Grants

National Park Service

Create a cooperative weed management area (CWMA) that encompasses but is not limited to National Park Service and Cleveland Metroparks property located in the Cuyahog River Watershed with Geauga, Portage, Summit, and Cuyahoga Counties in northeast Ohio.

$75K

natural resources

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Control of biomolecular systems to guide cell phenotypes

NIGMS - National Institute of General Medical Sciences

Project Summary/Abstract Phenotype control, an active area of research in network control, is applicable to interacting biomolecular systems and can identify targeted interventions that lead to desired cell phenotypes. Phenotype control distinguishes itself from classical control theory in that (i) its objectives are related to dynamical attractors (e.g., stable states), and (ii) its interventions don’t need to be continuously adjusted based on the state of the system. This type of control is well-suited for guided cell differentiation, inducing cell fate changes, or inducing apoptosis of a target cell population. This research program will further develop two phenotype control methods. Feedback vertex set (FVS) control is based on the interaction network that underlies a biological system, and stable motif (SM) control is based on a dynamic model of the system. The PI has participated in the establishment of both of these methods, and has a track record of collaborative construction of experimentally validated dynamic models of biological systems. This research program will overcome the remaining challenge to the wide implementation of each phenotype control method. The barrier to wide application of FVS control is that in many systems the characterization of the target cell phenotype (e.g., the known state of a few biomarkers) is not sufficient to specify the desired state of all FVS nodes. This barrier will be eliminated by identifying the most parsimonious and sufficiently discerning characterization of each phenotype and extrapolating the existing biological knowledge to achieve this characterization. The bottleneck to the wide application of SM control is the long time needed for the development and verification of dynamic models. Automating the key steps of model construction and refinement, building on the recently developed BOOLean MOdel REfiner (boolmore) tool, will substantially decrease this time. The FVS and SM control methods will be implemented on networks constructed from curated pathway databases, on ensembles of dynamic models generated for each network, as well as on select dynamic models constructed in collaboration with domain experts. Integration of the two methods will identify multiple high-confidence interventions for each system. The predicted interventions will be validated via experiments done by the PI’s collaborators (see letters of Prof. Nobile and Prof. O’Rourke). The outcomes of the next five years will include a publicly shared suite of computational methods for efficient control of cell phenotypes as well as novel control protocols for multiple specific systems.

Up to $401K

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Control of CSF hydrodynamics and brain-waste clearance

NIA - National Institute on Aging

ABSTRACT: The accumulation of waste and neurotoxic proteins, such as amyloid-β and tau, is a hallmark of aging and neurodegenerative disorders like Alzheimer’s disease. The glymphatic system plays a critical role in brain-waste clearance. It facilitates the perfusion of cerebrospinal fluid (CSF) into the brain, which interchanges with interstitial fluid to flush out harmful waste, nanoplastics, and neurotoxic proteins. Our recent findings indicate that conditions impeding CSF flow dynamics—such as craniosynostosis and normal aging—disrupt this clearance system, exacerbating amyloid plaque buildup. Importantly, we have also shown that pharmacological activation of Piezo1, a mechanosensitive ion channel, using Yoda1 agonist enhances CSF-mediated waste clearance in both craniosynostosis and aged wild-type mice. However, a major gap remains in our understanding of how waste clearance is regulated at the cellular level. This obscures the cellular mechanism(s) by which Piezo1 acts to control brain waste clearance. Key preliminary data suggest that mechanical forces exerted by CSF flow may activate Piezo1 in brain border macrophages (BBMs). These cells are essential for brain waste clearance as they degrade extracellular matrix (ECM) proteins along arterial basement membranes, enabling proper arterial motion to drive CSF flow. This proposal aims to determine whether Piezo1 functions in BBMs to control brain-waste clearance, leveraging our team’s expertise in mouse genetics, high-resolution multi-photon imaging, and computational modeling. Aim 1 uses a pharmacological approach to investigate whether Yoda1 enhances brain-CSF perfusion by acting on BBMs to help regulate ECM remodeling. Aim 2 uses genetic approaches to directly test whether Piezo1 is required in BBMs to maintain CSF hydrodynamics and waste clearance by facilitating ECM degradation and arterial motion. Aim 3 examines the impact of Piezo1 manipulation in BBMs on amyloid pathology in mouse models of Alzheimer’s disease, including assessing whether stimulating Piezo1 activation can enhance amyloid clearance. By defining the role of Piezo1 in CSF- driven waste clearance, this work will establish a mechanistic framework for preserving glymphatic function across the lifespan. Targeting Piezo1 in BBMs may represent a novel therapeutic strategy to counteract age- related and disease-associated declines in brain-waste clearance, addressing a critical unmet need in Alzheimer’s disease and related dementias. As such, we expect our findings will lay the groundwork for translational efforts to develop new therapies aimed at sustaining cognitive health in aging populations. Our approaches may also be leveraged in the future to investigate how environmental pollutants (e.g., nanoplastic accumulation) may affect waste clearance and BBM functions, leading to cognitive impairment.

