University Of Illinois At Chicago

NIH Research Projects · FY 2024 · 2014-01

PROJECT SUMMARY Achieving functional ambulation post stroke continues to be a challenge for stroke survivors, clinicians and researchers. The proposed study builds on our earlier R01 where we successfully examined the feasibility of a clinically implementable walking program which involves high intensity speed-based treadmill training (HIISTT) in combination with cortical priming to improve walking speed of individuals with stroke. Cortical priming has emerged as a promising adjuvant to enhance the outcomes of motor training. Our research team has pioneered and successfully developed neuromodulation techniques for the lower limb motor cortex using non-invasive transcranial direct current stimulation (tDCS) and ankle motor skill training. In this renewal application, our goal is to quantify the effectiveness of 36 sessions of cortical priming plus HIISTT intervention in comparison to sham priming plus HIISTT. Outcome measures will include gait variables, balance, aerobic capacity, quality of life, neurophysiological measures of descending and interhemispheric corticomotor excitability measured with transcranial magnetic stimulation (TMS), and changes in serum BDNF before, immediately after and 3-months post training. There has been a growing interest in understanding responsiveness to training to personalize stroke rehabilitation. We aim to understand variability in responsiveness to training using patient-specific parameters such as participant demographics, neurophysiological measures and the presence of genetic variations such as brain derived neurotrophic factor (BDNF) polymorphism. With our innovative mechanistic approach to enhance walking recovery, we seek to optimize gait rehabilitation post stroke and characterize relationships between neural mechanisms, motor function and genetic variations. Improved gait will enable stroke survivors to be more independent in the community and advance their quality of life, which is highly relevant to the mission of the NIH.

NIH Research Projects · FY 2025 · 2013-01

Project Summary/Abstract The University of Illinois Chicago (UIC) College of Pharmacy is the third oldest of the 100+ pharmacy colleges in the U.S., founded in 1859, and even older than the University of Illinois itself. Our College consistently ranks in the top five nationally for NIH funding and overall research expenditures (AACP statistics). Enrolling an average of 120 graduate students and 20 postdoctoral researchers at any one time, this renewal application seeks continued support for our long-standing program for natural products research and graduate/postgraduate education. This program has two major elements: the Pharmacognosy Institute (PHCI), a UofIL-accredited research unit that evolved from Prof. Farnsworth's Program for Collaborative Research in the Pharmaceutical Sciences (PCRPS) and the UIC Center for Botanical Dietary Supplements Research; and the Department of Pharmaceutical Sciences (PSCI), the academic home department of most of the mentors, graduate students and postdoctoral researchers in this proposal. The natural product program at UIC enjoys a global reputation of excellence in graduate and postgraduate training, with several hundreds of alumni worldwide. Its signature is the emphasis on interdisciplinary and collaborative approaches to graduate and postgraduate education in natural products of biomedical relevance. PSCI offers a graduate program in pharmaceutical science with a pharmacognosy and three other tracks with strong natural product components, as well as a postdoctoral and scholarly training and exchange program that includes the UIC WHO Traditional Medicines Collaborating Center. Three additional research units, the UICentre (drug discovery), the Center for Biomolecular Sciences, and the Institute for Tuberculosis Research have expanded the educational opportunities for our trainees, especially in the outgoing Year 6-10 cycle. Mentored by a large group of well-funded faculty with expertise in biomedical natural products research, our graduates move on to leadership positions in academia, industry, regulatory, and government, predominantly in the U.S. but also globally. Training young scientists for careers in natural products research and health products is a core mission of our College of Pharmacy, the PHCI and PSCI, and the focus of this training grant.

