH Research Projects · FY 2026 · 2025-02

Project Summary: A critical step during development is organogenesis, the process by which primordial tissues give rise to complex three-dimensional organs. The question of how individual organs acquire their unique identity is of fundamental importance to understanding both normal development and congenital disease. The over-arching goal of this project is to understand how the earliest steps in the process of eye formation are controlled. Our efforts will focus specifically on the role that the Pax6 transcription factors, Eyeless (Ey) and Twin of Eyeless (Toy), play in specifying and patterning the Drosophila compound eye. The fly retina is an excellent model system for studying organ formation because the steps of its cellular development are well defined, a robust collection of genetic tools allow for the manipulation of relevant genes, a wealth of markers allow for identifying deviations in developmental trajectories, and the tissue is amenable to genomic methods which illuminate the transcriptome, transcription factor binding, chromatin accessibility, and histone modifications. While an abundance of reagents and tools has been applied to the study of other genes involved in eye formation, understanding the roles that Ey and Toy has been hampered by a scarcity of molecular and genetic reagents associated with these genes. Another obstacle has been the near complete lack of attention placed on studying the role that Toy plays in the eye. As such, we have an incomplete view of Pax6 function which is skewed heavily towards Ey. We have overcome these limitations by creating new methods as well as new molecular and genetic reagents that will allow us to determine the individual and combined contributions that Ey and Toy make to eye formation and patterning. Our studies will, therefore, fill an enormous gap in our knowledge about these important transcription factors. 1Our studies will also impact human health as mutations in human Pax6 are the most common single cause of Aniridia, a congenital eye disorder that occurs 1 in 50,000 live births. Patients with this disorder suffer from reductions in visual acuity, increased sensitivity to light, and progressive loss in vision.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT RNA-protein interactions underlie proper control of gene expression across all domains of life. Defining structural elements and sequences recognized by RNA binding proteins is critical to understand both the biological function and pathological consequences of dysregulated interactions. Viral, prokaryotic, and eukaryotic RNA binding proteins that recognize double-stranded RNA (dsRNA) impact nearly all aspects of RNA metabolism, yet a molecular understanding of how these proteins recognize specific cellular targets is lacking. This Maximizing Investigators Research Award application is proposed to support research in the Hundley lab focused on connecting the molecular mechanisms of dsRNA recognition by the ADAR family of RNA binding proteins to functional consequences on gene expression that impact development and disease. ADARs bind dsRNA and catalyze the deamination of adenosine to inosine in mRNA, both of which are essential functions of human ADARs and dysregulated in over 35 human diseases. The ability of ADARs to change the genome-encoded information present in RNA provides an important means to diversify the transcripts expressed in an organism’s tissues over time and is being harnessed for personalized medicine approaches to correct mutations at the RNA level and improve human health. However, factors that control ADAR function in vivo are poorly understood. The proposed work focuses on fundamental questions of how ADAR binding to target RNAs is influenced by transcription and cellular metabolism, and how these events influence RNA fate to impact neuronal function. To answer these broad questions, we are taking an integrated approach using human cell lines and Caenorhabditis elegans, the latter of which provides an important platform for mechanistic discovery as RNA binding and deamination are controlled by different proteins. Biochemical and transcriptome-wide discovery of binding sites of these two proteins coupled with in vivo model testing and new efforts in structural biology will afford a unique opportunity to reveal how binding and deamination are coordinated. Furthermore, the use of a genetically tractable multicellular organism amenable to behavioral assays and neural-specific transcriptomics allows us to connect consequences of ADAR binding and editing to neuronal function and organismal physiology. Unbiased and genome-wide approaches will facilitate identification of novel cellular factors that influence the molecular signature of ADAR binding. Work in cell lines will be centered on ADAR3, a human deaminase-deficient ADAR protein that regulates editing in glioblastoma (brain cancer). New research will focus on dissecting the mechanistic connections between altered editing, RNA binding and immune activation by ADAR3. Overall, our work will define mechanism that regulate ADAR activity and provide possible targets for therapeutic development, in addition to fundamentally advancing the fields of RNA editing and dsRNA-mediated cellular pathways.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Cells with identical genomes can follow different developmental paths depending on their mechanical interactions with the environment. Archaea impact human health by playing critical roles in environmental cycles and animal microbiomes. Yet little is known about their cell biology. In contrast to most microbes, archaea are as plastic as mammalian cells, have low turgor pressure, and lack a rigid cell wall. Hence, to advance the mechanistic understanding of how microbiome complexity influences human physiology, it is crucial to understand how archaea respond to mechanical stresses under intermittent crowding changes that mimic the human microbiome. Under this light, our group studies the fundamental principles of how archaeal cells convert mechanical signals into biological outcomes in the face of shear, confinement, osmoshock, and crowding. This proposal furthers our vision by using (1) a top-down approach in which archaeal mechanoresponses are quantitatively and systematically described across spatial-temporal scales from populations to cells and cellular processes; (2) a bottom-up approach to uncover the specific activity-dependent molecules and molecular functions orchestrating cellular and populational responses. To address the first thrust, multi-layer microfluidic devices will be integrated with imaging-based analysis of cellular organization, behavior, biomechanics, sub- cellular dynamics, and gene expression profiles under different shear, compression, and crowding levels. Preliminary data suggests that shear and confinement trigger dramatic but distinct developmental programs in the haloarchaeon model Haloferax volcanii. Closing the gap toward the venture, the second direction will provide mechanistic insights into how different mechanoresponsive factors contribute to the described phenomena above. We will focus on mechanosensor candidates identified by us and other groups, including cytoskeletal polymers (volactin, halofilins, CetZs), mechanochannels, and immunoglobulin glycoproteins. In parallel, we will also leverage the power of protein pulldowns and in vitro reconstitution, combined with the whole-genome CRISPRi library recently built in our group, to expand the interactome and identify new molecular and biophysical pathways underlying mechanosensation. Our past studies and preliminary results demonstrate i) technical skills in mastering microfluidics and advanced archaeal live-cell imaging to probe molecular and biophysical mechanisms, ii) cultivation and reverse genetics of dozens of archaeal species, and iii) proof of concept that some of our dashing ideas will yield valuable insights in laboratory model systems. Our research program envisions a better understanding of how microbes adapt in reconstituted environments akin to human physiological conditions, supporting future mechanistic in vitro and in vivo multi-species microbiome studies.

