University Of Illinois At Chicago

NIH Research Projects · FY 2025 · 2021-09

Project Summary The goal of this project is to develop a new tissue assay method that permits single-cell resolution pharmacokinetics (PK) and pharmacodynamics (PD) profiling of macromolecular drugs in the spatial context of the organ-specific tissue microenvironment in both healthy and diseased states. With the integrated 3D microscopy, we will 1) map blood vasculature and transvascular transport of macromolecular drugs; 2) image the distribution and interaction of macromolecular drugs with multiple cell types in the tissue microenvironment; 3) determine cellular responses to macromolecular drugs in sub-microenvironment regions at the molecular level. This high-resolution 3D multiplex microscopy method will advance “Spatial Pharmacology” in the pharmaceutical sciences by enabling the mapping of the transport, distribution, and biological actions of macromolecular drugs in tissue specimens at the tissue-wide, cellular and molecular levels. The maps will provide new insights into transvascular transport of macromolecular drugs, drug-cell interactions, and biological responses of various cells to drugs in different sub-microenvironment regions of an organ. The collection of the maps, The Atlas of Spatial Pharmacology, will be a solid standard reference in the research and preclinical development of macromolecular drugs.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY Asthma is a chronic inflammatory disease of the airways. Asthma prevalence has increased markedly in the United States, with 19 million adults reporting current asthma and 62% of them with uncontrolled asthma. Poor diet quality is an important risk factor implicated in this alarming trend as a typical western diet features processed, energy-dense, nutrient-deficient foods, promoting a proinflammatory host environment. Diet quality in asthma is an emerging area of research; few interventional trials have investigated healthy dietary patterns in adults with asthma, none was adequately powered to determine efficacy, and underlying mechanisms are poorly understood. OBJECTIVE: To fill this gap, the current 2-phase, milestone-driven ALOHA trial will rigorously evaluate the efficacy and mechanisms of a behavioral intervention promoting the Dietary Approaches to Stop Hypertension (DASH). This behavioral intervention showed promising results in a pilot trial among adults with uncontrolled asthma. METHODS: The R61 phase (1 year) will focus on finalizing trial planning and preparation and begin early enrollment; in the R33 phase (4 years) we will conduct a 2-arm randomized clinical trial over 12 months. Adults with uncontrolled asthma (n=320) on standard controller therapy will be equally randomized and assessed at baseline (0), 3, 6 and 12 months. The control and intervention groups will be matched on the number, frequency, and format of sessions over 12 months while the length of each session is proportional to the content delivered. Control participants will receive education on lung health, asthma, and other general health topics using American Lung Association and UpToDate materials. The intervention group will receive the same health education and materials in addition to DASH behavioral counseling. Central hypothesis: Compared with the education-only control, the DASH behavioral intervention will lead to significantly more participants with a clinically significant improvement (responders) in asthma-specific quality of life (primary outcome) and significantly greater improvements in related asthma and non-asthma outcomes, which will be mechanistically linked to improved diet quality. SPECIFIC AIMS: First, to determine intervention efficacy on the primary outcome of clinically significant improvement in asthma-specific quality of life at 12 months and secondary outcomes (asthma control, lung function, generic qualify of life, blood pressure, mental health, sleep health). Second, to examine the intervention effects on metabolomic (circulating short-chain fatty acids: propionate, butyrate, acetate), immune response (interferon-gamma, IL-5, IL-17A, IL-10, IL-1β, IL-6, IL-8, TNFα), and physiologic (bronchodilator responsiveness) biomarkers of asthma. Third, to examine the intervention effects on self- reported and objective indices of diet quality (DASH score, dietary inflammatory index, serum carotenoids). We also will conduct exploratory analyses of causal mediation linking diet quality, biomarkers, and asthma outcomes as well as effect modification by sex and other biological variables (age of asthma onset, atopy). IMPACT: This trial has high potential to advance the clinical and mechanistic understandings of diet quality in asthma.

NIH Research Projects · FY 2025 · 2021-09

RESEARCH SUMMARY/ABSTRACT OF PROGRAM The fundamental challenge in treating the hyper-inflammatory state underlying Acute Lung Injury/Acute Respiratory Distress Disorder (ALI/ARDS) is that broad anti-inflammatory interventions could compromise host defense and potentially exacerbate the underlying infectious process that triggered ALI/ARDS. Novel targeted approaches to treat ALI/ARDS thus require an in-depth understanding of the intricate inflammatory mechanisms to reduce the extent of injury and promote the resolution of inflammation as well as the initiation of lung repair without compromising host defense. It is now recognized that macrophages (Mφ) in lungs represent diverse multi-functional cell populations. They have the ability to sense pathogens and danger signals, and their plasticity and diversity allows them to respond in specialized manners to specific niche environments. They are able to change their phenotypes in a chameleon-like manner by activation of specialized transcriptional programs. Thus, they have the remarkable ability to amplify inflammation and also to coordinate resolution of lung inflammatory lung injury and restore homeostasis. Mφ carry out these functions through the release of an array of cytokines, phagocytosis of microbes, efferocytosis of dead cells, and provide the essential inflammatory or reparative signals to nearby cells. The central focus of this program will be to precisely define the roles of distinct macrophage subpopulations in inflammatory lung injury and signaling nodes to harness the plasticity of macrophages and thereby bring about the resolution of lung injury. Project 1 will test the hypothesis that two specific specific ion channels, P2RX7 (Purinergic Receptor 2 subtype X7) and the potassium (K+) efflux channel TWIK2 regulate the plasticity to either promote lung injury or to activate the repair program. Project 2 will test the hypothesis that the transcription factor CREB and its downstream targets are critical regulators of the anti- inflammatory and reparative function of alveolar Mφ. Project 3 will test the hypothesis that endothelial cells lining all lung vessels direct the plasticity of Mφ via modulation of Wnt signaling in Mφ. Project 4 will test the hypothesis that circulating postnatal CX3CR1+ monocytes replenish lung interstitial Mφ during inflammatory injury and can direct the lung tissue repair program. These four Projects are supported and complemented by highly innovative scientific Cores which will provide important optogenetic tools (Synthetic Biology and Optogenetics Core B), super-resolution and intravital imaging (Advanced Imaging Core C), and access to clinical samples as well as single cell transcriptomic analysis of macrophages (Clinical Sampling and Genomics Core D) to unravel the complexities of macrophage biology in lung injury, thus paving the way for much-needed novel therapeutic approaches in ALI/ARDS.