NIH Research Projects · FY 2026 · 2012-07

Elucidating the signaling pathways that control angiogenesis allows new therapies to be designed for treatment of diseases where blood vessels are contributors, including blindness, inflammation, and cancer. Notch1 signaling generally acts as a negative regulator of angiogenic sprouting. We hypothesize that Notch4, a Notch receptor primarily expressed in endothelium, has both overlapping roles with Notch1 and distinct endothelial functions. We demonstrated that Notch4 promotes angiogenesis and possibly inflammation of blood vessels and surrounding cells. By removing Notch4 expression in blood vessels of mice or blocking Notch4 using an inhibitor, we discovered that Notch4 promotes angiogenesis in the developing retina. Notch4 is expressed in blood vessels of many types of tumors and we demonstrated that blocking Notch4 inhibits tumor growth when Notch4 is in tumor vessels. We found that endothelial Notch4 appears to function to alter both vessels and adjacent stromal tissue. Analysis of Notch4-regulated genes led us to discover that specific cytokine signaling proteins are regulated by Notch4, and not Notch1, a possible mechanism for Notch4 broad influence on both vessels and surrounding tissue. In these studies, we will define the unique signaling mechanisms regulated by Notch4 to understand how Notch4 promotes developmental, inflammatory-driven, and tumor angiogenesis and evaluate anti-Notch4 treatment for therapeutic benefit. We will use a new technique called CUT&RUN to see which genes are directly activated by Notch4 or Notch1 and use a novel RiboFlag translational analysis to understand expression control by each Notch protein. We will determine if newly discovered Notch4-regulated proteins promote angiogenesis and inflammation in cultured endothelial cells and remove Notch4 expression from endothelial cells in mice to determine if this causes reduced blood vessel growth, reduces the response to inflammation and reduces tumor growth. We will separately remove Notch1 or Notch4 genes from endothelium or remove both genes and describe result of Notch loss on developmental and pathological angiogenesis, establishing unique and overlapping roles for these genes. A new Notch inhibitor allows us to investigate pre- clinical therapeutic potential for treatment of proliferative retinopathy, an inflammatory eye disease, and in tumors that have Notch4 in the endothelial cells. We will investigate the stromal changes in tumors caused by genetic or pharmacologic blockade of Notch4 using flow cytometry and focused single cell RNA sequencing. In all of these studies, we will determine if select cytokines are regulated by Notch4 in healthy and disease-associated blood vessels, with the goal of understanding the mechanisms by which Notch4 impacts inflammation of blood vessels and surrounding tissue or tumor. Our goals for this proposal will be to discover the unique ways that Notch4 works to build normal blood vessels and contributes to diseased vessels, and to evaluate therapeutic strategies to prevent blindness caused by excess angiogenesis, reduce vascular inflammation, and block tumors.

NIH Research Projects · FY 2025 · 2012-05

ABSTRACT The maintenance of an intact alveolar epithelial barrier is crucial for lung function. Failure of steady-state replacement or post-injury regeneration of alveolar epithelial cells underlies the pathogenesis of many lung diseases. In recent years, certain subgroups of cells have been identified as putative stem/progenitor cells in the alveolar epithelium during homeostasis and regeneration. However, the identities of these cells and the mechanisms regulating their behavior are still incompletely understood. Recent studies have indicated that some immunity related signaling molecules can regulate the activity of alveolar epithelial progenitors, but the mechanisms that direct these signaling events during lung homeostasis or regeneration have not been well characterized. The objective of this proposal is to determine the distinct roles of immunity related signaling pathways in the regulation of alveoli progenitor cell functions, both during steady-state maintenance as well as post injury repair. An additional goal is to explore the possibility that dysregulation of these signaling processes is related to chronical lung diseases such as emphysema or fibrosis. Two types of epithelial cells cover the lung alveoli: alveolar type I cells (AT1) cover >95% of the surface area and facilitate O2-CO2 exchange, whereas alveolar type II cells (AT2) are responsible for the secretion of surfactant. Importantly, AT2s also function as stem/progenitor cells by undergoing self-renewal and differentiation into AT1s. In preliminary studies, we demonstrated that 1) A small subset of AT2s (1-3% of total) showed stem cell characteristics indicating a role of these cells for steady-state maintenance of alveoli. These cells had intrinsic NFκB and STAT1 activity and these immunity related signals were able to regulate their progenitor functions; 2) After bacterial induced lung injury, more AT2s are activated and behave as facultative stem cells to repair the alveoli. The reparative functions of these cells are regulated by STAT1 and STAT3 mediated signals; and 3) AT2 specific disruption of STAT1 causes sustained fibrosis after bleomycin induced lung injury. This effect is likely induced by an aberrant subpopulation of AT2/AT1 intermediate cells resulting from a failed transition of AT2s to AT1s. Based on these data, we hypothesize that the progenitor function of a subset of AT2s in alveolar homeostasis and post injury regeneration is regulated by distinct immunity related signals. Disruption of these signals is related to the pathogenesis of chronic lung diseases. We will test these ideas with the following specific aims: Aim 1: To determine how NFκB and STAT1 mediated immunity related signaling regulates the stem cell properties of CD44high AT2 subsets during steady-state homeostasis. Aim 2: To determine the role of STAT1/STAT3 dependent, likely NFκB independent, immunity signaling in regulating the facultative progenitor cell functions of AT2 cells in post injury repair. The goal of these studies is to advance our understanding of molecular mechanisms underlying alveolar homeostasis and repair in mouse and human lungs, and to identify novel therapeutic targets to prevent complications related to insufficient epithelial steady-state replacement or repair.