NIH Research Projects · FY 2026 · 2024-11

PROJECT SUMMARY/ABSTRACT Wolbachia pipientis is an obligate intracellular alpha-proteobacterium that infects 40-60% of insect species on the planet. Wolbachia infection inhibits RNA virus replication in insects, a phenomenon known as pathogen blocking. Therefore, Wolbachia infected mosquitos are being released in many parts of the world to control the spread of human diseases. Importantly, although the mechanism behind Wolbachia’s virus inhibition is not known, Wolbachia must manipulate host biology to infect new hosts, persist, and be transmitted to the next generation. Our long-term goals are to identify the molecular toolkit used by Wolbachia to establish infection and the host targets of these tools; to define the co-evolution of that molecular interface. To that end, we focus on the ankyrin repeat containing proteins found in Wolbachia proteomes. Our hypothesis is that via these effectors, the host cell is modified, allowing Wolbachia to invade and persist. Our preliminary data identified multiple ankyrin repeat containing proteins in Wolbachia (WARPs) and established their phenotypes in Drosophila melanogaster. Wolbachia strain wMel encodes 25 such proteins and we see striking phenotypes upon overexpression in the fruit fly. The phenotypes are dependent on the ankyrin repeat domain, establishing its importance in binding host targets. These results led to our central hypothesis that Wolbachia uses WARPs to modify the host cell environment and that these ankyrin repeat proteins have evolved across the clade, as Wolbachia has spread to new host backgrounds. Towards this hypothesis, we have begun several large-scale screens to identify host targets for the WARPs and suppressors of toxicity for these secreted effectors. We have already identified some direct interactions between WARPs and Drosophila proteins and look to further define the molecular interface between symbiont and host using evolution-guided chimeras and molecular biological assays such as bacterial-2-hybrid and reciprocal co-IPs. Guided by strong preliminary data, we propose to pursue three Specific Aims to identify and characterize WARP-target interaction, and their co-evolution, using the power of the Drosophila system. We will (1) determine WARP targets (2) identify the relevance of WARPs and their targets to Wolbachia and host biology, and (3) define the co-evolution of the host-symbiont molecular interface. Studies of Wolbachia - host interactions are still in their infancy despite the recognized contributions of endosymbiotic associations to insect reproduction and evolution, and the ability to alter vector competence. These proposed studies will significantly advance our understanding of how Wolbachia manipulates host biology to establish infection, a necessary prerequisite to its use in vector control.

NIH Research Projects · FY 2025 · 2024-09

“Modulation of Corneal Endothelial Mitochondrial Activity and Dysfunction by Estrogen” ABSTRACT The broad long-term objective of this project is to determine if estrogen is protective or detrimental to the health of corneal endothelial cells. Estrogen has been shown to be protective of many tissues and this protection is lost during menopause. Estrogen has many cellular effects including modulation of mitochondrial activity and antioxidant status. The corneal endothelium, responsible for maintaining the transparency of the cornea, is metabolically very active and has a very high density of mitochondria. Fuchs Endothelial Corneal Dystrophy (FECD) is characterized by an accelerated loss of endothelial cells, basement membrane deposits (guttae), and corneal edema. FECD specimens show dysfunctional mitochondria, reduced mitochondrial density, and high levels of oxidative damage to DNA, protein, and lipids. Two-thirds to three-quarters of FECD patients are postmenopausal women, suggesting that like glaucoma, macular degeneration, dry eye, and cataract, estrogen is protective. Conversely, an alternate hypothesis that premenopausal estrogen exposure is toxic to the endothelium via UV-light facilitated formation of nuclear and mitochondrial Estrogen-DNA adducts has been put forth. Studies examining estrogenic effects on corneal endothelium have been done with cultured cells or an acute damage model in mice. FECD however develops slowly over many years. Therefore, mouse models that provide a slower development of endothelial dysfunction will be best for determining if estrogen modulates dysfunction. To test the hypothesis that estrogen influences endothelial function, mitochondrial activity, or antioxidant capacity, in Specific Aim 1 corneal thickness, Endothelial Cell Density and morphology will be measured in an equal number of male and female estrogen receptor knockouts (KO) over one year. At that time endothelial explants will be examined for levels of mitochondrial activity and density; reactive oxygen species; oxidative damage and gene expression changes. Using the same methods, in Specific Aim 2, to test if estrogen protects the corneal endothelium, we ask if sex is a factor in oxidative stress models of endothelial dysfunction. Lastly, in Specific Aim 3, using a relatively new mouse menopause approach, we ask if corneal endothelial function is better, worse or the same in oxidative stress models following menopause. Together, completion of the aims will determine unequivocally whether the corneal endothelium is protected by estrogen, damaged by estrogen, or neutral. If protective, estrogen receptor agonists could delay progression of FECD and extend the useful life of endothelial grafts. If estrogen receptor agonists are going to be used to treat dry eye disease, lower IOP, or protect retinal ganglion cells in glaucoma or other eye disorders, it is essential to know if estrogen is protective or toxic to the corneal endothelium.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Charge detection mass spectrometry (CD-MS) is an emerging technology that allows accurate mass distributions to be measured for heterogeneous and high mass samples. It is a single ion approach where the mass to charge ratio (m/z) and charge are measured simultaneously for each ion, and then multiplied to give the ion’s mass. Measurements are performed for thousands of ions, which are then binned into a mass distribution. The m/z ratio and charge are measured using a detection cylinder embedded in an electrostatic linear ion trap (ELIT). Trapped ions oscillate back and forth through the detection cylinder and the signal from the oscillating ions is detected by a charge sensitive amplifier. The oscillation frequency gives the m/z ratio, and the charge is obtained from the signal amplitude. CD-MS is early enough in its development cycle that substantial technical improvements are still occurring. In this project we address the two main limitations of CD-MS: 1) its moderate resolving power, and 2) the relatively long time needed to measure a spectrum. The mass resolving power is limited by the precision of the m/z determination. The best m/z resolving power reported to date is 700. Using computer simulations, we have designed ELITs with resolving powers over 300,000. However, to perform at this level, the ELITs need to be perfectly aligned. Computer simulations indicate we can overcome the alignment problem by segmenting some of the ELIT electrodes and applying slightly different voltages to the segments to recover the high resolution. Our second goal is to substantially reduce the time needed to measure a spectrum. To achieve this goal, we will a) reduce the trapping time needed to resolve charge states, and b) reduce ion-ion interactions so that more ions can be trapped and measured at the same time. The trapping time required for charge state resolution can be reduced by lowering electrical noise, which will be achieved by implementing a novel design for the charge sensitive amplifier. Ion-ion interactions will be reduced by optimizing ELIT designs so that ions are trapped in trajectories that do not interact. Combining these advances, we expect to perform high-resolution CD-MS measurements at 500-1000 ions/s. The advances described above will be transformative for CD-MS and are expected to have a broad impact. We will explore three applications. 1) high resolution CD- MS analysis of the adeno-associated virus (AAV) gene therapy vectors will reveal subpopulations with different combinations of capsid proteins. The subpopulation relative abundances, and any correlations with post translational modifications, may help understand lot-to-lot variability in AAV preparations. 2) Heteroaryldihydropyrimidines (HAPs) lead to aberrant assembly of hepatitis B virus (HBV) capsids, and they are being investigated as potential HBV antivirals. High resolution CD-MS measurements will be performed to monitor HAP binding to HBV capsids and assembly intermediates to probe the nature of the binding interactions. 3) To explore the use of high resolution and high throughput CD-MS to detect and monitor biomarkers, we will use CD-MS to measure intact urinary proteins to determine how many can be directly detected.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Salient signals, like aversive stimulation and reward, should be faithfully detected, and processed by the nervous system to generate an adaptive action. One of the universal circuit mechanisms linked to salient signal processing in cortical operation is the activation of dis-inhibitory neurons by subcortical afferents. Aversive signals and reward delivery profoundly excite cortical GABAergic interneurons expressing vasoactive intestinal polypeptide (VIP), which selectively inhibit other GABAergic interneurons, leading to the dis-inhibition of cortical pyramidal cells. In this project, we propose to reveal the functional diversity of VIP interneurons in a cortical structure. The central idea of our project rests on our earlier anatomical findings that distinct groups of VIP interneurons innervate different types of GABAergic interneurons, observations that prompted us to suggest a heterogeneity in their activity during various cortical processes. However, recent imaging studies reported rather similar activity of VIP interneurons following aversive and appetitive stimuli. In contrast to these in vivo imaging data, our preliminary experiments obtained in a frontal cortical area of anesthetized mice have revealed a considerable heterogeneity in VIP interneuron spiking upon delivery of foot shocks. Building on these preliminary results, our goal is to determine the functional complexity of cortical VIP interneurons, including their connectivity and operation in awake mice. To achieve these aims, we will combine viral techniques, neuroanatomical methods, in vivo and in vitro electrophysiology with optogenetics in three different genetically modified mouse lines. The results of this project will uncover the heterogeneity of spike responses generated by genetically defined dis-inhibitory VIP interneurons upon salient signal delivery and their downstream effects on postsynaptic partners within the local microcircuits. Our project will reveal the complexity of dis-inhibitory circuit motifs in cortical networks, which may be a general phenomenon in a cortex- wide manner. In addition, our results will help form novel concepts underlying the pathological operation of cortical circuits linked to deficits in attention and salient signal detection that typifies many malfunctional cognitive processes, including those observed in schizophrenia, autism, and attention deficit.