NIH Research Projects · FY 2024 · 2021-09

Project Summary Triple negative breast cancer (TNBC) makes up to 15-20% of breast cancer diagnoses. While surgery and adjuvant chemotherapy are effective treatment options for early-stage disease, there are very few therapeutic options for advanced metastatic TNBC, and the 11% relative five-year survival rate highlights an urgent need to discover actionable targets. In the hematogenous metastatic cascade, a few aggressive tumor cells are capable of crossing the endothelial barrier at least twice: when entering systemic circulation (intravasation) and then again when exiting circulation to colonize distant organs (extravasation). High expression of JAGGED-1 (JAG1), a Notch ligand, is strongly associated with TNBC metastasis and consequent mortality. Our preliminary work in static culture suggests that JAG1 enhances TNBC binding to the endothelium and transendothelial migration (TEM), thereby promoting dissemination of tumor cells through vascular beds. We propose to study two distinct mechanisms for JAG1 in the metastatic cascade. In Aim 1, we will investigate how tumor JAG1 signals in trans to the endothelium to prime the vascular barrier for invasion. We will examine extravasation of our recently generated TNBC CRISPR JAG1 knockout clones and control cells using a microfluidics system that faithfully models capillary fluid shear forces and permits visualization of multiple critical steps of extravasation in vitro. We will also test the role of JAG1 in vivo by examining the rate of lung capillary extravasation and pulmonary seeding following tail vein injection of JAG1 knockout and control TNBC cells. In Aim 2, we will define the tumor cell- intrinsic transcriptional program regulated by JAG1. Our preliminary RNA sequencing data suggest that novel JAG1 targets promote cell surface interactions distinct from Notch targets. We will determine the metastatic importance of key JAG1 targets by restoring expression and testing for TEM phenotypes. In the training plan of the fellowship, I highlight an integrated scientific, clinical, and educational blueprint to enhance my personal research and doctoring skills as an aspiring physician-scientist in oncology.

NIH Research Projects · FY 2024 · 2021-09

Project Summary. Vestibular afferent responses deviate from the coherent mechanical stimulation imparted by their overlying accessory structures. This implicates further processing by hair cells (HCs) and primary afferent conductances, and by afferent and efferent synapses. Processing is complicated by the parallel modes of transmission between HCs and afferents, and the convergence of multiple HCs onto single afferents. Type I HCs are enveloped by an afferent calyx, creating a restricted volume in the cleft between them. Type II HCs synapse onto the external face of a calyx and/or onto bouton endings via relatively small contact areas. This results in three types of HC-to-afferent convergence. In the simplest form, HCs converge onto an afferent solely at bouton endings. Increased complexity is found at calyces, including both simple calyces enveloping one HC and complex calyces encompassing two or more HCs. The highest complexity occurs at dimorphic endings that receive input from both HC types through a combination of bouton and both inner- and outer-face calyceal synapses. Prior studies have shown that for calyceal endings, rapid excitatory quantal transmission via glutamatergic AMPA receptors may be modulated by K+, H+, and Ca2+ accumulation. Dynamic changes in cleft ion concentrations occur in response to HC or afferent depolarization. These in turn impact responses in both the type I HCs and their afferents due to changes in the conductances and equilibrium potentials facing the cleft. As a result, properties of inner-face calyceal contacts differ significantly from those of HC and afferent conductances bathed in the bulk perilymph. For that reason, prior single-electrode biophysical experiments on HCs or their afferents in situ, or on isolated cells, have been unable to distinguish the contributions of HCs and afferents resulting from reciprocal interactions created by the unique volume of the synaptic cleft coupling the two. In this project, biophysical and morphological experiments will be performed on HC and afferent synaptic pairs in the posterior semicircular canal crista ampullaris of the red-eared turtle, T. scripta elegans, taking advantage of our unique ability to record simultaneously from both a HC and the afferent it contacts. This approach will be used to characterize the ionic environment of the synaptic cleft, the biophysical properties of HC and afferent conductances under conditions where the membrane potentials of a HC and its associated afferent are controlled simultaneously, and the structural elements responsible for these properties. The project has two major aims: (1) to contrast the biophysics and morphology of synaptic inputs from type I HCs onto the internal face of the calyx with those from type II HCs onto the calyceal external face and/or bouton endings of nearby branches, and examine their modulation by accumulation of ions and potential transmitters; and (2) to identify the mechanisms, modulators, sites of action and regional differences in nicotinic and muscarinic cholinergic efferent input to type I and II HCs and calyx afferents across the crista. Overall, this project will provide an integrated structural, functional biophysical characterization of peripheral vestibular signal processing.

NIH Research Projects · FY 2025 · 2021-09

Project Summary/ Abstract Background: Time restricted feeding (TRF) has greatly increased in popularity in recent years. TRF typically involves confining the eating window to 6-8 h, and fasting for the remaining hours of the day. During the eating window, individuals are not required to monitor energy intake. One of the reasons why TRF is so popular, is because it does not require individuals to count calories in order to lose weight. This feature of TRF may greatly improve long-term adherence to this diet, and in turn produce lasting weight control. Despite its growing popularity, only four human trials have examined the effect of TRF on body weight. While these preliminary studies show promise for TRF as a weight loss intervention, these previous trials are limited by short duration (2-4 months), lack of a control group, and no comparison to traditional dieting (daily calorie restriction; CR). We recently conducted a pilot study to compare the weight loss efficacy of 6-h TRF versus daily CR in adults with obesity and prediabetes. Our findings show that TRF produced greater adherence, energy restriction, and weight loss (-5%) versus CR (-3%) over 3 months. TRF also produced more pronounced reductions in insulin resistance, blood pressure, and oxidative stress, versus CR. What remains unknown, however, is whether these improvements by TRF would become more pronounced over longer periods of time (12-months), and if TRF can be implemented to help individuals maintain weight loss and sustain reductions in metabolic disease risk. The mechanisms (microbiome, appetite, gut peptides) that underlie the superior effects of TRF on body weight and adherence, also remain unknown. Methods: A 12-month randomized, controlled, parallel-arm trial, divided into: (1) 6-month weight loss period; and (2) 6-month maintenance period, will be implemented. Adults with obesity and prediabetes (n = 120) will be randomized to 1 of 3 groups: (1) 6h-TRF (n = 40) ad libitum food intake from 1-7 pm, fasting from 7-1pm daily, (2) CR (n = 40), 25% energy restriction daily; or 3) control (n = 40), ad libitum food intake daily. Hypotheses: The present proposal will test the following hypotheses: (Hyp1) The TRF group will be more adherent with the intervention versus CR, which will result in greater energy restriction, weight loss and weight loss maintenance; (Hyp2) The TRF group will experience greater improvements in insulin sensitivity (measured by clamp), plasma lipids, blood pressure, inflammation, and oxidative stress versus CR; (Hyp3) The TRF group will produce greater improvements in the composition, structure, and metabolic activity of the gut microbiota, as well as in appetite and gut peptides, vs CR, which will be related to superior adherence and weight loss. Significance: This study will be the first to show that TRF can be implemented as an alternative to traditional dieting (i.e. daily calorie restriction) for long-term weight management. This study will also show that TRF can be used as an effective non-pharmacological therapy to improve insulin sensitivity and decrease metabolic disease risk in individuals with prediabetes and obesity. The mechanisms (gut microbiome and appetite) that underlie the beneficial effects of TRF will also be elucidated.