NIH Research Projects · FY 2025 · 2011-09

7. PROJECT SUMMARY/ABSTRACT This is a competitive renewal application for the University of Illinois at Chicago (UIC) K12/Independent Clinician Vision Scientist (ICVS) Program. The overall goal of the K12/ICVS Program is to align with the 2021- 2025 NEI Strategic Plan “to train clinicians (e.g., M.D., O.D., D.V.M.) for the scientific workforce to create more opportunities for translational and population-based research.” Our long-term objective is to promote training and career development of a new generation of clinicians equipped with the knowledge and career skills necessary to advance vision health and science for the next decade and beyond. The Department of Ophthalmology at UIC is among the leading institutions for eye care and research, ranking #9 in NIH funding in the last fiscal year (#1 among institutions in the Midwestern United State). Since its inception in 2011, the UIC K12/ICVS Program has fostered the academic careers of 12 Scholars. Their success is evident in 12 NIH grants and 17 non-NIH grants as PI and over 400 peer-reviewed publications. We seek funding over the next 5 years to train 5 junior faculty as clinician-scientists in eye research. Our short-term objectives build upon these strengths through ongoing program activities and several new initiatives. Ongoing activities include supplementing team mentoring programs with new training and tools, optimizing existing and new UIC partnerships, and augmenting our strong didactic curriculum. We also have three novel initiatives. First, the Diversification of the Sciences Initiative identifies institutional and other barriers to optimal academic quality of life among new investigators and pursues policy changes and program activities to improve recruitment, retention, and advancement of underrepresented minorities and women. Second, we will incorporate new curriculum content on reproducibility, transparency, and rigor, as well as the responsible conduct of research. Lastly, we will provide training on fundamental research approaches, opportunities for hands-on bioinformatics training, and experimental design for personalized medicine.

NIH Research Projects · FY 2024 · 2010-09

ABSTRACT Several clinical and preclinical studies suggest that adolescent binge drinking is one of the major risk factors for the development of psychiatric disorders, including anxiety and alcohol use disorder (AUD) later in life. Adolescence represents an important stage of brain development, and epigenetic mechanisms are known to orchestrate developmental maturation of the brain from adolescence to adulthood. This research component of Neurobiology of Adolescent Drinking in Adulthood (NADIA) consortium will examine how epigenetic modifications induced by adolescent intermittent ethanol (AIE) at the genome-wide level lead to an aberrant gene network pathway regulating various synaptic mechanisms in the amygdala that are responsible for anxiety- like and alcohol drinking behavior in adulthood. This component will identify closed and open domains of the epigenome after AIE in adult amygdala using Assay for Transposase-Accessible Chromatin-sequencing (ATAC- seq), and the corresponding regulation of the transcriptome by merging this dataset with existing RNA-seq data. The overarching hypothesis of this proposal is that AIE will produce differential gene expression due to altered status of the epigenome in adult amygdala. The dynamic changes in epigenetic targets (HATs/EZH2/G9a/LSD1/DNMT3b) will induce changes in the transcriptome that regulate synaptic mechanisms in the amygdala after AIE in adulthood, ultimately regulating anxiety-like and alcohol- drinking behaviors. Specific Aim 1 will examine a) the status of chromatin accessibility and loci of genomic epigenetic marks using ATAC-seq in the adult amygdala of rats (male & female) after AIE. The emerging data set will be merged with existing RNA-seq data to identify epigenetically regulated transcriptomic changes, and b) To validate expression and epigenetic enrichments of new genes in the amygdala after AIE and use them for functional studies. Specific Aim 2 will examine the effects of neuronal epigenomic editing in the CeA using CRISPR/dCas9-p300, CRISPR/dCas9-KRAB, CRISPR/dCas9-Lsd1 (histone acetylation/methylation), or CRISPR/dCAS9-Tet1 (DNA methylation mechanism) on AIE-induced changes in gene expression and on anxiety-like and alcohol drinking behaviors in adult male and female rats. Specific Aim 3 will examine whether treatment with G9a inhibitor (UNC0642) will normalize epigenetic, gene expression, and dendritic spine changes in the amygdala and attenuate AIE-induced anxiety-like and alcohol drinking behaviors in adult male and female rats. Finally, Specific Aim 4 will translate epigenetic dynamics and expression of novel genes that will be identified from RNA-seq and ATAC-seq in the AIE rat amygdala to post-mortem amygdala of human alcoholics with early age onset and correlate them to drinking data (daily or weekly ethanol intake). The proposed studies will provide new information about epigenetic regulation of the whole transcriptome in the amygdala after AIE, leading to identification of epigenetic targets for drug development for the treatment of adult psychopathology.