NIH Research Projects · FY 2025 · 2024-09

Abstract Fentanyl’s high potency, facile synthesis, abuse liability, and propensity to cause profound respiratory depression via the mu opioid receptor (MOR) have combined to create the opioid epidemic. Fentanyl now accounts for ~80% of opioid overdose deaths and is predicted to contribute to more than 1.2 million deaths during the current decade. The rapid onset of fentanyl-induced respiratory depression requires a fast-acting therapy. For practical purposes, this needs to be a pharmacological treatment. The primary pharmacological treatment for opioid overdose is naloxone. Naloxone is a competitive orthosteric antagonist of MOR and thus its effectiveness depends on the dose of naloxone given, naloxone’s affinity for MOR compared to the opioid, and the rate at which the opioid leaves the receptor. While naloxone can be lifesaving, there are numerous examples of naloxone failing to reverse an opioid overdose, emphasizing the importance of improving the pharmacological treatment of opioid overdose. One way to improve naloxone’s efficacy at MOR is by using a negative allosteric modulator (NAM) of MOR. NAMs decrease agonist signaling by either increasing the rate at which the agonist leaves the receptor or by decreasing the efficiency of signaling. Either could be beneficial combined with naloxone to reverse an opioid overdose. Interestingly, cannabidiol (CBD) is a low potency MOR NAM. In preliminary experiments, we screened a CBD analog library for their ability to reverse fentanyl-mediated inhibition of adenylyl cyclase (AC). We identified potent NAMs that reversed fentanyl inhibition of AC and fentanyl analgesia, but they failed to prevent fentanyl induced respiratory depression or enhance naloxone reversal of respiratory depression. These results suggest that pathways other than MOR inhibition of AC mediate fentanyl-induced respiratory depression. Thus, in the proposed work, our first goal is to screen our candidate NAMs for attenuation of fentanyl/MOR signaling across a broad range of signaling pathways with the goal of identifying CBD analogs that inhibit MOR signaling pathways in addition to AC. Even though our potent MOR NAMs didn’t decrease respiratory depression, an important second goal is to determine if they affect other key behaviors mediated by fentanyl/MOR: reward, dependence, and tolerance. We will address these two goals with two specific aims. Specific Aim 1. Screen the CBD analog library for attenuation of fentanyl/MOR modulation of the following pathways: adenylyl cyclase, GIRK, MOR internalization, ERK1/2, phospholipase C, and arrestin. Specific Aim 2. Determine the ability of the novel MOR NAM, JGC8, to attenuate key fentanyl/MOR-mediated behaviors: reward, dependence, alleviation of neuropathic pain, and tolerance. We feel Aim 1 will likely identify compounds with unique signaling profiles. Aim 2 will determine if the already identified MOR NAM, JGC8, affects therapeutically important fentanyl-elicited behaviors and, combined with results from Aim 1, will provide insights into the signaling pathways involved in these MOR-related behaviors.

NIH Research Projects · FY 2025 · 2024-09

Hispanics are the fastest growing population in the U.S. that has been identified as being at higher risk for Alzheimer’s disease and related dementias (ADRD). They are 1.5 times more likely to develop ADRD, and Hispanic ADRD informal caregivers experience more burden compared to other impacted groups. There is an identified need to adapt interventions and make them relevant to meet the needs of Hispanic ADRD informal caregivers. My past research has focused on examining various factors as they related to ADRD cognition and symptomatology. In the proposed K23 application, I aim to fill an existing gap in my training by applying the knowledge I’ve gained and gain experience and training in clinical trial research and methodology. I plan to pursue a career as an independently funded investigator in the field of tailored interventions for ADRD caregivers and patients from groups at high risk for ADRD. The proposed study will use a mixed method approach to conduct the necessary stage 0 and 1A activities of the NIH Stage model to assess needs of Hispanic ADRD informal caregivers and develop modifications to Brain CareNotes, a secure mobile telehealth application for informal caregivers to manage behavioral and psychological symptoms of dementia (BPSD) with the aid of a remote care coach. Preliminary data on a general sample have shown that BCN reduced caregiver burden (Neuropsychiatric Inventory [NPI]-Caregiver Distress) and BPSD at 3 and 6 months. Focused tailoring of this intervention requires more than just Spanish translation, but integration of factors which effect psychological and neurological functioning in both caregivers and ADRD patients. Guided by an framework for intervention adaptations, I propose to tailor Brain CareNotes for Hispanic ADRD caregivers. This will be accomplished by first conducting a needs assessment among Hispanic ADRD informal caregivers (aim 1) in relation to managing BPSD and how life factors play a role. I will then use participatory co-design methods to adapt and modify Brain CareNotes (aim 2). Once the focused adaptations are complete, I will conduct a pilot study to ensure a future R01 proposed RCT will be powered to detect reduction in caregiver burden and BPSD among Hispanic ADRD patients (NPI scores).