NIH Research Projects · FY 2024 · 2021-09

Mild cognitive impairment (MCI) occurs along a continuum from normal cognition to dementia and affects nearly a quarter of individuals 70-79 years old, with the prevalence drastically increasing each decade after. Although most older adults with MCI (OAwMCI) are independent in their daily living, they are known to have significantly greater likelihood of falls compared to their cognitively intact counterparts. In addition to cognitive deficits, persons with MCI can experience motor dysfunction, including deficits in gait and balance. While changes in stance posture control and gait functionality have been thoroughly investigated in this population, reactive balance control and protective stepping responses that are recruited to recover from unpredictable, larger external perturbations have not yet been extensively examined. Additionally, though OAwMCI show slower adaptation and motor learning in comparison to their healthy counterparts, it remains to be unknown whether OAwMCI can adapt to task-specific training via repeated exposure to unpredicted perturbations as healthy older adults (OA) do. Furthermore, it is well established that OAwMCI have worse dual-task performance during both stance and gait. This presentation is related to impaired executive function, visuomotor function and spatial awareness. However, dual-task performance during perturbed stance and gait in association with increased fall-risk has not yet been investigated in OAwMCI. In addition, it is well-established that higher cortical centers play a vital role in modulation of reactive balance control. Interestingly, in OAwMCI, the decline in volitional balance control under sensory and cognitive challenges is corelated to an increased resting state activation of the default mode network, reduced white matter integrity and reduced gray matter volume. However, there is limited evidence examining the association between impaired structural integrity and neural correlates with reactive balance control measures and resulting higher occurrence of falls in this population. Our previous research has shown that two key variables, reactive control of stability and vertical limb support, contribute to more than 90% of laboratory slip-falls in OA. Thus, improving these key variables can contribute to significant reduction in fall risk in OA. However, such task-specific intervention-based studies are lacking in the MCI population. To fill the gap in the literature, our study proposes to investigate the differences in neuromechanics of reactive stepping responses to externally-induced balance perturbations in OAwMCI compared to OA. Further, our study proposes to relate reactive stability control to changes in brain structural and functional connectivity. Lastly, our study proposes to determine the effect of a novel task- specific perturbation-based cognitive-motor intervention for enhancing fall-resisting skills in OAwMCI.

NIH Research Projects · FY 2024 · 2021-09

Abstract The lung alveolar epithelium is exposed to the environment and pathogens and is thus highly susceptible to injury. Repair of the alveolar epithelium requires the activation of alveolar epithelial stem cells by signals from their surrounding niche. Significantly, the role of lung microvascular endothelial cells (LMVECs) in mediating this repair is poorly understood. In this proposal we address this gap in knowledge by focusing on a novel mechanism of bioactive lipid mediated interaction between lung microvascular endothelial cells (LMVEC) and alveoli epithelial cells (AEC) in the reparative niche. LMVECs account for >40% of total lung cells. They are juxtaposed to AECs (both alveolar type I cells (AT1) and type II cells (AT2)) and play essential roles in regulating their repair, although the underlining mechanisms remain unclear. AT1s have a thin and extended squamous shape, occupy > 95% of the alveoli surface area and mediate O2–CO2 exchange. AT2 occupy only 5% of the surface area, but play multiples roles, including producing surfactant and, importantly, acting as adult tissue stem cells to repair injured alveoli. Studies, including ours, have shown that while AT2s are normally quiescent, they can respond to signals released by surrounding niches and initiate a repair program by differentiating into AT1. However, the signals that regulate AT2 stem cell function(s) remain unclear. Recent studies suggest that AT1 also exhibit a certain degree of plasticity, but it is almost completely unknown whether and how AT1s participate in lung repair after injury. In preliminary studies, we generated a mouse model with endothelial cell (EC)-specific deletion of sphingosine kinase 1 (Sphk1), the enzyme responsible for spinhgosine-1-phosphate (S1P) production. These mutant mice manifest a significantly defective repair of AECs in the standardized Pseudomonas aeruginosa bacterial lung injury model. We further showed that S1P functions through its receptor S1PR2 expressed in AT2, leading to nuclear translocation of the transcriptional regulator Yes-Associated Protein (YAP), which mediates the differentiation of AT2 to AT1 and repair of injured alveoli. Furthermore, we observed that in response to S1P, AT1s undergo substantive alteration which likely contribute to the repair process. These fundamental observations led to our central hypothesis: that LMVECs constitute a niche that, when activated by alveolar injury, releases the bioactive lipid factor, S1P, which acts via S1PRs on both AT2 and AT1 to promote their reparative capacity required for the restoration of alveolar epithelium. To test this hypothesis, we propose three specific aims: Aim 1: To determine S1P-mediated interactions between the EC niche and AEC required for lung repair. Aim2: To define the functional significance of S1P-S1PR2-YAP signaling axis in regulating AT2 to AT1 transition and mediating alveolar repair. Aim 3: To test the hypothesis that S1P induces AT1 alteration leading to alveolar repair. This research program will throw new light on the fundamental mechanisms driving lung repair after injury, with the long term potential for innovative therapeutic approaches.

NIH Research Projects · FY 2025 · 2021-09

ABSTRACT. Approximately 42% of the U.S. adult population is obese and data suggests that persons with obesity are at a 30% greater risk of developing colorectal cancer (CRC). Therefore, efficacious approaches to preventing and treating obesity will have significant effects on CRC incidence in the U.S. Although calorie restriction through lifestyle intervention is the most common approach to treat obesity, clinically meaningful weight loss is difficult to achieve via this method due to low adherence with calorie monitoring, indicating a need for innovation. Time-restricted eating, a type of intermittent fasting, has been shown in animals to impart cancer protective effects including lower body weight, decreased systemic inflammation, and improved glucose metabolism. Time-restricted eating is where individuals are asked to consume all their food for the day within a specified time frame, and water fast for the remaining hours of the day. We recently performed two short-term (≤12-weeks) pilot studies of time-restricted eating to evaluate its safety and preliminary efficacy on body weight and chronic disease risk markers in adults with obesity. Our results show the intervention is a safe and acceptable approach to weight loss among obese adults. Moreover, time-restricted eating produced approximately 3% weight loss from baseline and reductions in systolic blood pressure, oxidative stress and insulin resistance. Although these pilot findings show promise for time-restricted eating as an effective tool for CRC risk reduction among obese individuals, these data still require confirmation by a well powered longer-term clinical trial. The present proposal aims to implement a 12-month (6-month active weight loss phase, 6-month maintenance phase), controlled, parallel arm trial among 255 obese adults (45-65 years old) who are at elevated CRC risk. Subjects will be randomized to 1 of 3 groups: 1) Time-restricted eating (weight loss phase: daily ad libitum food intake from 11am – 7pm), 2) Calorie restriction (weight loss phase: daily 25% calorie restriction), or 3) Control (daily ad libitum food intake, no meal timing restrictions) to compare the effects on: (1) Body weight, body composition, and intervention adherence; (2) Circulating metabolic, inflammation, and oxidative stress- related biomarkers; (3) Colonic mucosal gene expression profiles and mucosal inflammation, DNA damage and cellular growth; and (4) maintenance of benefits on body weight/composition and systemic/mucosal CRC risk markers. This proposal will be led by a transdisciplinary team with expertise in nutrition science, time-restricted eating, behavioral science, molecular markers of cancer, gastroenterology, and biostatistics. If the aims of this proposal are achieved, it will show for the first time that time-restricted eating can be implemented as a novel alternative to traditional dieting (i.e., daily calorie restriction) for weight control and CRC risk reduction in adults with obesity. The proposed study will also be the first and most comprehensive examination of molecular mechanisms that mediate the anticancer effects of time-restricted eating and calorie restriction.