NIH Research Projects · FY 2026 · 2010-07

Abstract Adolescence is a vulnerable period of postnatal development for the onset of major psychiatric disorders where the prefrontal cortex (PFC) is involved. According to the NIMH Council's Workgroup Report, many psychiatric disorders can only be understood as an interaction between brain development and susceptibility to risk factors. Although many progresses have been made in the field during the past few years, a comprehensive understanding of the cellular and circuit level mechanisms regulating the developmental trajectory of neural processes involved in these disorders remains incomplete. Thus, our long-term goal is to identify sensitive developmental processes during adolescence that contribute to the onset of psychiatric disorders where the PFC is compromised. From studies performed during the preceding grant period, we have found that a hallmark of PFC maturation during adolescence is the functional re-calibration of an excitatory-inhibitory (E-I) balance state. In addition to the gain of GABA function, there is a facilitation of GluN2B and GluN2A NMDAR transmission in the PFC that is intimately linked to ventral hippocampal and basolateral amygdalar inputs. Yet, the extent to which coordinated activation of ventral hippocampal and basolateral amygdalar inputs during adolescence are required for the functional maturation of the PFC remains unclear. We will fill this gap in knowledge through the pursuit of 3 Specific Aims. We will use an input-specific chemogenetic strategy to transiently inhibit PFC afferent transmission at 3 non-overlapping adolescent periods to establish the exact window(s) of susceptibility for the gain/functional maturation of the GABA and NMDA synaptic components of the PFC E-I balance and their impact on PFC-dependent behaviors in adulthood. Together, the proposed aims are expected to uncover key neural circuit processes that contribute to the enhanced PFC vulnerability during adolescence to developmental insults. Such knowledge is expected to provide insights on the implementation of new therapeutic interventions to prevent/mitigate the incidence of cognitive and affective deficits often seen in mental illnesses that emerge during adolescence.

NIH Research Projects · FY 2024 · 2009-07

Project Summary/Abstract Combined, the preventable diseases of obesity and drug addiction impact an enormous number of people and cost billions to treat. Physiological need (e.g. thirst, hunger), its hormonal signals and related central circuits, modulate seeking for and consumption of both nutritive and drug stimuli and thus may serve as risk factors for overeating and drug relapse. Ventral tegmental area (VTA) dopamine neurons and dopamine release in the nucleus accumbens play critical roles in reinforcement. This mesolimbic system also integrates physiological state with primary reward and environmental cues to tune approach and consumption. Indeed, the parent grant of this competitive renewal determined that deviations from homeostasis potentiate phasic mesolimbic signaling evoked by cues predictive of restorative stimuli. It also determined that gut hormones signaling deviations from homeostasis act centrally to modulate phasic mesolimbic signaling in the context of both food and drug reward. Peripheral signals act on central “first order” hypothalamic sites (e.g. subfornical nucleus (SFO), arcuate nucleus (ARC)) that have a permeable blood-brain barrier. Modulation of discrete populations of the SFO or ARC is sufficient to induce negative affect and modulate consummatory behavior for restorative stimuli in a manner consistent with negative reinforcement. How first order hypothalamic neurons communicate with the mesolimbic system for reinforcement and to bias approach and consummatory behavior is unknown. We hypothesize that parallel circuits for thirst and hunger access the VTA via lateral hypothalamic area (LHA) orexin neurons. As LHA orexin neurons are recruited during morphine withdrawal and orexin receptor blockade reduces negative affect associated with morphine withdrawal, we also hypothesize that aberrant activity in first order thirst and hunger circuits during morphine withdrawal are excellent targets for the treatment of negative affect and to break the cycle of addiction. While hypothalamic signals clearly modulate aspects of psychostimulant seeking and taking, their role in modulating responses to other classes of drugs – chiefly opioids – has received little attention. In light of the obesity and opioid epidemics and their co- morbidity, these are critical gaps in knowledge which will be addressed here. We will measure VTA dopamine cell body activity or nucleus accumbens dopamine release using in vivo fiber photometry in behaving rats while selectively modulating first and second order hypothalamic neurons. The aims of the proposal are: 1) to determine the mechanism by which first order thirst neurons (SFO) modulate phasic mesolimbic signaling to cues that predict water and drive approach; 2) to determine the mechanism by which first order hunger/satiety neurons (ARC) modulate phasic mesolimbic signaling to cues that predict food and drive approach; and 3) to intervene at the level of first order thirst and hunger neurons to modulate the aberrant dopamine signaling that contributes to the negative affective state of morphine withdrawal. Results will identify novel therapeutic targets for treating disorders of motivation, including obesity and opioid dependence.