NIH Research Projects · FY 2025 · 2024-09

Modified Project Summary/Abstract Section The proposed research is a longitudinal study in adolescents aged 13-20 years old (N = 1,000) triangulating (1) ecological momentary assessment (EMA) with (2) concurrent data/meta-data text collected from adolescents’ smartphones using the Effortless Assessment Research System (EARS). The project aims to model the bidirectional association between the language used on social media and internalizing symptoms. This study builds on our prior work, the Studies of Online Cohorts for Internalizing symptoms And Language (SOCIAL), which have focused on (1) adults (21+; SOCIAL-I: N=1,123), (2) late adolescents (SOCIAL-II: N = 6,105), and (3) individuals with internalizing symptoms being treated with internet based cognitive-behavioral therapy (CBT, SOCIAL-III: N= 421). The SOCIAL data suggest that language that is cognitively distorted (CD), unduly negative, rigid, or absolutist, can be detected from passively-acquired social media text. Moreover, CD language is associated with internalizing symptoms and more likely to be used by late adolescents than their adult counterparts. Thus, CD language may partly account for observations that social media use are associated with internalizing symptoms in adolescents. SOCIAL-IV extends on SOCIAL I-III by (a) including 13-16 olds to study a more variable (i.e., 13-20) year age range, (b) with a more diverse sample, (c) using intensive longitudinal self-report data derived from EMA, and (d) studying all text adolescents produce on their smartphones, including social media content and non-social media content. The SOCIAL cohorts are based on the idea that by curating large samples that triangulate self-report with natural language and meta-data from social media, we can improve our understanding of the effects of social media on mental health, paving the way for future interventions. SOCIAL-IV will help us uncover how CD language is linked to internalizing symptoms, to study how CD language propagates on social media, and to explore individual differences in the susceptibility to CD language. Aim 1 uses dynamic structural equation modeling (DSEM) to triangulate the intensive longitudinal data derived from EARS with the intensive longitudinal data derived from EMA. We hypothesize a bidirectional relationship between CD language and internalizing symptoms. Aim 2 will sample public social posts from SOCIAL-IV participants to establish whether CD content is more contagious on social media than non-CD content. We hypothesize that, consistent with our prior data, CD language will yield more engagement than non-CD language. Aim 3 seeks to explore whether individual differences, including psychiatric symptoms (e.g., comorbid externalizing symptoms), self-reported social media use (e.g., perceived impairment), and data and meta-data collected from social media (e.g., follower count), moderate the bidirectional association between CD language and internalizing symptoms.

NIH Research Projects · FY 2025 · 2024-09

Exposure to ultraviolet light between ages 15 and 20 years is the most important etiological factor in skin cancer, yet adolescents and young adults (AYAs) this age are more likely to engage in health-compromising behaviors like indoor and outdoor tanning without skin protection. As an intervention modality, social media (SM) represents an opportunity to reach AYAs, who are among the most active Facebook, Instagram, and Twitter users. Characterizing the skin cancer communication landscape and creating effective risk/prevention posts, with an “understanding of which messages will resonate with specific groups” (The Surgeon General’s Call to Action to Prevent Skin Cancer), could enable targeted prevention methods for AYAs. Our long-term goal is to reduce health-compromising behaviors (e.g., indoor tanning, sunscreen nonuse) in at-risk AYAs, who are vulnerable to developing skin cancer. This proposal’s main objective is to: 1) characterize the SM landscape regarding skin cancer-related posts; and 2) develop/test theory-based messages for skin cancer prevention among AYAs that are clear, specific, consistent, and scientifically up to date. With a robust multidisciplinary team, we will accomplish this objective via 3 specific aims—AIM 1: Characterize skin cancer-related communication across three popular SM platforms. AIM 2: Build a predictive, explainable health communication model to determine the diffusion potential of skin cancer-related messages. AIM 3: Develop/pilot test theory-based sun-protection and indoor tanning-related messages for AYAs for future implementation and evaluation. In AIM 1 we will use content analyses to assess the skin cancer communication landscapes on Facebook, Instagram, and Twitter, describing message features, source characteristics, posters/users, and social networks. In AIM 2, we will apply machine learning methods to characterize message features; develop/evaluate a predictive model of a message diffusion potential using large-scale training data; apply the model to predict a set of online diffusion metrics for a given message; and assess its ability to reach skin cancer prevention-relevant populations. In AIM 3, we will engage 2 stakeholder segments in iterative rounds of message development/testing: 1) cancer organization staff (who post on their SM accounts); and 2) intended recipients of these messages: adolescents and young adults aged 15-20 years. The research is innovative because of its focus on posts across 3 SM platforms and the Multilevel Model of Meme Diffusion (M3D). This work will provide a strong basis for the future development of improved and targeted prevention efforts via digital platforms frequently used and easily accessed by AYAs, effectively supporting the NCI’s mission to “advance scientific knowledge and help all people live longer, healthier lives.”

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Cardiovascular disease (CVD) has become a leading cause of morbidity and mortality in persons with HIV (PWH). Although clinical guidelines recommend detecting and addressing CVD risk among PWH, CVD prevention has not been effectively implemented in routine HIV Care. Addressing this implementation gap is critical for reducing the disproportionately greater burden of adverse CVD outcomes facing PWH. My K01 research aimed to address this gap by examining CVD risk among PWH, CVD preventive practices in HIV care, and implementation strategies to improve these practices. My work showed CVD risk in PWH is driven by traditional risk factors (e.g., hypertension) which HIV clinical guidelines recommend addressing. My K01 research also showed that lack of awareness about clinical guidelines, low clinician motivation to follow the guidelines, lack of CVD preventive resources, and the clinic culture influence guideline adoption. I then developed an agent-based model to simulate the effects of implementation strategies on these barriers: I found education, audit and feedback, and leadership engagement are promising strategies to improve guideline adoption. To determine if these findings are valid and aligned with current HIV care practices, my model needs to be externally validated using data from diverse HIV care contexts. Further, to determine its acceptability and real-world relevance, the model needs to be evaluated by HIV stakeholders and refined through participatory modeling approaches. Thus, the overall goal of this R03 application is to externally validate and refine my K01 model through participatory agent-based modeling. First, I will externally validate the model that simulates the effects of implementation strategies on hypertension care guideline adoption (AIM 1). Second, I will evaluate and refine the model through participatory agent-based modeling with HIV stakeholders (AIM 2). The proposed study responds to NHLBI’s call to explore CVD prevention in the HIV population and to optimize implementation research to improve health. This study will contribute a tool that HIV decision makers can use to inform their CVD prevention efforts, and a prototype implementation strategy that can be tested in real-world HIV clinics.