Up to $573K

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Control of hemoglobin expression by the chromatin remodeler CHD7

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY / ABSTRACT The developmental switch from fetal (HbF) to adult (HbA) hemoglobin expression is important scientifically as a paradigm of developmental transcriptional control and clinically as a target for treatment of hemoglobinopathies. Reversing this switch to increase HbF expression is an essential approach for gene therapy and new small molecule therapeutics to treat sickle cell disease and b-thalassemia. BCL11A, expressed exclusively in adult cells, is the predominant transcriptional repressor of HbF. However, attempts to develop specific small molecule BCL11A modulators have not been successful, leading to a concerted effort to understand the developmental regulation of BCL11A itself to uncover basic principles of developmental globin control and identify more amenable targets. We used two converging approaches to identify the CHARGE- syndrome associated chromatin remodeler CHD7 as a specific HbF regulator. First, CHD7 scored as an HbF activator in a CRISPR screen of chromatin remodeling proteins. Independently, we found that CHD7 is expressed at higher levels in a small subset of adult erythroblasts that can turn on HbF either spontaneously or in response to pharmacological inducers. In preliminary experiments, we find that CHD7 is expressed predominantly in fetal cells, but that ablation of residual CHD7 in adult erythroblasts leads to transcriptional upregulation of BCL11A and repression of HbF. We hypothesize that CHD7 is a developmentally controlled activator of HbF expression through BCL11A and potentially through direct action at the b-globin gene locus. In Aim 1, we will determine the mechanisms of CHD7 gene selectivity in globin gene regulation. In Aim 2, we will characterize the developmental control of CHD7 expression. This dissection of CHD7’s regulation and selectivity may provide new opportunities to therapeutically manipulate fetal hemoglobin for the treatment of sickle cell disease (SCD) and b-thalassemias. Additionally, we will use the extensive tools and data sets developed in erythroid cells to better understand the activity of CHD7 in other biological contexts.

Up to $134K

2028-02-28

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Control of HIV-1 latency and reservoir persistence in primary cells

NIAID - National Institute of Allergy and Infectious Diseases

ABSTRACT The latent HIV-1 reservoir that persists despite the effect antiretroviral therapy (ART) comprises infected cells with intact integrated proviruses that are transcriptionally near silent. The existence and maintenance of this reservoir in essentially all ART-treated individuals is a major barrier to curative interventions in HIV-1 infection, and necessitates the lifelong administration of ART. In the preliminary studies that underpin this proposal we developed a xenograft based model system in NSG mice that reliably generates populations of human primary memory CD4+ T-cells that contain latent proviruses carrying reporter genes. Our methods overcome some of the key limitations of existing approaches to study HIV-1 latency. We determined hundreds of HIV-1 integration sites in active and latent cell populations and uncover relationships between provirus genomic location, infected cell clonal expansion, and the establishment of HIV-1 latency after engraftment. Uniquely, we have recovered and cultivated in large numbers primary memory CD4+ T cell single-cell clones each harbouring a unique HIV-1 integration site in which latency was (or was not) established in vivo. Comparison of these clones with the small number of CD4+ T cell clones that harbor intact HIV-1 proviruses that have been cultivated from ART-treated individuals reveals features in common that suggest that the model system we have developed more accurately recapitulates features of HIV- 1 latency than those deployed heretofore. In Aim 1, we will build on our preliminary studies by deriving a diverse collection of primary CD4+ T-cell single cell clones that harbor latent or active HIV-1 proviruses. Therein, we will investigate the stability, dynamics an mechanisms of transitions between active and latent states at defined integration sites and, whether the new DNA synthesis that accompanies cell proliferation enables these transitions. We will determine relationships between the epigenetic profile of loci containing proviruses and whether proviruses are transcriptionally active or latent. We will further assess how the physiologic status of T-cell clones conspires with epigenetic profile of loci containing proviruses to impact the establishment of latency and transitions between active and latent states. In Aim 2 we will manipulate epigenetic modifications at or surrounding the site of provirus integration in the genome of primary memory CD4+ T-cell clones and determine their effects on HIV-1 latency. We will build a custom, targeted sgRNA library, focused on epigenetic modifiers and gene expression regulators and identify genes that affect HIV-1 latency in various genomic contexts. We will further conduct genome wide CRISPR screens in primary memory CD4+ T-cell clones to identify genes that regulate latency therein. Ultimately, we will aim to provide mechanistic insights into HIV-1 latency and evidence about how manipulation of latency might be accomplished, such that HIV-1 infection might be cured.

