Grants

NSF

The U.S. population is aging, and millions are affected by neurodegenerative disorders, yet their causes remain largely unknown. Emerging research suggests that the gut microbiota plays a role in neurodegenerative processes by influencing brain pathophysiology. However, the mechanisms behind this microbiota-gut-brain axis (MGBA) are still poorly understood. Current studies of neurodegenerative diseases rely on animal models and clinical trials, which face major limitations such as ethical concerns, high costs, low throughput, and significant time and labor demands. Hence, it is essential to develop alternative in vitro platforms to study interactions between gut microbiota and brain tissue models, thereby enabling deeper insight into the MGBA. The educational goal of this project is to integrate research with education to train both undergraduate and graduate students in interdisciplinary studies to produce next-generation bioengineers. The investigators will incorporate this work into their existing Vertically Integrated Program (VIP), Targeting Neurodegenerative Diseases Using Bioengineering Approaches. Building on years of mentorship experience, they will engage undergraduate, graduate, and K–12 students in interdisciplinary research. The aim is to equip students with strong technical knowledge and hands-on lab skills to support their future careers. The goal of this proposal is to develop a new, on-chip reductionist model to evaluate the essential role of gut microbiota and its interactions with in vitro brain models through an in vitro blood brain barrier (BBB). This platform will facilitate the studies of the interactions between the microbiota and an in vitro brain model that will permit the investigation of mechanisms of organ development, cellular interactions, and disease model progression under the influence of the microbiota within microenvironments. Specifically, the proposed efforts include (1) the development of a chip consisting of chamber arrays to mimic the bidirectional communication between the gut bacteria/microbiota and brain in vitro; and (2) the studies of the behavior of brain models under the influence of the microbiota using this chip. Major innovations of this proposed project include: (1) Using this type of chip, large-scale studies of the interactions between gut bacteria/microbiota and brain models can be performed rapidly and inexpensively; (2) Using the integrated sensors on-chip, the concentrations of the metabolites specifically the neurotransmitters produced by microbiota can be determined quantitatively in real-time; and thus (3) Using this chip will facilitate the quantitative studies of the effects of these biologically active chemicals on both healthy and diseased brain models. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

National Institute of Standards and Technology

CHIPS Incentives Program – Facilities for Semiconductor Materials and Manufacturing Equipment

Velanidi Technologies LLC

CHIPS Manufacturing & Research Application Assistance Grant

Rogue Valley Microdevices, Inc.

CHIPS Manufacturing and Research Grant Program

National Institute of Standards and Technology

CHIPS Research and Development Office (CRDO) Broad Agency Announcement (BAA)

Woodstock

Chipseal 2022 Spring

Theater Et Al, Inc.

Local

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY The vagus nerves transmit sensory information from the gastrointestinal tract to the brain, playing a crucial role in the neural control of feeding and energy homeostasis. These signals are conveyed to brain systems that regulate both the homeostatic control of feeding and the cognitive aspects of food reward. The gut-innervating afferent fibers of the vagus nerve demonstrate lateralized activation of midbrain “reward” circuitry, with projections through the right, but not the left, vagus nerve driving reward-related behaviors and dopamine release. One key hormone involved in feeding regulation is cholecystokinin (CCK), a peptide released in the gut in response to food intake. Acting through the vagus nerve, CCK signaling is traditionally known to promote satiety, a physiological state in which feelings of fullness signal the cessation of eating. However, recent research has shown that CCK also plays a critical role in the vagal signaling pathways that drive post-ingestive macronutrient preference. The ability of vagal CCK signaling to reinforce food-seeking behaviors suggests that it may play a role in vagally-mediated reinforcement. The central hypothesis of this proposal is that asymmetrically expressed CCK receptor-expressing vagal neurons critically contribute to lateralized interoceptive reward signaling. The goal of this project is to determine the extent to which these neurons contribute to lateralized vagus-mediated reinforcement of appetitive behaviors. In Aim 1, we test the hypothesis that right vagal neurons are more responsive to CCK than left vagal neurons. In Aim 2, we test the necessity of right versus left CCK receptor-expressing vagus neurons in the development of fat preference. In Aim 3, we determine the extent to which CCK receptor-expressing vagal neurons are required for the reinforcement of learned behaviors by right vagus nerve stimulation (VNS). These experiments will reveal new insights into the mechanisms underlying lateralized interoceptive reward signaling. In doing so, the proposed work will critically inform the development and optimization of VNS and other therapeutic approaches for the treatment of obesity and metabolic disorders.

NIAID - National Institute of Allergy and Infectious Diseases

ABSTRACT Increased Treg T cell receptor (TCR) signaling is correlated with increased Foxp3+ regulatory T cell (Treg) function in organ specific autoimmunity. In the context of autoimmunity, both Tregs and autoimmune T cells target similar self-antigens, potentially increasing competition for TCR ligands. We propose that Tregs possess cell-intrinsic features that can increase their competition for antigen. Our preliminary data suggest that Tregs have higher levels of cholesterol within their cell membrane compared to conventional effector T cells, which correlate with tetramer binding, TCR signaling, and might increase relative Treg antigenic sensitivity and competition for antigen in vivo. It is well established that Tregs exhibit distinct metabolic profiles skewed towards fatty acid oxidation. Our intriguing new observations suggest that cholesterol metabolism impacts plasma membrane composition and TCR activation in Tregs. Furthermore, our data suggest that lipid metabolism could be manipulated to improve Treg function. This proposal will test the hypothesis that cholesterol metabolism is regulated by the transcription factor Foxp3 and can be increased to boost regulatory T cell function. We will begin addressing this hypothesis by pursuing two specific aims: 1) Test the specific role of recently identified regulator of cholesterol metabolism Spring1 in Treg function, and 2) Assess the impact of exogenous cholesterol uptake on Treg suppressive function. The objective of this proposal is to establish whether we can manipulate Treg function through cholesterol metabolism. The proposed research is significant, because it will determine Treg- specific regulation of cholesterol metabolism and its effect on Treg function in autoimmune and inflammatory models with implications for cancer, metabolic and heart disease.