NIH Research Projects · FY 2024 · 2024-09

SUMMARY Lactation mastitis is an extremely painful and debilitating condition that affects 10-25% of breastfeeding people and can progress to breast abscess or septic fever. This significant disease burden occurs mostly during the first six months when birthing people are still in recovery from pregnancy and childbirth. The objective of the proposed study is to compare classes of antibiotics on first-line treatment failure and document disparities in severity at presentation and antibiotic prescription rates by race/ethnicity. Our central hypotheses are that some treatments are more effective than others for avoiding treatment failure and that there are measurable disparities in severity at presentation and treatments prescribed by race/ethnicity. We will construct a cohort of >5,000 diagnosed mastitis cases utilizing a nationwide healthcare claims dataset and conduct rigorous analyses to explore these hypotheses. Our team is uniquely poised to answer these critical research questions and includes an infectious disease epidemiologist, a lactation clinician who co-authored the current mastitis treatment guidelines, and an expert in using claims data to asses downstream impacts of medication use. Specifically, we aim to: (1) Compare the effectiveness of classes of antibiotics (e.g., first and second generation penicillins, cephalosporins, lincosamides, sulfonamides) prescribed for lactation mastitis on first-line treatment failure, abscess, and hospital admission. We hypothesize that given community and hospital transmission of MRSA, short-course penicillins will have the highest rate of first-line treatment failure. (2) Describe disparities by race/ethnicity in the severity of mastitis at presentation and the antibiotic prescription patterns after mastitis diagnosis. We hypothesize that given barriers to antenatal care and implicit provider bias, Black and Latina/e/x breastfeeding people will present with more severe cases of mastitis and are prescribed antibiotics less frequently after diagnosis in comparison with white breastfeeding people. The proposed study will make significant and novel contributions toward understanding current patterns in antibiotic prescriptions for mastitis treatment and the relative effectiveness of current antibiotic treatments. The formation of a mastitis diagnosis cohort using the Optum dataset will provide a platform to assess a number of other important factors such as local antibiotic resistance patterns and to assess the impact of changing policies (both mastitis treatment and antibiotic stewardship policies) on successful treatment. These results will also provide information on the most effective treatments to assess in future randomized trials. Innovative aspects of our proposal include: (1) high-quality observational studies that advance our understanding and can guide the design of future randomized trials, (2) assessment of treatment disparities by race/ethnicity which is critical for responding to clinical and social realities, and (3) large data that covers the US geographically.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Cancer is driven by interactions between diverse cell types and their tissue microenvironment. Emerging single- cell and spatial transcriptomic systems are mapping cancer tissues, in the process capturing the diversity of cell types and states and exposing the importance of spatial cell interactions in determining therapeutic response in individual patients. Multi-omics software developed in ITCR—including CoGAPS, projectR, SpaceMarkers, and Domino developed by our group—can analyze single-cell and spatial multi-omics data to infer cell types and phenotypes in the tumor microenvironment, identify which cells interact, and discover how cell-cell interactions drive molecular changes. However, these analyses yield static snapshots that cannot capture the dynamics of cancer ecosystems. Mathematical modeling can “fill in the gaps” between these snapshots, allowing teams to form hypotheses on how and why cells interact, “encode” their hypotheses as simulation rules, and perform “virtual experiments.” However, simulation rules and their parameters are difficult to match to genomic data. This proposal bridges the gap between bioinformatics and mathematical biology by merging our bioinformatics soft- ware for single-cell and spatial multi-omics data with PhysiCell, an agent-based modeling framework developed by our group to simulate the movement and interaction of many individual cell agents in virtual tissue environ- ments. The “glue” between these packages is a novel cell behavior grammar that “encodes” cell rules learned from high-throughput data as intuitive, interpretable hypothesis statements that can be automatically transformed into simulation code. In this proposal, we refine the cell behavior grammar while analyzing previously published cancer data to create digital “templates” for key cell types in cancer ecosystems, refine PhysiCell to import the templates, and create PhysiCell Cloud: a free, “zero-install” cloud resource to build, execute, and visualize can- cer models without writing computer code. We refine CoGAPS, SpaceMarkers, projectR, and Domino to learn cell behavior rules from spatial transcriptomics data and format them with the grammar, and extend PhysiCell to read cell types, positions, and rules stored in standard single-cell, spatial, and multi-omics classes. We develop sophisticated pipelines for PhysiCell models that can quantify model uncertainty, automatically fit models to tran- scriptomics data, and validate models on real world tumor datasets. We extend PhysiCell Cloud to a full-fledged science gateway that includes secure and searchable user storage, data structures and code (APIs) to connect PhysiCell Cloud to Python, R, and Bioconductor pipelines in ITCR, and a cost-free high-performance computing backend to seamlessly run large-scale model exploration and uncertainty quantification pipelines. Educational expertise and community feedback—including from an advisory board, annual training workshops, and daily classroom use—will drive usability refinements. Altogether, this approach will bridge bioinformatics and mathe- matical modeling to provide a comprehensive platform for patient-specific mechanistic tumor modeling, to enable future computationally-drien experimental design, virtual clinical trials, and digital twins research. ‘