Up to $2.4M

2030-05-31

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Control of host invasion by protein complexes conserved across apicomplexan parasites

NIAID - National Institute of Allergy and Infectious Diseases

7. PROJECT SUMMARY/ABSTRACT How apicomplexan parasites recognize host cells to invade them remains a mystery. Since these parasites only replicate intracellularly, invading host cells is essential to their survival. Invasion relies on the coordinated secretion of proteins from two distinct types of organelles: micronemes and rhoptries. Rhoptries are exclusively discharged upon host-cell contact; however, the molecular events that trigger this process remain completely unknown. Understanding the factors required for rhoptry discharge can help us uncover the basis of host-cell recognition. Two conserved microneme complexes—the CLAMP and CRMP complexes—have recently been shown by the Lourido and Lebrun labs to be required for rhoptry discharge, making them likely mediators of host-cell recognition. Our preliminary studies have identified N-glycosylation pathways as key host requirements for rhoptry discharge. Loss of host N-glycosylation significantly reduced rhoptry discharge, while buffering any additional effect from knocking down the CLAMP or CRMP complexes. Based on these observations, we hypothesize that the CLAMP and CRMP complexes recognize host cells through N-glycans to mediate rhoptry discharge. This proposal brings together the two teams that discovered these critical complexes to examine how they recognize host N-glycosylation and mediate rhoptry discharge. Aim 1 will determine the glycan specificity of the CLAMP and CRMP complexes through traditional or liquid glycan arrays. Aim 2 will characterize how N-glycosylation alters the various stages of invasion using high-speed live-cell imaging to dissect the multi-stage invasion process and pinpoint defects to rhoptry discharge. Aim 3 will characterize the signaling events triggered by host-cell recognition through phosphoproteomics and proximity-labeling. Taken together the proposed experiments will uncover how apicomplexans respond to host contact to discharge rhoptries and initiate invasion. Beyond its fundamental importance, this information can be used to design inhibitors of host cell entry that would block parasite infection.

Up to $900K

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Control of obesity by an appetite-suppressing peptide

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

SUMMARY There is an urgent need for new therapies for metabolic disorders, including obesity, which is associated with a significant decrease in life expectancy by 5–10 years and increased mortality resulting from diabetes and cardiovascular diseases. Peptide hormones comprise a class of small (<100 amino acids), low abundance, bioactive molecules involved in regulating physiological processes such as glucose and insulin levels, food intake, and energy expenditure, making them attractive targets for modulation of energy metabolism. However, the functional identification and characterization of small, proteolytically cleaved peptides have traditionally been challenging because of their low abundance and the difficulties in distinguishing bioactive from inactive fragments or degradation products. Recently, my lab discovered a 12-mer secreted non-incretin human peptide called BRP that controls obesity by lowering food intake through the central activation of Fos. This innovative proposal will explore the mechanisms and biology of BRP to validate the receptor target for this promising cleavage product. Based on preliminary data, we hypothesize that BRP is endogenously cleaved from the precursor BRINP2 by the proconvertase PCSK1, and degraded by proteolytic processing. Based on a receptor screen, we also hypothesize that its function is linked to its binding to a GPCR, thereby activating a CREB signaling pathway leading to Fos transcription. Our hypotheses are based on robust preliminary data generated using in vitro models, structure- activity relationships, and in vivo studies. In Aim 1 of this proposal, we will test the hypothesis that BRP is generated by cleavage of a proconvertase and that BRP is regulated by degradation. These studies will be important to understand the endogenous mechanism of regulation. In Aim 2, we determine the causal hypothalamic region and cell type activated by BRP. In Aim 3, we will validate the target receptor candidate and the signaling mechanism for BRP that is responsible for its appetite-suppressing effects. In conclusion, these studies will determine the endogenous regulation and mechanistic action of BRP, which will open up a new pathway of peptide signaling in body weight regulation.