NIH Research Projects · FY 2025 · 2021-09

ABSTRACT The UIC Center for Healthy Work’s (CHW) aims to identify and promote employment programs, practices, and policies that will improve worker and community health. Our vision is a future of work that promotes inclusive and equitable opportunities for healthy work, and healthy work is recognized as a social and structural determinant of health and a human right, a pathway to advancing systemic change and racial justice, and a significant contributor to workforce well-being. Historical and systemic racism and injustices have led to inequitable job opportunities and job quality for women, Black, Indigenous, People of Color (BIPOC), and immigrants who are disproportionately employed in precarious jobs. The CHW aims to address these inequities through racial justice–centered policy, systems and environmental (PSE) change initiatives to support communities and institutions to build and sustain healthy work. The CHW specific aims are: 1) Conduct research to produce evidence gathered through transdisciplinary and participatory, applied, and racial justice– centered research to explore work as a social and structural determinant of health and identify actions to promote healthy work; 2) Build and strengthen multidirectional collaboration and engagement across eco-social levels to create networks that support healthy work; 3) Develop and expand the reach of PSE change initiatives to build capacity to address precarious work across eco-social levels and geographical locations; and 4) Translate and disseminate evidence to promote policies and practices that support healthy work and worker well-being for all workers, within and outside the workplaces. The CHW includes 1) a Research Core that designs and conducts participatory action research involving multi-disciplinary teams of investigators in collaboration with community and organizational partners, 2) an Outreach Core which aims to facilitate a strategic research translation agenda; to strengthen and expand networks of stakeholders, and to widely disseminate Total Worker Health best-practices through multi-directional partner engagement and capacity- building, and 3) a Planning and Evaluation Core which will provide leadership for the CHW, guided by an internal advisory board and an External Advisory Committee. The CHW addresses precarious employment across all economic sectors and supports the objectives of the Healthy Work Design and Well-Being cross- sector council and advances Strategic Goal 7 in the NIOSH Priority Goals for Extramural Research. Our research core uses Participatory Action Research (PAR) approaches where researchers and partners work together to understand and address a complex topic and focus on social or policy change. This approach is consistent with and advances the goals of r2p.

NIH Research Projects · FY 2025 · 2021-09

Cognitive impairment is prevalent, disabling, and poorly-managed among the 1 million Americans living with multiple sclerosis (MS). Indeed, 67% of adults with MS demonstrate cognitive impairment, particularly slowed cognitive processing speed (CPS), and this is associated with worse fatigue, depression, anxiety, and quality of life (QOL). This underscores the importance of identifying efficacious approaches for managing CPS impairment and its consequences among those with MS. There is merit in a remotely-delivered physical activity (PA) intervention for managing MS-related CPS dysfunction in MS. We have provided evidence from a pilot, randomized controlled trial (RCT) that an Internet-delivered PA intervention resulted in a clinically meaningful improvement in CPS among those with mild MS-related ambulatory disability; there were additional improvements in fatigue, depression, anxiety, and QOL. Importantly, the pilot RCT did not a priori recruit persons with MS who had objective CPS impairment nor examine sustainability of CPS changes over time, and it further involved a waitlist control that did not account for the effects of attention and social contact. We leverage our experiences and preliminary results, and propose an appropriately-powered, Phase-II, RCT of a highly-developed and refined Internet-delivered PA intervention for yielding immediate and sustained improvements in remotely-assessed CPS among persons with mild MS-related ambulatory disability who demonstrate impaired CPS. The proposed study, if successful, will provide Class I evidence regarding the efficacy of a 6-month, Internet-delivered, PA intervention compared with an active control condition for improving important outcomes in 280 adults with MS who present with both mild MS ambulatory disability and impaired CPS. The primary outcome is the remotely-delivered Symbol Digit Modalities Test as a measure of CPS; the secondary outcomes are self-report measures of fatigue, depression, anxiety, and QOL; the tertiary outcome is accelerometry as a device-based measure of PA. The conditions will be delivered by persons who are uninvolved in screening, recruitment, random assignment, and outcome assessment. We will collect outcome data on 3 occasions over a 12-month period (i.e., pre-intervention, immediately post-intervention, and 6-month follow-up). The outcome data will be collected using a blinded assessor. Data analyses will involve intent-to-treat principles, and mixed-effects models and logistic regression. The proposed research may yield “real-world” guidelines for free-living PA change that can be implemented for the treatment of CPS impairment in MS. Such an opportunity for rehabilitation of cognitive function using an approach with broad reach and scalability is paramount considering the prevalent, disabling, and poorly-managed nature of CPS impairment in MS and limited resources for its treatment. The proposed research is further consistent with the National Center for Medical Rehabilitation Research’s mission of fostering the development of scientific knowledge for enhancing the health, productivity, independence, and QOL.

NIH Research Projects · FY 2025 · 2021-08

Pulmonary arterial hypertension (PAH) is a life-threatening disease with no cure characterized by severe lesions in the pulmonary vessels due to hyperproliferation of vascular cells, including endothelial cells. The primary cause of these lesions is largely unknown, but several studies indicate they result from chronic inflammation, such as that caused by Schistosoma mansoni infection. ~10 million people infected with S. mansoni develop PAH (Sch-PAH). Thus, a better understanding of how the infection promotes the formation of vascular lesions will provide insights for identifying novel molecular targets for PAH treatment. Recently, we reported that endothelial cells that survive chronic lung injury show reduced expression of the anti-proliferative scaffolding protein caveolin-1 (Cav-1) and elevated response to pro-fibrotic TGF-β signaling. Activation of TGF-β requires recruitment of Th2 cells into the lungs, which in turn expands Cav-1-depleted endothelial cells and promotes PAH. Although it is unknown how Cav-1-depleted endothelial cells contribute to Sch-PAH, our preliminary data indicate enhanced expression of inhibitor of apoptosis protein 2 (c-IAP2) may participate in this process. In line with this observation, data suggest that S. mansoni-primed endothelial cells retain in vitro a memory of the in vivo infection. Specifically, this memory is characterized by impaired function of the death-associated receptor P2X7, which is controlled by Cav-1 expression. Thus, I hypothesize that while S. mansoni infection leads to lung endothelial cell death and secretion of c-IAP2, recipient cells generate a long-lasting survival memory required for endothelial-immune cell crosstalk and the development of Sch-PAH.