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT Early detection of cognitive decline in older adults (OA) is a public health priority. The pathology of Alzheimer's disease (AD) begins more than 20 years before memory loss develops, but dementia diagnoses often occur late in the process of cognitive decline. AD is a progressive disease and early detection of cognitive decline may slow disease progression by providing appropriate treatments earlier. There is growing evidence to suggest the possibility that depression in OA is a risk factor for cognitive decline and AD, potentially acting through perceived stress. However, it remains unknown whether depression in OA is a prodrome, a cause, or a consequence of cognitive decline. Moreover, we often rely on cognitive assessments in the lab, and could instead leverage real-world behaviors to detect early shifts in cognition. This study seeks to fill this knowledge gap through three aims: (Aim 1) identification of cross-sectional and longitudinal relationships between cognitive performance, perceived stress, and psychiatric symptoms in an existing sample from the Indiana Alzheimer's Disease Research Center; (Aim 2) development of natural language processing algorithms to detect and quantify risk factors for depression in midlife and OA; and (Aim 3) ecological momentary assessment of the daily cognitive functioning, emotions, and stress in OA, using validated mobile cognitive tasks. Completion of these aims will provide a test of the relationship between cognitive aging and depression in OA using a multimodal approach. Dr. Rutter's overarching K01 career development goal is to develop a naturalistic paradigm for early detection of cognitive decline. Aim 1 will define the theoretical framework for this paradigm; Aims 2 and 3 then apply this framework to real-world stimuli to determine whether these provide more sensitive measures of detecting cognitive decline. The integrated training and research plans proposed here will provide Dr. Rutter with advanced training in several critical areas needed to position here as an expert on aging. The mentorship and guidance from her team of national leaders will allow Dr. Rutter to achieve targeted training in the following domains: (1) cognitive aging, AD, depression and wellbeing in OA, and technology use in OA (Krendl & Holden), (2) natural language processing approaches to understanding risk factors for depression in midlife and OA (Bollen), (3) implementation of ecological momentary assessment and analysis of intensive longitudinal cognitive data in OA (Finn & Germine), and (4) career development skills in grantsmanship, leadership, and research (Krendl, Holden, & Hawkins). These training objectives will be achieved through a combination of coursework, conferences, workshops, directed readings, mentorship meetings, and completion of the primary K01 study. Indiana University Bloomington provides an outstanding environment for these training and research objectives. This K01 award will provide an essential bridge between Dr. Rutter's prior training and research experience, and her career goal of becoming an independently funded researcher who specializes in the interplay of depression and pathological cognitive aging.

NIH Research Projects · FY 2026 · 2024-08

PROJECT SUMMARY: Alzheimer’s disease (AD) affects over 6 million Americans, and its incidence is projected to double by 2050 due to an aging population. In the fight against AD, there is a pressing need for novel biomarkers to 1) identify clinical trial participants at risk of decline and 2) identify and track patients eligible for emerging treatments. Gold standard AD biomarkers require positron emission tomography (PET) imaging or cerebral spinal fluid (CSF) collected via lumbar puncture. These procedures are expensive and/or invasive, presenting a barrier to widespread adoption. Blood-based biomarkers are under development but are not yet validated and may benefit from combination with other biomarkers. A principal goal of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) 3 is to promote development of novel AD biomarkers, including the use of functional magnetic resonance imaging (fMRI). FMRI is used to study the functional connectivity (FC) and organization of the brain, and fMRI studies have revealed functional brain changes associated with AD. FMRI- based biomarkers of AD could complement existing biomarkers by providing a non-invasive, first-line screening method before PET and CSF are collected. FMRI could also be combined with blood biomarkers and established structural MRI markers—all of which can be routinely collected clinically—to construct powerful and widely available multimodal biomarkers. Despite all of this, no fMRI-based biomarker for AD exists to date. This is in part due to the high noise levels of fMRI and the common use of naive statistical methods, which together lead to noisy estimates of FC and other functional brain features. Two conventional workarounds—averaging many subjects or collecting hours of data on individual subjects—are not viable clinically. This project will address this gap by developing computationally efficient Bayesian techniques with high accuracy and deploying those methods for fMRI-based biomarker discovery in AD. Our models leverage information across subjects via population-derived priors or “templates”, which are previously estimated, to extract nuanced and precise functional brain features in individuals. These models avoid the need for burdensome prolonged scans. They can be fit to data from a single subject at a time, making them clinically viable and computationally advantageous. To maximize the benefits of hierarchical modeling, we utilize grayordinates data, a recent technological advance in image processing that improves inter-subject anatomical alignment. To deploy these techniques effectively in multi-site datasets like the ADNI, image harmonization is necessary to avoid confounding site effects. Existing harmonization methods can be applied to fMRI summary measures, but are not applicable to fMRI time series, which are a complex mixture of latent features. To address this critical gap, we will develop a novel harmonization method for fMRI time series data, with high potential impact on fMRI processing pipelines. Finally, we will analyze fMRI data from ADNI to extract functional brain features and build novel fMRI-based AD biomarkers. While our focus is AD, this project will have broad implications for fMRI-based research and care.