Up to $783K

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Control of Renal Function in Health and Disease 2026

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY: 2026 Control of Renal Function in Health and Disease: Next Generation This NIH R13 grant application seeks support for a travel award program for the upcoming 2026 conference entitled “Control of Renal Function in Health and Disease: Next Generation”. The American Physiological Society is sponsoring this conference, which is scheduled for June 22-26, 2026 in Fontana-on-Geneva Lake, Wisconsin. There are several major translational and therapeutic areas included in the meeting that have relevance to the scientific community. To encourage engagement and participation of trainees and early career investigators in the field, we propose implementing an NIH-funded travel award program specifically designed to support their attendance at the conference. Nearly half of U.S adults have hypertension, and among those affected, only 24% have their blood pressure under control. Both clinical and preclinical studies have demonstrated that hypertension alters the kidney's ability to maintain salt and water homeostasis through disruptions in renal hemodynamics and inflammation-driven mechanisms. Thus, the kidney is central to the pathogenesis of hypertension and is a major target of end-organ-damage, which further exacerbates hypertension. Furthermore, the rising prevalence of obesity, metabolic syndrome and diabetes has significantly contributed to the increasing incidence of chronic kidney disease (CKD). Also, the incidence of acute kidney injury (AKI) is increasing, driven by a rise in ischemic and nephrotoxic events. As such, it is essential to deepen our understanding of how hypertension, CKD, and AKI contribute to the development of kidney injury. Over the past 5 years, several novel methodologies have emerged for studying kidney function and disease, offering valuable insights for both renal physiologists and nephrologists alike. Therefore, there is a strong need within the scientific community for a dedicated conference addressing these critical topics. The organizing committee has designed a meeting program that highlights emerging areas in kidney function and disease including symposia on topics such as obesity, diabetes and metabolic syndrome; inflammation and the kidney; developmental programming of kidney disease; genetics, epigenetics of the kidney; immunology and the kidney, circadian biology of kidney function, single cell RNAseq and spatial transcriptomics in kidney disease and organoids. The symposia will also explore recent advances in established areas of renal research including hemodynamics, acute kidney injury, integrative control of kidney function, chronic kidney disease, autocoids and the impact of nutrition on kidney function and hypertension.

Up to $15K

2027-06-30

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Control of T-cell stemness and T-cell exhaustion by KEAP1-NRF2 axis

NCI - National Cancer Institute

PROJECT SUMMARY In cancer and chronic infection, T cells develop into a dysfunctional state called exhaustion because of persistent antigen stimulation. Exhausted T cells upregulate immune checkpoints, display dysregulated metabolism, and progressively lose effector function and the ability to persist and develop immune memory. T cell exhaustion hinders the clearance of pathogens and malignant cells by the immune system and limits the effectiveness of immunotherapies such as chimeric antigen receptor (CAR) T cell therapy. Therefore, understanding how T cells adapt to chronic antigen receptor signaling is critical for developing more effective immunotherapies. A stem-like CD8 T cell subset has been identified in chronic infections and cancers. Stem-like CD8 T cells mediate long-term immunity by self-renewal and replenishing other CD8 T cell subsets. Stem-like properties in T cells are essential for the efficacy of immunotherapies. We have identified key transcription factors that regulate the differentiation of stem-like CD8 T cells. However, the molecular program underlying the adaptation of stem-like CD8 T cells to chronic antigen receptor signaling is incompletely understood. Our recent findings show that the redox sensing KEAP1-NRF2 pathway is critical for the differentiation of stem-like CD8 T cells and adaptation of CD8 T cells to chronic antigen receptor signaling. In the proposed study, we will determine how the KEAP1-NRF2 pathway regulates the adaptation of CD8 T cells to persistent antigen receptor signaling through preventing TCR hyperactivation and promoting metabolic fitness. Our study will shed important new light on the development of more potent and efficacious immunotherapies for cancers and chronic infections. Furthermore, KEAP1 and NRF2 have been extensively investigated as potential drug targets for chronic diseases. Therefore, our findings hold significant promises for informing interventions that aim at modulating this pathway.