NIH Research Projects · FY 2024 · 2009-03

Project Summary/ Abstract The mechanism underlying progressive memory loss and cognitive deterioration in Alzheimer’s disease (AD) is not fully understood and effective approaches to prevent or reverse memory deficits are unavailable. Here we show that augmentation of hippocampal neurogenesis in a mouse model of familial Alzheimer’s disease (FAD) reverses deficits in spatial recognition. Notably, new neurons are recruited into the memory circuit and serve as part of the engram during memory acquisition and retrieval. The number of new neurons in the engram of FAD mice is reduced compared to wild type. However, it is significantly increased following augmentation of neurogenesis. Importantly, new neurons encompass the majority of engram cells during memory retrieval. Thus, this project will test the hypothesis that new neurons play a major role in the engram and that increasing hippocampal neurogenesis in FAD restores the engram and rescues learning and memory. By manipulating levels of neurogenesis in FAD mouse models and using engram labeling techniques, experiments in Aim 1 will establish the role of new hippocampal neurons in the engram in FAD. Experiments in Aim 2 will determine the role of neurogenesis in memory retrieval in FAD. Aim 3 will unravel the signaling pathways underlying impaired hippocampal neurogenesis and engram function in AD. Aim 4 will examine the association between Alzheimer’s pathological hallmarks and the Engram. This program is designed to establish the role of hippocampal neurogenesis in cognitive deficits in AD and determine the efficacy of augmented neurogenesis in rescuing learning and memory in this disorder.

NIH Research Projects · FY 2024 · 2004-04

Dyslipidemia-induced endothelial dysfunction plays a major role in the initiation of atherosclerosis. Our studies discovered that plasma hypercholesterolemia results in suppression of endothelial inwardly- rectifying K+ (Kir) channels and that Kir channels play a major role in endothelial response to flow. Our long term goal is to elucidate the mechanisms responsible for cholesterol-induced regulation of endothelial ion channels and determine the impact of cholesterol-induced suppression of Kir on vascular function and atherosclerosis development. During the previous funding period of this grant, we discovered a new mode of cholesterol-Kir2 interactions via multiple dynamic contacts, provided direct evidence that Kir2.1 plays a crucial role in flow-induced vasodilation and NO release, and showed that hypercholesterolemia-induced impairment of flow-induced vasodilation can be attributed to Kir2.1 suppression. In the current proposal, we extend these studies to address three new goals: In Aim 1, we address the fundamental question of how cholesterol binding to the specific binding sites that we have already identified translates into the inhibition of channel gating. Specifically, we address a novel hypothesis based on our computational studies predicting that cholesterol binding uncouples specific residues within the channels, crucial for the gating process. This hypothesis will be addressed using a combination of multi-scale Molecular Dynamics simulations, a state-of-the-art computational approach, followed by site-directed mutagenesis, functional analysis of the channel function by high throughput electrophysiology, and biochemical and neutron scattering studies to evaluate direct cholesterol interactions with Kir2 channels. In Aim 2, we will extend our studies to determine the role of cholesterol suppression of Kir2.1 in two major endothelial flow responses: 1) activation of PECAM1/Src/VEGFR2/PI3K/Akt signaling axis and 2) cytoskeleton remodeling. This aim is based on our RNA sequencing analysis that revealed a major role of Kir2.1 in flow-sensitive gene expression including the expression of PECAM1/VEGFR2 mechanosensor complex. Specifically, we will test the hypothesis that suppression of endothelial Kir channels by hypercholesterolemic conditions impairs flow-induced activation of VEGFR2 and activation of a small GTPase, RhoA, and alters flow-induced cytoskeletal remodeling. Finally, in Aim 3, we will determine the role of endothelial Kir2.1 in lesion formation of dyslipidemic mice. We have already established that the global deficiency of Kir2.1 exaggerates lesion formation in dyslipidemic ApoE-/- mice. In the proposed study, we will determine if the effect is specific for endothelial Kir2.1. Furthermore, we will also employ a new model of Kir2.1 rescue, a transgenic CRISPR mouse that expresses a cholesterol-insensitive Kir2.1 mutant. We believe that taken together, these studies will make a significant contribution to the understanding of cholesterol regulation of ion channels, dyslipidemia-induced endothelial dysfunction, and the mechanisms of lesion formation.