NIH Research Projects · FY 2025 · 2021-08

Maternal hyperglycemia including Gestational Diabetes Mellitus (GDM) disproportionately affects 5-11% of African American Pregnant Women (AAPW). GDM and even nondiabetic hyperglycemia are linked to pre-eclampsia, primary cesarean section, macrosomia, birth trauma in the short-term, and increased risks of obesity, Type 2 diabetes and cardiovascular disease in mothers and offspring in the long-term. National medical costs of GDM even for short-term consequences are high at $1.8 billion yearly. Overweight/obese AAPW have the highest increased risk of GDM, GDM recurrence and nondiabetic hyperglycemia of any race. Sleep differences also exist. AAPW have shorter sleep, worse sleep continuity and quality than White women. We and others have shown short sleep duration, poor sleep quality and later sleep timing are associated with increased GDM risk. Sleep disturbances, ubiquitous in pregnancy, may represent MODIFIABLE risk factors for maternal hyperglycemia. While cognitive/behavioral methods have yielded robust improvement in sleep duration and quality in general population, we are the only group to test the effects of a nonpharmacologic sleep intervention to improve maternal glucose metabolism in AAPW. Our preliminary work suggests that sleep B.E.T.T.E.R. addressing 6 principles of wake-sleep hygiene (Bedroom, Exercise, Tension, Time in bed, Eating, and Rhythm), targeting 24-hr behaviors and multiple lifestyle components can successfully improve sleep in pregnant women. The purpose of this randomized controlled trial is to establish the effectiveness of our culturally targeted and individually tailored BETTER intervention to promote maternal glucose metabolism in AAPW. We will enroll 150 overweight/obese nulliparous AAPW aged 18-40. They will be randomized (75 per group) to: 1) sleep BETTER or 2) attention control (Birth-Prep). Data will be collected at 16-20 (baseline), 28-30 (primary endpoint) and 34-36 (durability period) gestational weeks (GWs) using valid and reliable instruments monitoring sleep in free-living conditions with state-of-the-art methods assessing glucose levels and insulin sensitivity. Our specific aims are to test the hypotheses that: (1) BETTER will improve glucose tolerance (fasting glucose-primary outcome), insulin sensitivity from baseline to 28-30 GWs and glycemic control from baseline to 34-36 GWs; (2) BETTER will result in greater sleep duration, better sleep quality, and earlier sleep timing compared to the Birth-Prep intervention from baseline to 34-36 GWs. Our exploratory aim (3) is to determine the extent to which other factors represent key effect modifiers including economic hardships, psychosocial stress and unfair treatment for the intervention. The long-term goals of our research are 1) to develop a cost-effective sleep intervention that can be easily implemented in prenatal care from hospital- or community-based clinics, and 2) to integrate sleep hygiene principles in mainstream prenatal education to improve maternal glucose metabolism in low income African American women. This can contribute to better health outcomes in mothers, their offspring and next generations. This supports NIMHD’s mission of improving minority health and eliminating health differences.

NIH Research Projects · FY 2024 · 2021-08

Abstract Pregnant women are more likely to be infected with the intracellular pathogen Listeria monocytogenes (Lm) than the general population, and the bacterium can be vertically transmitted leading to fetal infection and pregnancy loss. Despite its public/health/relevance, the determinants of maternofetal transmission remain undefined. Examination of clinical Lm isolates indicates that subpopulations of strains possess an enhanced ability for vertical transmission. One of these strains, 07PF0776, was first noted for its ability to target the heart, and this cardiotropism requires InlB, a bacterial surface protein known to be important for the invasion of mammalian cells. Experimental evidence indicates that InlB is similarly required for vertical transmission and that high InlB expression alone is sufficient to significantly enhance vertical transmission in an unrelated strain. The goal for this project is to elucidate the mechanisms by which InlB enhances the vertical transmission of hypervirulent Lm strains and of Lm generally. The project aims are designed to connect strain-specific genetic variations to altered bacterial behavior, host pathology, and immune responses. The current working hypothesis is that enhanced translation of inlB occurs in Lm hypervirulent subpopulations as the result of a trinucleotide substitution in the 5’ untranslated region (UTR) of the inlB transcript that promotes ribosome binding. It is also hypothesized that amino acid variations within InlB enhance InlB binding to the bacterial cell wall and thus increase InlB surface abundance. Aim 1 will determine how InlB levels are altered in 07PF0776 by looking at InlB synthesis, degradation, and cell wall affinity. This aim will also explore how the 5’ UTR contributes to increased protein expression. Aim 2 will determine how increased InlB expression promotes bacterial colonization of the placenta and fetus. Experiments will use pregnant mice as a model and compare strains with varying levels of InlB activity. Fluorescence microscopy combined with immuno-histochemistry will determine if InlB-high-expressing strains have enhanced invasion of specific placental cell types, or alternatively gain access through new portals of entry. RNAScope in situ hybridization and flow cytometry will establish how bacterial localization impacts the nature of the placental immune response. The ultimate goal of the above aims will be to establish the mechanisms by which strains of Lm cause severe fetal and neonatal disease. These studies may eventually allow for improved treatment of severe Lm infection and more effective strategies to protect pregnant women from Lm-induced pregnancy complications.

NIH Research Projects · FY 2025 · 2021-08

Experiments proposed here offer key training and significant elements in a path toward Dr. Paola Rosas’ career goals with focus on the understanding of the relations among gender, obesity and heart failure with preserved ejection fraction (HFpEF, EF>50%). HFpEF is more frequently seen in postmenopausal women (2:1) vs men and in obese patients. Moreover, obesity and extreme obesity are higher in women than men. However, the cause of these differences are unclear. Proposed studies build on preliminary evidence of localization of p21-activated kinase 1 (PAK1) in adipose tissue and its involvement in female fat accumulation that accentuates with aging. Aged female global PAK1 knock-out (PAK1-/-) mice exhibit significantly increased visceral adiposity, similar to post-menopausal women. Furthermore, with aging, unlike male PAK1-/- mice, female PAK1-/- mice show diastolic dysfunction. PAK1 is a pleiotropic serine/threonine protein kinase demonstrated to be cardio-protective against different stressors. There is evidence, in other organs, that PAK1 is involved in estrogen signaling pathways; however, these processes have not yet been studied in the heart or in the adipose tissue. These discoveries led to the hypothesis that PAK1 is regulated by estrogens, and that dysregulation of PAK1 due to lack of estrogens, contributes to obesity and HFpEF. With these findings in mind, I propose the following aims. Aim #1: Investigate the mechanisms by which estrogens regulate PAK1 in the heart and the adipose tissue. I will study how PAK1 is activated by estrogens in the heart and the adipose tissue and how this activation involves estrogen receptor α (ERα) and/or G protein-coupled estrogen receptor (GPER). Aim #2: Investigate the mechanisms by which PAK1 regulates cardiac function in female mice. I will study how the absence of PAK1 in a PAK1-cardiac specific knock-out mouse model, affects intracellular Ca2+ kinetics and the response of myofilaments to Ca2+, thereby affecting cardiac relaxation. Aim #3: Investigate the mechanisms by which PAK1 regulates adipose tissue homeostasis in female mice and the effect of its dysregulation on cardiac function. I will examine how lack of PAK1 in adipose tissue promotes increased visceral adiposity leading to obesity which subsequently affects diastolic function in the female heart. Impact: Addressing these aims will significantly advance our understanding of the role of PAK1 on the regulation of cardiac and adipose tissue function in females, by exploring the relation between estrogens and PAK1 signaling in the heart and the adipose tissue. Furthermore, these contributions will explain, at least in part, the higher incidence of HFpEF and obesity in post-menopausal women. Results are expected to bring novel alternatives and open new horizons in the treatment of HFpEF and obesity in women. This research will also form the basis for Dr. Rosas’ first R01 application to conduct further studies on the role of PAK1 as an anti-obesity kinase and as a metabolic regulator in women.