NIH Research Projects · FY 2025 · 2024-08

Project Summary/Abstract Distressing psychosis symptoms (i.e., hallucinations and delusions), exist on a spectrum from subclinical to those observed in diagnosed individuals, occur in an astonishing 5-8% of the general population, and are often accompanied by disability, reduced social functioning, and cognitive impairments. Mechanisms underlying psychosis-spectrum symptoms remain unclear, limiting development of targeted treatments. A new approach focuses on internal body states (e.g., heartbeats, temperature) that shape experiences of self, others, and the world, and are essential to adaptive behavior. Interoception encompasses the detection, integration, and interpretation of internal body states, which appears disrupted and critically understudied in psychosis. Clinical exemplars include mismatched behavior (e.g., wearing a parka in hot weather), reality distortions (e.g., believing back pain is from a tracking device), and loss of body ownership (e.g., perceiving external control). Interoceptive accuracy tasks reveal poor detection of internal body states across the psychosis-spectrum; however, this cannot be separated from cognition. To move beyond descriptive work and limitations, the current study non-invasively manipulates internal body states in a predictive coding paradigm. Further, computational modeling dissects interoceptive predictive coding into subprocesses and disentangling relationships with psychosis symptoms versus cognition to provide translational insights that may inform future treatment targets. Predictive coding is a neuro-cognitive framework, where ‘prior beliefs’ allow for predictions about incoming sensory information for efficient responding. A prediction error results from a discrepancy between the ‘prior belief’ and sensory information, which should update the belief for future adaptive behavior. Therefore, the brain makes sense of the world through iterative hypothesis testing, by comparing ‘prior beliefs’ (top-down predictions) with sensory information (bottom-up stimuli). This framework has provided valuable insight to exteroceptive perception (e.g., auditory, visual) in psychosis-spectrum samples, where strong ‘prior beliefs’ dominate perception. Similarly, strong interoceptive ‘priors’ may drive poor interoceptive accuracy in psychosis, and be a critically untested process contributing to both false perceptions (hallucinations) and formation of false beliefs (delusions) that fail to reflect the environment. Computational models of predictive coding can dissect interoceptive perception into higher- and lower-level subprocesses, including weighting of ‘prior beliefs’, adaptability, and behavioral consistency, to test differential relationships with key clinical features of psychosis. Thus, the current study will move the field forward by 1) testing a hypothesis of strong interoceptive ‘prior beliefs’ within the psychosis-spectrum, and 2) investigating differential relationships for subprocesses of interoceptive predictive coding with psychosis symptoms versus cognition. Together, the proposed research and training plan establish a critical foundation integrating cognitive science theory and computational methods with basic interoception research to advance our understanding and treatment targets for distressing psychosis symptoms.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Excess dietary salt is associated with increased risk for hypertension and cardiovascular disease (CVD), the leading cause of death in the United States. High dietary salt is also associated with increased chronic kidney disease (CKD) risk, another leading cause of morbidity and mortality. Yet, 90% of adults consume excess dietary salt based on the Dietary Guidelines for Americans recommendation. Americans struggle to reduce their salt intake because the vast majority (~70%) of dietary salt comes from processed foods and meals prepared at restaurants, making it difficult to alter their dietary salt. As a result, there have been calls for alternative strategies to counteract excess consumption of dietary salt. We have identified Beta-hydroxybutyrate (β-OHB) as a promising tool to counteract the adverse cardiorenal health effects of high dietary salt. β-OHB is a ketone body typically produced during prolonged exercise, fasting, and ketogenic dieting. Alternatively, oral ketone monoesters are a type of ketone supplement that are metabolized into β-OHB. While most individuals are unable to adhere to strict ketogenic diets, oral ketone supplements are convenient, typically well tolerated, and increase β-OHB to a similar or greater extent. Recent rat data suggests that high dietary salt suppresses β-OHB production and that increasing β-OHB via ketone supplementation counteracts the adverse effects of high salt on cardiorenal function. Similar to the published rodent data, our pilot data also indicate that high dietary salt reduces fasting plasma β-OHB in humans. Recently published data also demonstrate that increasing β-OHB with ketone supplementation can improve blood pressure and vascular function in humans under certain contexts. However, it is unclear whether raising β-OHB via ketone supplementation can protect older humans against the adverse cardiorenal effects of high dietary salt. Therefore, we are proposing to examine whether taking a ketone monoester supplement concurrently with high salt for 10 days counteracts the adverse effects of short-term high dietary salt on blood pressure (Aim 1), vascular function (Aim 2), and kidney injury and blood flow (Aim 3). We will utilize a double masked, randomized, placebo-controlled crossover design pilot trial in 30 older adults who will also undergo a low salt control intervention and high salt alone. The PI (Dr. Austin Robinson) has a strong record of productivity investigating the cardiorenal consequences of short-term high dietary salt and has assembled an outstanding interdisciplinary team of co-investigators and consultants to help secure future R01 funding for this line of research. The public health impact of this innovative project is that establishing strategies (e.g., ketone supplementation) to attenuate the adverse cardiorenal effects of high dietary salt could lead to reductions in CVD and CKD risk and mortality.

NIH Research Projects · FY 2025 · 2024-08

This F31 award will allow Kelsey Sinclair (PI) the research training that will advance her toward her goal of becoming an independent cancer multimorbidity scientist with an expertise in intervention adaptation and implementation to optimize cancer care in underserved groups. Cancer-obesity co-morbidity is common and especially deadly for Black breast cancer survivors (BCS). Although Black women have lower breast cancer incidence, they have the highest breast cancer mortality rate (40%) of any U.S. race/ethnic group – an effect attributed to comorbid obesity. Obesity predicts higher mortality among Black BCS, and post-cancer diagnosis weight gain predicts increases in mortality. One way to fight back against the effects of obesity is to develop and to deliver obesity treatments adapted to address the unique challenges of the BCS community. Identification of important risk/protective factors can be applied to evidence-based weight loss interventions to provide potentially life-extending care. The proposed multi-method study will use a socioeconomic framework and multi-methods to discover actual risk/protective factors for Black BCS with obesity compared to other BCS. PI Sinclair will leverage resources from a parent trial to first use a quantitative survey to assess 100 BCS from any race-ethnicity to test potential risk and protective factors that differ for Black BCS (Phase 1). Second, using co-design qualitative methods, initial tailoring of an evidence-based weight loss intervention for obesity will be done in collaboration with our patient partners – five Black BCS with obesity (Phase 2). This tailored weight loss protocol will then be delivered in a pilot with 15 Black BCS with obesity, with preliminary evaluation of potential treatment heterogeneity factors (Phase 3). Via these phases, the following F31 aims will be addressed: Aim 1: To proactively identify lifestyle and multimorbid factors of an obesity intervention for Black BCS and Exploratory Aim 2: To explore obesity treatment response in Black BCS via subgroup analyses.  The proposed F31 will thus utilize Phase 1 survey data and Phase 2 qualitative interviews (Aim 1) as well as Phase 3 post-treatment data (Exploratory Aim 2). Accordingly, it will benefit from the existing parent pilot infrastructure (e.g., recruitment strategies, participants, trial conduct). For the parent trial, the outcomes are acceptability, feasibility, and preliminary weight loss of the program. PI Sinclair’s project and training plan will allow for a comprehensive multi-method analysis of adaptation factors to inform future larger-scale trials and foundations of a future F32 or K23 for PI Sinclair, a future scholar with expertise in multimorbidity interventions in cancer, obesity, and other chronic diseases differently impacting breast cancer survivors.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY. Sensorimotor function is aberrant in psychosis, with 60-80% of patients being affected and motor disturbances contributing to hospitalizations. One sensorimotor function is motor learning, which allows us to engage with and adapt to our world through generating and updating internal models. Deficits in model updating are linked to symptoms in psychosis, such as delusions, hallucination, negative symptoms, and disorganization, making this fundamental process key to understanding the disorder. My prior work shows that sensorimotor and cognitive cerebellar regions required for model updating processes are smaller in a subset of patients, which may account for variability within and across motor tasks as well as symptom heterogeneity in psychosis. Critical knowledge gaps in these brain-behavior-symptom relationships have limited our ability to leverage the motor system for intervention, despite it being a highly accessible system. Thus, fundamental sensorimotor subprocesses are key to understanding psychosis and determining viable targets for treatment. Using longitudinal approaches and cross-discipline advances in measurement that allow us to parse previously ignored or indistinguishable sensorimotor processes, this project will determine how sensorimotor aberrations and psychotic symptoms relate, to inform mechanistic models and future intervention research. This K23 mentored patient-oriented career development award employs a novel computerized motor learning task and neuroimaging. The project goals are to: (Aim 1) cross-sectionally localize aberrant subprocesses of motor learning in psychosis and link these processes to brain structure and symptoms; (Aim 2) longitudinally map the malleability of sensorimotor deficits during natural course of illness to identify viable, clinically relevant intervention targets. This work sets the foundation for robust mechanistic studies on the role of unique neural circuits in distinct sensorimotor subprocesses and the data may serve as primary and secondary outcomes to investigate entirely new avenues of treatment for psychosis, given the lack of intervention on this system (planned follow-up R-mechanism grant). The applicant is an tenure-track Assistant Professor of Psychological and Brain Sciences at Indiana University Bloomington with dual PhD in Clinical Psychology and Neuroscience. She holds expertise in sensorimotor processes and cerebellar neuroimaging in psychosis. Her long-term career goal is to be a recognized expert on sensorimotor function in psychosis and to develop a mechanistic model of sensorimotor disturbance in psychosis that can be leveraged for clinical assessment and intervention. To accomplish these goals, the applicant will expand her current expertise with training in computational psychiatry, longitudinal methods, and intervention science for translation of targets to viable treatments. Training will include formal coursework and hands-on training, guided by a mentorship team of experts in these domains. Mentored training and completion of this project will provide the necessary skills, experience, and data to launch a successful independent research career.