NIH Research Projects · FY 2025 · 2003-09

Our proposed UIC Midwest Roybal Center for Health Promotion and Translation seeks to accelerate the translation of behavioral research interventions into practical outcomes to improve the functioning (cognitive and physical) and quality of life of older adults at risk of Alzheimer’s Disease and Alzheimer’s Disease Related Dementias (AD/ADRD). Our work recognizes that interventions that target individuals take place in families, neighborhoods, and communities that are impacted by external factors that influence initiation and maintenance of behavior change. Our work is guided by the PRISM Framework to identify behavioral interventions that have the greatest potential for broad public health impact. Our Center will support the design and testing of principle-driven and mechanism-focused, potent and sustainable health promotion interventions that have a strong promise of progressing through the NIH Stage Model. Our renewal Center retains its current focus on designing interventions for older racial/ethnic minority adults and expands our focus to target older adults at risk of AD/ADRD with a focus on behavioral interventions that address cognitive health. This renewal application targets four thematic areas of focus: Develop and test principle driven interventions to increase physical activity (PA) among older adults at risk of ADRD, Design interventions to maintain and/or enhance cognitive function and mobility; harness technology to improve intervention scalability and fidelity; and target mechanisms of behavior change to promote and sustain behavioral and lifestyle change. These foci simultaneously will advance science in these areas and reflects areas of substantial expertise within our Roybal Center. Faculty serving on the Administrative and Behavioral Intervention Development (BID) Cores will constitute the Center’s Executive Committee. These faculty have extensive expertise related to the thematic foci of the center and are committed to assisting to fulfill the mission of the Center. These faculty have experience conducting research across all stages of the Stage Model and will work to transition promising interventions across the Stage Model as quickly as possible. The MPI’s will serve as the Administrative Core co-leads and provide oversight to and work collaboratively with the BID Core co-leads. The BID Core will provide grant funding for up to two trials per year, one solicited from all departments across UIC and other University of Illinois campuses and one solicited externally via a National competition. The overall performance of the Center will be guided by a distinguished External Advisory Committee that includes representatives from diverse academic, provider, funder, consumer, and media stakeholder groups; including health care systems and plans. Collectively our work is expected to substantially advance science in these critically important areas of focus and provide currently unavailable information about the impact of behavioral change interventions that focus on underserved older adults.

NIH Research Projects · FY 2025 · 2001-09

PROJECT SUMMARY This application is submitted in response to RFA-DK-22-502, “Limited Competition: Continuation of the Chronic Renal Insufficiency Cohort (CRIC) Study (U01)” on behalf of the University of Illinois Chicago (UIC) CRIC Clinical Center. Since its inception in 2001, the CRIC Study has recruited and followed a racially and ethnically diverse cohort of 5,625 participants with reduced kidney function from 13 recruitment sites at seven Clinical Centers across the US. The original aim of CRIC was to establish a clinical research laboratory designed to (a) identify novel predictors of CKD progression, and (b) characterize the manifestations of cardiovascular disease and identify its risk factors among individuals with CKD. As the landmark prospective cohort study of CKD, the CRIC Study has accomplished extensive biological, physiological, and social phenotyping, longitudinal follow- up, and ascertainment of clinical and patient-centered outcomes across multiple domains. Findings from the CRIC Study have defined trajectories of CKD progression, catalogued development and evolution of comorbidities in CKD, and identified a diverse array of factors and pathways that explain the progression and complications of CKD in adults. During the most recent funding cycle (Phase 4: 2018-2023), three innovative sub-protocol studies were implemented to enrich CRIC data with highly granular home-based assessments of kidney function and cardiovascular measures. During the fifth and final phase of the CRIC Study, the major focus will be to (1) ascertain the clinical outcomes for all participants including those enrolled in the Phase 4 sub-protocols, (2) perform analyses linking the sub-protocol measurements to clinical outcomes, (3) integrate data from multiple domains to identify sub-phenotypes underlying the heterogeneity in CKD progression outcomes, (4) conduct final study visits for the full CRIC cohort eligible for Phase 5, (5) create mechanisms for future data collection via linkages with external sources of health data, (6) generate tools and resources to facilitate ongoing use of CRIC data and biospecimens by a broad group of investigators, and (7) support UIC CRIC participant enrollment into the recently funded UIC Kidney Precision Medicine Project (KPMP) CKD Recruitment Site. During the first four phases of the CRIC Study, the UIC research team enrolled nearly 1,200 participants and has been successful in retention, protocol implementation, data quality, and scientific productivity. Additional noteworthy achievements include a strong focus on heath disparities in CKD, a significant number of UIC investigator-led publications, leadership on funded ancillary studies, and the promotion of new physician-scientists. Consequently, the UIC team is well positioned to make a substantive contribution to the consortium by generating new scientific output and successfully transitioning the CRIC Study from its active prospective cohort phase to a long-lasting resource for supporting ongoing and future mechanistic, epidemiologic, and translational investigations.