NIH Research Projects · FY 2024 · 2021-08

Nearly 400 million people are infected with dengue virus (DENV) each year through the bite of infected mosquitos concentrated in the tropical and subtropical regions of the world. Symptoms can range from febrile illness to severe dengue that manifests as plasma leakage, sudden loss of blood pressure, organ failure, and shock that can ultimately lead to death. Severe dengue complications are often associated with a secondary heterotypic infection of one of the four circulating serotypes. In this scenario, humoral immune responses targeting cross- reactive, poorly-neutralizing epitopes lead to increased infectivity of susceptible cells via antibody-dependent enhancement (ADE). Additionally, DENV immunity has been implicated in increased susceptibility to Zika virus through ADE. Currently there are no available therapeutics to combat DENV disease. Dengvaxia, the only licensed DENV vaccine, was found to increase hospitalization rates in naïve populations, and thus is not recommended for a large portion of at-risk individuals. There is an urgent need for a safe and efficacious vaccine that elicits a robust, balanced, neutralizing response to all four DENV serotypes. We propose to develop a novel DENV vaccine utilizing an emergent platform: mRNA encoding for viral proteins encapsidated in a lipid nanoparticle (LNP). mRNA-LNP vaccines elicit robust humoral and cell-mediated immune responses in a safe, non-infectious platform. Additionally, we can direct the host immune response towards neutralizing epitopes by mutating the mRNA encoding for the viral protein. We hypothesize that a sequence-engineered tetravalent mRNA-LNP vaccine will induce a balanced, protective immune response against all four serotypes of dengue without the potential of causing immune enhancement and ADE. In Aim 1 of this study we will generate and optimize mRNA constructs encoding for the pre-membrane and envelope viral glycoproteins for all four serotypes of DENV. We will mutate the poorly-neutralizing, cross-reactive epitopes that drive ADE. In Aim 2 we will characterize the immune response to the vaccines in a mouse model. In addition to quantifying humoral and cellular immune responses, we will also measure the immune enhancement capacity of all vaccines. In Aim 3, we will evaluate vaccine efficacy and safety in susceptible mouse models, by challenging vaccinated mice with different DENV serotypes to monitor protection and ADE. We will also determine mechanism of protection via adoptive transfer experiments. Through this study, we will identify DENV vaccines that demonstrate broad protection and lack of immune enhancement for further evaluation as candidate human vaccines.

NIH Research Projects · FY 2025 · 2021-08

ABSTRACT Latina adolescents in the U.S. are disproportionately affected by HIV/AIDS/sexually-transmitted infections (STIs) and other adverse consequences of risky sexual behavior. The home environment is recognized to shape adolescents' health outcomes, but only one Latina mother-daughter sexual health program was identified in the literature. IMARA (Informed, Motivated, Aware, and Responsible Adolescents and Adults) is an evidence-based intervention for African American adolescent girls and their mothers, which is well-suited to be adapted for Latinas. In a randomized controlled trial (RCT) in Chicago, the program reduced the risk of new STIs by 45% compared to the control group among 14-18-year-olds. In this K99/R00 award, I propose to adapt IMARA to a Latina audience and pilot an optimization trial within community-based organizations (CBOs) in Chicago, using the multiphase optimization strategy (MOST). MOST is a methodological framework for developing an optimal intervention package by assessing the effectiveness of an intervention's components prior to subjecting the intervention to an RCT. This grant focuses on the preparation phase of MOST, using an implementation science (IS) approach and drawing on community-based participatory research (CBPR) principles to pursue three specific aims: 1) adapt the intervention for Latinas by establishing a community advisory board and engaging 12 mother-daughter dyads in 4 focus group discussions (K99 phase); 2) establish the acceptability, feasibility, and appropriateness of the intervention components through piloting among 24 new dyads (K99 phase); and 3) pilot an optimization trial of the adapted intervention among 92 new dyads and examine intervention component effects on risky sexual behavior (primary outcome) and STI incidence (secondary outcome) (R00 phase). These research aims will allow me to build on my strong research and publishing experience in adolescent health and capitalize on the expertise of my mentorship team in sexual risk interventions for youth to achieve four training aims, to: 1) gain knowledge in CBPR principles and their application; 2) develop expertise in IS theory/design and its application; 3) learn to employ innovative research designs, analysis strategies, and frameworks for behavioral interventions, including MOST; and 4) further my professional development to obtain a tenure-track faculty position prior to the R00 phase. I will accomplish my training aims through meetings, directed readings, and conference/workshop attendance, with support from my mentors (Primary Mentor: Geri Donenberg). Findings will form the basis of an R01 application for a fully-powered optimization trial to test intervention component impacts on STI incidence among Latina adolescents. The long-term goal is to generate an efficient, sustainable adapted intervention with potential for scale-up with CBOs serving Latinas. This K99/R00 award will give me a platform on which to launch my career as an independent adolescent health researcher, specialized in innovative methods for developing, implementing, and evaluating behavioral interventions.

NIH Research Projects · FY 2025 · 2021-08

PROJECT SUMMARY/ABSTRACT The malaria parasite is one of the most deadly eukaryotic pathogens and more than 40% of the world's population is at risk of contracting malaria. Due to growing resistance to currently available medications, there is a pressing medical need for new drugs to prevent and treat malaria infection. This grant application focuses on the optimization of two novel antimalarials (2a and (R)-3a) to target multiple life stages of the parasite that emerged from our previous work on the Malaria Box compound MMV008138 that targets the apicoplast. These compounds were identified using a combination of atomic property field-based virtual ligand screening (VLS) of a library of 5 million publicly available compounds and synthetic chemistry campaigns. Although 2a and (R)-3a bear a structural resemblance to MMV008138 and kill asexual blood-stages, their mechanism of action is independent of the apicoplast. In addition, whereas MMV008138 only affects asexual blood-stages, 2a also kills Stage V gametocytes, and (R)-3a weakly kills Plasmodium berghei liver-stages. For each of the two novel compound series, we will explore: i) structure activity relationships that control potency, cellular selectivity, and efficacy; ii) structure property relationships that govern adsorption, distribution, metabolism, and excretion; and iii) their potential mechanisms of action and resistance. The overarching goal of this project is to prioritize preclinical leads having novel mechanism of action, high selectivity for Plasmodium versus the human host, and physiochemical properties that are compatible with development of an orally available drug candidate. The two principal goals of this R01 proposal are to: 1) structurally modify 2a (lead) and (R)-3a (hit) to optimize in vitro asexual blood-stage potencies in addition to gametocicydal and/or liver stage activities, drug-like properties, and pharmacokinetics, achieving in vivo P. berghei-infected mice efficacy with a single oral dose ED90 ≤ 10 mg/kg for the 2a analogs (late lead) and an ED90 ≤ 40 mg/kg/day with 1-3 oral doses for the (R)-3a series (early lead), and 2) identify the antimalarial mechanisms of action and resistance of 2a and (R)-3a (or their more potent analogs) by chemoproteomic and resistance-selection approaches, respectively. The ancillary goal of this proposal is to develop structure-activity relationships (SAR) for the P. falciparum gametocytocidal potency and P. berghei liver-stage potency of these two series, and to determine consensus pharmacophores for multi-stage activities (asexual blood-stage potencies plus gametocytocidal and/or liver-stage potencies). Efficacious compounds identified in this way will thus be well-positioned for further preclinical development.