NIH Research Projects · FY 2025 · 2024-08

The recent COVID-19 pandemic, alongside the rise and recurrence of infectious diseases, has underscored the vital role of microbial science in addressing global public health challenges. The Midwest Microbial Pathogenesis Conference (MMPC) stands as an influential annual scientific meeting dedicated to showcasing exceptional research in microbial pathogenesis. MMPC focuses on nurturing the professional growth of junior faculty, students, and postdoctoral scholars in biological sciences at a yearly event with the purpose of exchanging scientific ideas and developing collaborations. Since its establishment in 1994, MMPC has been hosted yearly at academic institutions throughout the Midwest region of the United States. The steadily increasing attendance of >400 participants encompasses undergraduate and graduate students, postdoctoral fellows, research staff, and faculty, who engage in extensive interactions. Through career development forums, the "Meet the Speakers" series, and informal gatherings during poster sessions, receptions, and meals, each MMPC meetings aims to facilitate extensive networking among scientists and institutions across the Midwest and beyond. The conference's regional accessibility, affordability, and substantial financial support for travel and registration make it possible to attract a wide array of participants. This meeting has been consistently supported by the NIAID over the past 14 years, and here, we are requesting continued support for MMPC 2024-2028. Throughout the five years of this award, MMPC will be held in the fall each year. In alignment with MMPC's rich tradition, the majority of invited speakers (excluding the keynote and opening session speakers) will be trainees or junior faculty. Also, faculty speakers will be selected to cover many research topics within the field of microbial pathogenesis. Additional oral presentations will be selected from abstracts submitted by students and postdoctoral fellows. We aim to use funding from this grant application to waive registration and lodging fees for 33 meritorious scholars for each meeting. Each MMPC will feature a keynote address by renowned research leaders in the field of bacterial and viral pathogenesis. Support of this R13 grant application from the NIAID will facilitate the assembly of a large group of scientists from various microbiology subdisciplines, encouraging collaborative networks and advancing the careers of the next generation of scientists.

NIH Research Projects · FY 2025 · 2024-07

Project Summary Paranoia, a core feature of psychosis and a clinically significant transdiagnostic construct, manifests dimensionally in the population and significantly impacts social functioning and well-being across the severity spectrum. This proposal addresses critical knowledge gaps in understanding the dynamics contributing to the persistent observation of heightened paranoia among Black Americans compared to their White counterparts, irrespective of clinical status. Specific Aim 1 bridges current knowledge gaps by identifying both risk and resilience factors that may mediate and moderate the relationship between group status and self-reported paranoia in Black and White Americans using self-report survey methodology. To our knowledge, we are the first team to systematically investigate the intricate interplay between both individual- and group-level factors that may influence heightened paranoia endorsements observed among Black Americans. Furthermore, while adverse experiences related to race have been implicated as a potential driver of group differences in paranoia, the correlational nature of current research limits causal inferences. Specific Aim 2 addresses this limitation by employing a randomized experimental paradigm to test the causal relationship between exposure to adverse experiences related to race and increased paranoia among Black Americans. In addition, we will meticulously examine the factors that may influence the magnitude of experimental effects, shedding light on nuanced factors at play. By elucidating these dynamics and causal pathways, the proposed research will refine the understanding of paranoia expression across groups—providing crucial information for culturally sensitive and accurate measurement of the psychosis spectrum within diverse populations.

NIH Research Projects · FY 2024 · 2024-07

PROJECT SUMMARY The Molecular Genetics of Bacteria and Phages (MGBP) meeting is a reputable national scientific conference held annually since 1940 that brings together investigators to present and discuss advances in the molecular biology of bacteria and their viruses. The MGBP Meeting is significant because it directly and positively impacts molecular research focused on the causative agents of human disease, commensals, symbionts, and phages while prioritizing the training of a diverse scientific workforce. A core objective of the MGBP Meeting is to provide an engaging and supportive forum for trainees and junior faculty to share their work in a collegial, inclusive environment. The 2023 attendees (516) hailed from 30 US states and >10 countries and included undergraduate and graduate students, postdoctoral scholars, faculty members and professional scientists from the private sector. Several innovative aspects distinguish the MGBP meeting including: (1) the Diversity Showcase to highlight scientists from historically marginalized groups, (2) mentoring tables for discussion of career paths, inclusivity, and diversity, (3) the Sternberg Thesis Award for the most outstanding Ph.D. thesis, (4) trainee poster awards, and (5) community building events. The 2024 MGBP Meeting will be held from August 5-9 at the University of Wisconsin-Madison, an ASM-designated “Milestones in Microbiology Site”. Aligned with the tradition of past MGBP Meetings, ~70% of the oral presentations will be from postdoctoral scholars and graduate students, chosen from submitted abstracts based on scientific merit and diversity of their backgrounds. The remaining 30% of the presentations will be from faculty, including the keynote and session chairs, and junior faculty chosen from the submitted abstracts. Among the 9 invited talks for the 2024 meeting, 5 are female and 3 are scientists from historically marginalized people in STEM; 55% are Assistant or Associate Professors. The keynote speaker for the 2024 meeting will be Dr. George O’Toole, a long-standing member of the MGBP Community who is an active advocate for promoting equity in science. Dr. O’Toole will present his pioneering research on biofilms produced by the opportunistic human pathogen Pseudomonas. To promote diversity and inclusion, we propose to select 13 meritorious trainees from the submitted abstracts for registration waivers and provide childcare/ family care funding grants for trainees and faculty. Together, the rigor and inclusivity of the scientific program, the focus on increasing diversity and inclusion of trainees, and the opportunities for collegial interactions will positively impact the broad field of molecular biology of bacteria and their viruses.