NIH Research Projects · FY 2026 · 2001-03

This is the fourth competitive renewal of this grant application that was funded for the past 20 years. Over the years funding through this grant application led to several milestone observations and new discoveries. In the current grant application, we will follow intriguing observations made during the last period of funding. Our genetic studies in mice, using systemic deletion of Akt isoforms after tumor onset, recapitulate some of the adverse effects observed in patients after treatment with PI3K and Akt inhibitors such as hyperinsulinemia, and hyperglycemia, severe diarrhea, and liver damage. Our studies in mice could therefore provide mechanistic explanations for the adverse physiological consequences induced by PI3K and Akt inhibitors. Our results using mouse models of breast cancer and inducible systemic deletion of Akt isoforms after tumor onset to emulate drug therapy, suggest the followings: (i) Systemic Akt1 inhibition after tumor onset reduces metastasis by inhibiting tumor associate and pro-metastatic neutrophils. This is relevant to human breast cancer as high ratio of neutrophils to lymphocyte (NLR) is associated with worse overall survival and disease-free survival. (ii) Neutrophils’ specific deletion of Akt1 is sufficient to inhibit breast cancer metastasis. (iii) Specific Akt1 inhibitors could inhibit tumor progression and metastasis of Her2 enriched, Luminal B, and triple negative breast cancer. (iv) Systemic Akt1 inhibition prohibits breast cancer metastasis regardless of primary tumor type (Akt1 specific inhibitors should be developed). (v) Systemic Akt2 inhibition may not be beneficial for breast cancer therapy because of increased circulating levels of insulin and hyperactivation of the other Akt isoforms (drugs that inhibit Akt2 might be avoided). (vi) Pan-Akt inhibitors may not be effective unless they don’t inhibit Akt2 activity to a high extent. In the first part of the current grant application, we will investigate how tumor associated neutrophils are programmed by the tumors both transcriptionally and metabolically and how Akt1 deficiency impairs their ability to promote breast cancer metastasis. In the second part of the grant application will investigate mechanistically the adverse effects induced by pan-Akt or Akt2 inhibition and how to alleviate them. The long-term goal of this grant application is to establish the rationale for developing Akt1 specific inhibitors and enable the efficient use of Akt inhibitors for cancer and cancer metastasis therapy.

NIH Research Projects · FY 2025 · 1997-09

PROJECT SUMMARY: CENTER CORE The vision science research program at the University of Illinois at Chicago (UIC) has been supported by one of the longest-running core grants from the National Eye Institute (NEI). The overarching goal of the Center Core Grant for Vision Research is to support, strengthen and expand basic and translational vision science research at UIC. A major advantage of the Center Core Grant is that it facilitates inter-disciplinary and inter-departmental scientific interactions and collaborations among members of the Vision Science Research Community (VSRC). Current VSRC investigators hold a total of 25 NEI-funded research grants, of which, 16 are qualifying R01s. The Center Core Grant resources have significantly impacted performance of pioneering research in wide- ranging and clinically-relevant areas. These resources have enhanced research capabilities and productivity of individual investigators, created an environment conducive to resource-sharing and collaborative scientific interactions, assisted new investigators to develop research projects, and aided established NEI R01-funded investigators to pursue research in emerging fields. This renewal Center Core Grant application responds to the evolving research needs of participating investigators and requests funding to support 4 resource Cores: Cellular and Molecular Biology Core, Imaging and Image Analysis Core, Animal Services Core, and Translational Core for Therapeutic and Diagnostic Development. These resource Cores provide exceptional facilities, cutting-edge bioinstrumentation, and experienced technical expertise in molecular biology, cellular biology, histology, proteomics, genomics, imaging, disease modeling, biostatistics, data science, and artificial intelligence services. The Center Core Grant will continue to sustain and promote conduct of exemplary basic and translational inter- disciplinary and collaborative vision science research. It will provide the essential catalysts needed to collectively advance knowledge of the biology and pathophysiology of the visual system and develop novel diagnostic and therapeutic approaches for prevention of vision loss.

NIH Research Projects · FY 2025 · 1995-07

Project Summary This T32 renewal application, with demonstrated excellence in creating meritorious and next- generation predoctoral and postdoctoral trainees in lung research, requests continued support for the Lung Biology and Pathobiology Training Program (TPLBP) at the University of Illinois College of Medicine, Chicago, for years 32–36. Our steadfast goal remains to train the next generation of high-caliber trainees specializing in lung biology and the pathobiology of lung disease and its relentless impact on patient survival worldwide. The program fosters career growth by enhancing critical thinking and problem-solving skills and developing the resilience and determination to succeed in research-focused professions. Each trainee will receive funding for two years. To this end, in addition to our existing cohort of accomplished mentors, we have included newly NIH-funded faculty mentors to reinvigorate our program. The trainees have the opportunity to engage with a diverse group of 40 faculty members who specialize in five interconnected research areas: 1) Lung Vascular Homeostasis, Pathobiology, and Regeneration; 2) Cellular, Humoral, and Mechanical Bases of Lung Injury and Repair; 3) Microbiome and Metabolism in Lung Biology and Pathobiology; 4) Lung Genomics and Data Science in Inflamed and Regenerated Vessels; and 5) Therapeutics Targeting Lung Vessel Regeneration. In this renewal, the program has placed our trainee’s interests above faculty research interests, and we call this approach "trainee-centric." Our program involves mentoring through a primary preceptor, engaging in co-mentorship overseen by several committees, including executive, external, and trainee advisory committees, crafting individual development plans, and emphasizing communication and presentation skills. We have also added a "feedback loop" workshop to benefit our trainees. Additionally, the program prioritizes diversity, equity, and inclusivity, emphasizing women's roles and strong recruitment and retention efforts. The program is highly multidisciplinary, as we have added expertise in computational biology, data science, bioinformatics, stem cells, epigenetics, and physician science. We are requesting 5 predoctoral and 3 postdoctoral trainee positions. In the last 10 years, 75% of our trainees, including underrepresented minorities, have engaged in academic research, and 40% received F31, AHA, or KO9, R21, and RO1 grants. With recent advances and expanded thematic areas, we are repositioned and re-empowered to train a select group of individuals in lung-related research. This training will allow them to intersect with other disciplines, enhancing their careers in academia, research institutes, the biopharmaceutical industry, and other emerging fields.