NIH Research Projects · FY 2025 · 2021-08

Enter the text here that is the new abstract information for your application. The mission of the proposed program is to develop a lasting, robust institutional training program for highly talented students to pursue careers in biomedical research. Our program builds on the existing partnership between Malcolm X College (MXC), a community college in Chicago IL, and University of Illinois Chicago (UIC), the largest, public, Research I University in the region. The program is built upon the idea that a training program, if it is to be successful in serving associated students, must also change the students’ undergraduate experience, the faculty, and the institutions involved. Hence, we have three specific aims: (1) recruiting and supporting trainees, (2) engaging in faculty development to enhance student success in biomedical careers, and (3) institutional transformation at multiple levels. Weaving through these three aims is a consistent focus on how people are impacted by health, with particular attention paid to cancer research, but also incorporating methodology and themes applicable to a variety of STEM-related fields. Activities associated with Aim 1 include completion of introductory science courses at MXC, engagement with admission transfer advisors before and after transfer to UIC, participation in UIC workshops on research methods ethics, and nature of science, participation in summer research experiences with UIC mentors, and presentation of results at local and national conferences. Activities associated with Aim 2 include focus on cancer research in introductory courses and structured research experiences for students, and participation in annual mentoring workshops and expanding initiatives that address cancer biology in a laboratory setting. Finally, activities associated with Aim 3 include development of research career advising at MXC, advising about the B2B training program and biomedical research opportunities, and monitoring progress of our program. We hypothesize that a program focused on questions of health can support trainees in their development as biomedical researchers, change how instructors and mentors approach the teaching and training in science, and develop robust activities at the institutional level that can make research, health care, and education more effective.

NIH Research Projects · FY 2025 · 2021-08

Project Summary / Abstract The main pathological changes found in patients with Alzheimer’s disease (AD) are extracellular amyloid β (Aβ) deposits in the brain parenchyma (amyloid plaques) and abnormal aggregates of hyperphosphorylated tau protein in brain neurons (neurofibrillary tangles, NFTs). Amyloid plaques and NFTs are accompanied with chronic inflammation characterized by activated microglia and increased levels of cytokines. Except a small subset of early-onset familial AD cases, the causes for the vast majority of AD cases are unknown and satisfactory therapeutic and preventive measures for AD are unavailable. Therefore, an urgent need exists to identify the molecular mechanisms that increase the risk for the vast majority of AD cases and to develop the preventive and therapeutic measures. Systemic inflammation promotes AD progression and even initiates microglial activation and neurodegeneration. Indeed, recent genetic studies on late-onset AD have identified about a dozen genetic risk variants that are highly expressed in microglia and involved in innate immune responses, highlighting the importance of immune responses, particularly activated microglia, in the pathogenesis of late-onset AD. Aging is the largest known risk factor for AD and is characterized by chronic, systemic inflammation (inflamm-aging). Systemic inflammation caused by certain bacterial and viral infections is a strong risk factor of dementia, also. Additionally, our preliminary data indicate that activation of NLRP3 inflammasome through the MyD88 signaling pathway in microglia in the central nervous system (CNS) plays essential roles in the AD pathogenesis. In Aim 1, we will produce a microglia specific MyD88 deficiency in AD mouse models during aging and determine their effect on Aβ and tau pathology and cognitive function. We further hypothesize that microglial MyD88 signaling plays a predominant role in accelerating brain Aβ and tau pathology and neuroinflammation, which are induced by chronic, systemic inflammation, in AD mouse models during aging. In Aim 2, we will determine the effects of systemic LPS treatment on Aβ and tau pathology and cognition in AD mouse models with brain and peripheral immune cell-specific MyD88 deficiency. In Aim 3, we will determine the age and sex dependent effects of LPS treatment on NLRP3 inflammasome activation as disease mechanisms in the brain/microglia-specific and peripheral immune cell-specific MyD88 deficient AD mouse models. Our hypothesis is that LPS-induced systemic inflammation causes NLRP3 inflammasome activation in microglia via MyD88 signaling, leading to exacerbation of AD-like pathophysiology in AD mouse models. The long term goals are to determine the role of microglial MyD88/NLRP3 inflammasome signaling in the AD pathogenesis, to elucidate the molecular mechanism underlying the increased AD risk associated with systemic inflammation and to develop new preventive and therapeutic strategies for AD.

NIH Research Projects · FY 2024 · 2021-08

ABSTRACT The core pillars of academic medicine that serve as the foundation for the training and development of the clinical workforce are widely recognized to be education, research and exceptional patient care. Physician-investigators represent the lifeblood of academic medicine and recent declines in the numbers of this group represent nothing less than an existential threat to academic medicine as it is currently known. Our commitment to work to reverse these trends serves as the basis now for our Stimulating Access to Research in Residency (StARR) program proposal. The University of Illinois at Chicago (UIC) Department of Medicine (DOM) has a vibrant clinical program that provides excellent healthcare services to an inner city population of predominantly African-Americans and Hispanic/Latinx patients, in the third largest metropolitan area in the middle of our nation. Our physicians provide care for patients at the UIC Hospital and Clinics (UI Health) and the Jesse Brown Veterans Affairs Medical Center. Stimulated by the opportunities and scientific questions that are presented by this large and unique patient base and active collaborations with outstanding basic science departments at UIC, the entire research portfolio at UIC has been rapidly expanding. At the same time, our internal medicine residency program has been committed to recruiting physicians in training, from diverse backgrounds and life experiences, who are dedicated to our mission. Core to this mission are our ongoing efforts to assume a leading role nationally in the training, growth and development of the next generation of clinician investigators. Notably, the UIC DOM is primely positioned to support this program by virtue of its highly accomplished prospective faculty mentors from across a broad range of research disciplines, a well-established pre-existing commitment to promoting scholarly activities including research amongst trainees and faculty, opportunities to synergize with three existing NHLBI- sponsored T32 training grants within the department, and an internal medicine residency program with core structural components already in place to promote resident research opportunities and career development. Additionally, a key element of our proposal is a commitment to the recruitment of a diverse group of resident- investigators including underrepresented minorities (URM). It is important to note that the UIC StARR program will build on already existing programs and infrastructure with closely aligned goals and objectives. Our program also has the full and unwavering support of the UIC College of Medicine and its leadership.

NIH Research Projects · FY 2025 · 2021-07

SUMMARY Caries prevalence, morbidity, and associated disparities in children have been well documented nationally and locally. Research now is trying to understand why these disparities persist. Caries risk for an individual is considered a combination of genetics and behaviors (diet, oral hygiene, and fluoride exposure). The Coordinated Oral Health Promotion (CO-OP) Chicago Cohort Study will use the social ecological theory lens to examine caries risk factors on multiple levels. CO-OP Chicago was previously funded by NIDCR to reduce oral health disparities in children. The original CO-OP Chicago study [UH2DE02583] established baseline estimates of tooth brushing behaviors and determined the feasibility of objective assessment of tooth brushing behaviors in the homes of high-risk children under the age of three years old. CO-OP Chicago [UH3DE025483] then recruited 420 child/caregiver dyads to participate in a two-arm, cluster-randomized controlled trial testing the effectiveness of a family-focused CHW oral health intervention to improve tooth brushing behaviors for young children. The primary outcome was caregiver-reported brushing frequency and observed plaque score at 12-months. At entry into the study, the mean child age was 21.5 months. Forty-two percent of participants described themselves as Black race, and 54% as Hispanic ethnicity. Most children (89%) had Medicaid health insurance. CO-OP Chicago collected a range of self-reported and observed oral health data as well as family psychosocial factors from these low-income families over one year. However, the study did NOT include a caries assessment. The proposed CO-OP Chicago Cohort Study will transition trial participants into a longitudinal cohort (minimum N=315) to determine multi-level predictors of oral health behaviors and caries risk in low-income, urban young children over time. The CO-OP Chicago Cohort Study uses the social ecologic model to organize oral health risk factors into individual (child), interpersonal (family), organizational (healthcare), and community domains. We will collect four additional years of data with data collection every six months that includes caregiver-reported and observed child oral health behaviors, dental plaque scores, diet, parenting styles, dental provider access, and social risk factors. We will also conduct two caries examinations on children at ages five and seven. Community-level data will be extracted from public data sources. Specific Aim 1 is to examine associations between child, family, healthcare, and community factors on young child home oral health behaviors (child brushing frequency and plaque score) over time. Specific Aim 2 is to examine associations between child, family, healthcare, and community factors on young child caries prevalence over time. Specific Aim 3 is to examine the mediating effects of child brushing frequency and plaque score on the prior identified risk factors associated with caries prevalence. An Exploratory Aim will determine the ability of plaque scores to predict risk of caries. These data will advance our understanding of caries risk factors and inform future research and intervention development.