NEI - National Eye Institute

Although intraocular pressure (IOP) is the only clinically modifiable risk factor for glaucoma, the exact role of IOP elevation in glaucomatous neurodegeneration is unclear, as the cause of glaucoma remains unknown. Even worse, glaucoma may progress in patients under controlled IOP, indicating that additional factors are pivotal to its pathogenesis. A critical barrier to progress in investigating glaucoma mechanisms is the limited comprehensive, quantitative, and non-invasive approaches for detecting and predicting the involvement of the entire visual system during glaucoma development. We recently developed these needed approaches using magnetic resonance imaging (MRI) and spectroscopy (MRS) to identify, for the first time, cholinergic dysfunction in the brains of glaucoma patients and experimental animal models. Despite the known importance of choline- containing compounds to the integrity of cell membrane and neurotransmission, very little is known about how changes in cholinergic signaling in glaucoma reflect the structural and functional damage along the visual pathway. Our primary objective is to investigate the role of this newly identified pathogenic cholinergic pathway in glaucoma patients and our novel rat models using advanced MRI and MRS techniques. We will test the central hypothesis that glaucoma is driven by impairments of the visual pathways that are mediated by the cholinergic nervous system. Aim 1: Test how cholinergic lesioning, neuromodulation, and supplementation contribute to glaucomatous damage and ameliorations in experimental rat models. Adult Long Evans rats will be induced with experimental glaucoma by chronic IOP elevation via intracameral hydrogel injection or lesioning of the basal forebrain followed by longitudinal eye, brain, and behavioral assessments. We will stimulate the cholinergic neurons of these animal models to examine their role in modulating IOP, visual brain activity, and visual function. We will also give different regimes of oral choline supplementation to determine their dose-dependency, therapeutic windows, and efficacy in ameliorating the deteriorations of glaucomatous visual pathways. Aim 2: Test the contribution of cholinergic nervous system to glaucomatous damage in patients. By examining the brains of healthy subjects and primary open-angle glaucoma patients with varying disease severity, we will determine the changes in neurochemicals relevant to the cholinergic system and how they alter with the structure and function of the visual system. To ascertain when cholinergic changes emerge in disease progression, we will define the relationships between cholinergic brain features across glaucoma stages using advanced statistical modeling and information gain assessment. Impact: Establishment and optimization of new, non-invasive glaucoma neuroimaging biomarkers and experimental modeling systems will open up opportunities to determine the neurodegenerative substrates of glaucoma in vivo and validate glaucoma neurotherapeutics. These findings will allow us to better monitor glaucoma progression and guide future studies to determine the cause or the effect of glaucoma for more targeted interventions.

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary Homeostatic Synaptic Plasticity (HSP) is the ability of neurons to exert compensatory changes in synaptic strength in response to altered neural activity, thereby acting as a critical protective mechanism during physiological processes such as learning/memory and development, as well as pathological conditions. Although nearly all HSP studies have focused on glutamatergic synapses, there is substantial evidence that cholinergic regions of the brain also experience significant changes in neural activity in multiple disorders and diseases, including Alzheimer’s disease (AD). Nevertheless, cholinergic HSP, especially at central synapses, and the mechanisms that regulate it have remained remarkably understudied. In the proposed studies, we will use the primarily cholinergic CNS of Drosophila as a genetically tractable model in which to unravel the molecular mechanisms underlying and regulating cholinergic HSP. This is currently the only model that has been developed to study central cholinergic HSP. In the proposed studies, we will validate cholinergic HSP in neurons in their intact circuitry for the first time. We will also use this model to address outstanding questions about the mechanisms that underlie and regulate HSP. We will dissect the role of the ER protein NACHO in the inactivity- induced up-regulation of the Drosophila α7 nAChR that underlies HSP. We will also examine in vivo the role of the transcription factors, NFAT and CREB, in regulating HSP, and identify downstream ion channel gene targets that contribute to HSP. Since ion channel/receptor genes and cellular regulatory mechanisms have proven to be highly conserved across species, we expect our findings to inform our understanding of cholinergic HSP in mammalian systems, and have broader, potentially, therapeutic, value.

St. Bonaventure University

Choose the Right Path

NYC Department of Cultural Affairs

Choral Chameleon, Inc.

Spanish Dance Arts Company, Inc.

Choreg. Fee: A. Hidalgo/New Work& Reconstructionof 3 Pieces by R.Lorca

Ukrainian Chorus Dumka of America Inc

Chorus, Dance & Drama Ensemble

Croda, Inc.

Commercial

JP Morgan Chase

CHP Equiptment

Christ Hospital Foundation

Christ Hospital Foundation is an active grantmaking foundation based in Cincinnati, OH. Focus: health. Contact the foundation directly for current funding opportunities.

State of Maryland

Christ Rock M.E. Church

State of Maryland

Christ Rock M.E. Church

State of Maryland

Christ Rock M.E. Church

State of Maryland

Christ Rock M.E. Church

State of Maryland

Christ Rock Methodist Episcopal Church

Christchurch School Foundation

Christchurch School Foundation is an active grantmaking foundation based in Christchurch, VA. Focus: education. Contact the foundation directly for current funding opportunities.