NIH Research Projects · FY 2025 · 1993-06

PROJECT SUMMARY / ABSTRACT Polymorphonuclear neutrophil (PMN or neutrophil) maintain human health by rapidly eliminating the invading pathogens. These circulating cells transmigrate across the endothelial adherens junctions (AJs) to enter into the infected tissue and to clear the pathogens. Little is known about the role of mechanical forces which PMN experience during transmigration across the endothelium. Our Supporting Data describe the potentially important role of adherens junctions in activating PMN’s host defense function. We observed that activation of PMN-expressed Piezo1 during paracellular transmutation induced calcium influx, which in turn, promptly stabilized Hif1α and upregulated expression of NADPH oxidase 4 (Nox4) in PMN to program these cells to efficient “killers” of the pathogens. These findings have for the first time linked PMN-expressed Piezo1 to the host-defense function, leading to the fundamental question “how Ca2+ influx in PMN via Piezo1 program the host-defense function of PMN?” In Aim 1, we will determine the role of PMN-expressed Piezo1 signaling pathway in activating the host-defense function of transmigrating PMN. Here we will delineate the signaling pathways downstream of Piezo1 activation that promptly stabilizes Hif1α in PMN and programs PMN to become more efficient bacterial “killers”. The studies will involve genetic analysis of Piezo1- Hif1α signaling of the transmigrating PMN such as PMN-specific Piezo1 and Hif1α knockout mice. We will also determine whether pharmacological activation of Piezo1 or expression of gain-of-function Piezo1 mutant in PMN is sufficient to activate the PNM defense system in the relevant P. aeruginosa-induced pneumonia model. In Aim 2, we will determine the role of PMN-expressed Nox4 in regulating oxidative and lytic properties of PMN and in the efficient elimination of pathogens in lung. These studies will address the function of Nox4 in PMN in the mechanism of innate immune defense program. Using in vitro and in vivo experiments, we will determine how Hif1α induces activation of Nox4 gene and how Nox4 regulates oxidative and lytic properties of phagolysosome and efficient pathogen killing. The proposed studies will be essential for understanding the regulation of PMN host-defense function with the goal of identifying therapeutic potential of Piezo1 activators.

NIH Research Projects · FY 2026 · 1992-09

This renewal application for Years 31-35 of the University of Illinois at Chicago’s T32 application is designed to support a scientific environment to prepare the next generation of cancer researchers through cancer educational programming, mentored research training, and career and leadership development for predoctoral and postdoctoral trainees. Over the past 30 years, the University of Illinois at Chicago’s National Cancer Institute (NCI) T32 program has prepared trainees to focus on the transdisciplinary skills needed to address cancer prevention, control, and survivorship. This renewal application will continue to train and advance cancer educational training and research by supporting pre and postdoctoral trainees to become independent scientists. Since our initial funding under the R25T mechanism in 1992 (transitioned to T32 in 2018), our T32 has received continuous NCI support resulting in a significant contribution to the cancer research workforce. Of the 18 completed predoctoral trainees, 72% went on to postdoctoral fellowships and of the 14 completed postdoctoral trainees, 71 % accepted academic positions following the training. This renewal application is in response to PA-20-142. Aim 1. To continue to recruit and train pre and postdoctoral trainees who are dedicated to academic careers in cancer prevention, control, and survivorship. Aim 2. To continue to provide a rigorous skills training program with a comprehensive curriculum; transdisciplinary seminars; leadership certificate programs; experiential learning with scientific writing; and experiences in basic, clinical, and applied settings. Aim 3. To prepare trainees to develop, implement, and disseminate independent research by providing strong mentorship and scientific specialization in cancer prevention, control, and survivorship. Aim 4. To continue to provide plans for Instruction in the Responsible Conduct of Research and in Methods for Enhancing Reproducibility in alignment with NIH policies. Aim 5. To continue to provide ongoing evaluation of our training program to ensure that it is meeting educational, mentored research training, and career and leadership development metrics.