NIH Research Projects · FY 2025 · 2021-07

Cancer cells are metabolically different from normal matching cells, and this is manifested by the high rate of glucose metabolism in cancer cells. The high rate of glucose metabolism in cancer cells is, at least in part, due to the marked induction of hexokinase (HK2) expression, which is not expressed in most normal cells. Most normal adult tissues and cells express hexokinase 1 (HK1), but when they convert into cancer cells, they start expressing high levels HK2. Thus, HK2 could be a hallmark of cancer cells and could be targeted for cancer therapy. Over the years we provided genetic proofs of concept that HK2 can be systemically deleted in mice to inhibit cancer without adverse consequences. We showed that HK2 deficiency inhibited both initiation and maintenance of cancer in mouse models of lung cancer, breast cancer, liver cancer, and prostate cancer. Likewise, inducible knockdown of HK2 in human cancer cells inhibited the growth of tumors after tumor formation. In this grant application we will investigate novel HK2 activities that were not previously explored. These activities include: (i) A novel moonlighting function of HK2, independently of its glucose kinase activity. This activity could determine the stability of certain proteins such as MCL1, NRF2, and SNAIL that are associated with cell survival, redox regulation, and EMT and metastasis respectively. (ii) A role of HK2 in glycosylation, tumor microenvironment and immunotherapy. (iii) The effect of HK2 on gene expression through histone lactylation.

NIH Research Projects · FY 2025 · 2021-07

Project Summary The Illinois occupational surveillance program, now in its 11th year of funding, is seeking program renewal in order to continue to pursue population and case based occupational surveillance activities with the goal of proactively identify emerging hazards and promoting policies to protect workers. As the bona fide agent of the Illinois Department of Public Health, our research team at the University of Illinois Chicago, School of Public Health has taken on the role of building occupational health surveillance capacity in Illinois. We are applying for an expanded program comprising of a fundamental program and three expanded projects. We plan to continue to lead the effort in the state of Illinois to enhance occupational safety and health surveillance with the following programs: -Fundamental Illinois Occupational Surveillance Program: Conduct active surveillance of occupational injuries and illnesses in the State of Illinois utilizing recognized and new data systems with a particular focus on high risk industries, as well as underserved and precarious workers. We will expand health informatics capacity, organize statewide communications, and continue to build partnerships with stakeholders. - Expanded Project #1- Linking Occupational Surveillance Data, Work Practices and OSHA Enforcement Activities in Illinois: We aim to develop a “system of systems” through coordination with OSHA and other public health stakeholders in Illinois. The proposed program will (1) develop a real-time surveillance program to inform OSHA’s unprogrammed inspections, (2) analyze occupational injury and illness data captured in data systems not available to OSHA in order to identify high risk industries, employers with recurring severe injuries, and characterize emerging hazards to inform OSHA’s programmed inspections, (3) assess the reliability of employer reporting of severe injuries, and (4) strategically coordinate efforts between OSHA and other stakeholders. - Expanded Project #2 - Work-related Injuries in Chiropractors: Surveillance and Training: We will conduct occupational surveillance of ergonomic hazards and musculoskeletal health risks among chiropractors. We will also develop continuing education material, deploy a CE course through a partnership with the national association, and survey chiropractors about workplace hazards, knowledge regarding injury prevention and barriers to mitigating these ergonomic hazards. -Expanded Project #3 - Pesticide Related Illness Surveillance Program: Develop occupational surveillance system to monitor pesticide related illnesses and use these data to develop outreach and training among high risk workers. We will build a collaborative network of stakeholders to assess and engage workers with the goal of reducing pesticide related illnesses in Illinois.

NIH Research Projects · FY 2024 · 2021-07

Abstract Krabbe’s Disease (KD) is a rare inherited leukodystrophy caused by mutations in the GALC gene encoding the lysosomal enzyme, galactosylceramidase (GALC). Lack of functional GALC leads to global demyelination and neurodegeneration. Untreated KD presents in infants as developmental delay and regression, failure to thrive, and ultimately death by 2-3 years of age. KD is treated with hematopoietic stem cell transplantation (HSCT) which slows the progression of disease and prolongs life expectancy into the teenage years, but it is not a cure. Adeno-associated viruses (AAV) have been utilized successfully as gene therapy treatment vectors in numerous pre-clinical and clinical trials. The initial success of AAV gene therapy in diseases primarily affecting neuronal cells led to investigations of their efficacy in monogenic diseases affecting multiple cells types such as KD. The Bongarzone lab previously developed a treatment protocol using AAV9- GALC to correct the deficiency in the Twitcher murine model of KD. This treatment completely prevented disease development for the first 6-8 months of life, such that AAV-treated mice were nearly indistinguishable from wild-type mice. Despite these promising results, our study also revealed a slow decline in treatment efficacy over time, including development of disease signs and focal demyelinating plaques in mice of advanced age; similar findings have been noted by other investigators as well. No alternative modifications to improve gene therapy have been proposed thus far. The overarching goal of this application is to establish whether gene therapy efficacy is declining due to exhaustion of AAV DNA in the adult brain and how to optimize gene therapy treatment efficacy and duration in Twitcher mice. As AAV-GALC DNA exists as a non-replicating extra-chromosomal episome after entering a cell, we hypothesize the decline in treatment efficacy is caused by loss of therapeutic vector in replicating cells, particularly oligodendrocyte precursors, in the Twitcher brain, which leads to a decrease in the average AAV- GALC episomes per cell over time. This hypothesis will be investigated by treating mice shortly after birth with AAV9-GALC at decreasing dosages and then observing how long the treatment is efficacious based on clinical score, survival, as well as biochemical and histological analyses. We will then examine if redosing utilizing oligodendrocyte targeted AAV (AAV-001) later in life, but prior to disease sign onset, delays or prevents development of disease signs. Finally, we will determine if utilizing AAV-001 singly will increase the efficacy and duration of treatment in comparison to AAV9. This study is important because we need to better understand what happens to episomal AAV DNA long term before attempting to use AAV based therapies to treat KD patients. Furthermore, our findings will have the intrinsic impact of better characterizing how episomal AAV DNA behaves in similar monogenic disorders.