Up to $402K

2031-04-30

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Control of the Tongue by the Primate Cerebellum

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary/Abstract The tongue mediates behaviors fundamental to survival, such as vocal communication and food manipulation. Cerebellar dysfunction disrupts normal tongue muscle activation patterns, leading to significant clinical pathologies in swallowing and speech that severely impact quality of life and can be fatal. Despite this clinical significance, the neural mechanisms of cerebellar tongue control in non-human primates remain largely unexplored, with no standardized behavioral tasks for measuring lingual motor learning in these models. Pathologically, cerebellar dysfunction is characterized by deficits in Purkinje cells (P-cells), the sole output neurons of the cerebellar cortex. P-cells produce two types of action potential: the simple spike, which is their primary output, and the complex spike, which is triggered by climbing fiber inputs to the P-cells. Complex spikes are often in response to error, and are always followed by complete suppression of the simple spikes. Though we know that P-cells sculpt the computational output of the cerebellar cortex, the way in which they enact population-level control of tongue movements remains mysterious. Here, I propose to establish the marmoset (Callithrix jacchus) as a model for cerebellar tongue control. Marmosets present several key advantages: 1) their long and protrusive tongue is easy to track with computer vision, 2) their cerebellum demonstrates developmental alignment with non-human primates while remaining accessible with recording instruments designed for mice, and 3) their survival depends on harvesting tree sap via skilled licks, suggesting robust cerebellar involvement in control of targeted tongue movements. Our recent work in marmosets has yielded a breakthrough: when a P-cell is briefly but completely suppressed by a complex spike, the result is a small displacement which serves as a proxy for that cell's causal contribution to behavioral output. I hypothesize that grouping P-cells by their downstream effects on licking will reveal population-level computations that the cerebellum performs to aid in control of the tongue. However, testing this hypothesis requires mapping downstream effects of P-cell suppression across cerebellar lingual regions, as it is a prerequisite for functional classification of P-cells and subsequent analysis of population-level dynamics during targeted licking. Here, my aim is to first develop an experimental setup that will allow for a wide range of errors during licking, thus driving complex spikes. Next, I will record from various cerebellar lingual regions and use spike-triggered averaging to measure the change in tongue kinematics caused by the complex spike-induced suppression of each P-cell. To test specificity of the effects due to suppression, and not error, I will consider movements in which there was no error, but a suppression occurred. This will test whether downstream effects of P-cells are regionally organized in the cerebellum. Overall, my proposed work will bridge the gap in our understanding of cerebellar control over tongue movements and will aid lingual neuroscience by developing a new non-human primate model in marmosets.

Up to $50K

2029-01-31

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Control of transcriptional integrity by Integrator and PP2A

NIGMS - National Institute of General Medical Sciences

Project Summary Objective: The overall goals of this application are understanding the molecular basis of RNA Polymerase II (RNAPII) pausing and pause-release and determining how disease-associated mutations in the PP2A phosphatase reverse the pausing balance to promote transcriptional elongation. Proposed research: The mammalian RNAPII transcription cycle is regulated by cyclin-dependent kinases (CDKs) that target the catalytic core of RNAPII and many of its co-factors. We recently identified Int-PP2A, a module of the RNAPII-associated Integrator complex that recruits the PP2A phosphatase to active genes to oppose CDK9 activity. We demonstrated that Int-PP2A targets Ser-2 residues at the C terminal domain (CTD) of RNAPII as well as DSIF/Spt5. While our work revealed that phosphatases are recruited co-transcriptionally in mammalian cells to promote pausing, it remains unknown how Int-PP2A’s activity is established at the proximal promoter and how it is modulated. Here we propose to: a) determine how Int-PP2A establishes paused RNAPII via the INTS3 subunit; b) determine the role of PP2A carboxy-methylation in transcriptional regulation; c) determine the effect of mutant PP2A on transcription in models of neuronal differentiation.

Up to $592K

2031-03-31

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Control of virus-induced lung sequelae by P2RX7-expressing CD4+ T cells

NHLBI - National Heart Lung and Blood Institute

Project summary: The overarching goal of this project is to define how the damage induced by severe respiratory infections can promote pathogenic lung CD4+ T cells which, in turn, perpetuates the lung sequelae. In response to infections such as influenza or SARS-CoV2, T cells are recruited to the lung parenchyma and establish tissue residency. That includes helper CD4+ T cells, which produce cytokines and support other lung immune responses. In mild infected individuals, lung-resident CD4+ T cells can form protective memory populations, which are important against viral re-exposure. In contrast, severe infections with these viruses can lead to an excessive accumulation of lung-resident CD4+ T cells, which is correlated with the development of widespread lung damage, which is often not reversible. These non-reversible sequelae are typical clinical observations of patients with “Long COVID” and (more recently appreciated) “Long Flu”, i.e., patients with irreversible loss of organ function due to past respiratory viral infections. Understanding how and whether lung pathogenic CD4+ T cell responses form will pave the way for novel strategies to prevent or treat the long-term complications of respiratory viral infections. On this direction, we found, in recently published studies, that lung- resident CD4+ T cells with characteristics of the follicular helper subset (called “tissue-resident helper” or TRH cells) accumulate at excessive numbers in response to severe influenza-infected mice and in COVID-19 patients with lung sequelae. These lung TRH cells express high levels of the receptor P2RX7, a purinergic ion channel that responds to the “danger signal” extracellular ATP (eATP). Notably, our recently published studies also defined that expression of P2RX7 is necessary for the accumulation of lung TRH cells in response to severe influenza, and knockout of this molecule protects mice from long-term lung damage. In this proposal, we aim to define how recognition of eATP through P2RX7 promotes the establishment of pathogenic lung TRH cells, and if P2RX7 blockade can prevent or revert lung sequelae caused by severe respiratory infections. In Aim 1, we will determine how P2RX7/eATP promotes the ability of CD4+ T cells to enter the lung tissue and differentiate into pathogenic TRH cells. We will build upon preliminary data and test the hypothesis that P2RX7 is needed for (a) the induction of CXCR3-mediated CD4+ T cell lung parenchymal infiltration, and (b) their localization into lung dysplastic areas for the conversion into the TRH cell phenotype. To answer these questions, we will use a combination of genetic and pharmacological approaches, as well as a series of ex vivo and in vivo imaging and spatial transcriptomics assessments. In Aim 2, we will test if pharmacological inhibition of P2RX7 can be used to (a) prevent and/or (b) revert the lung sequelae caused by severe influenza or SARS-CoV2. We will build upon preliminary data showing that blockade of this receptor is sufficient to decrease the numbers of lung TRH cells. Our proposed studies will define how eATP regulate lung-resident pathogenic CD4+ T cell responses, and how P2RX7 blockade can be used therapeutically to treat lung disease caused by respiratory viruses.

Up to $1.7M

2028-06-30

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Control Priority and/or Incipient Invasive Species on the Channel Islands

National Park Service

United States Department of the Interior, National Park Service (NPS) Notice of Intent to Award. This is not a request for applications. This posting is to provide public notice of NPS' intention to fund the following project activities without full and open competition: Task Agreement P17AC01684 under master Cooperative Agreement P17AC01703 with The Nature Conservancy, for the project titled, "Control Priority and/or Incipient Invasive Species on the Channel Islands."

$71K – $200K

natural resources

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Control Systems

U.S. National Science Foundation

The CS program supports innovative research on control theory and control technology driven by real life applications. The program accepts proposals on transformative research in established topic areas such as model-based control. However, the program emphasis is on paradigm-shifting ideas for control strategies that may be inspired by nature, unconventional applications, and the combined role of feedback and uncertainty in systems that incorporate large numbers of sensors and actuators. New sensor and actuator concepts that integrate feedback and signal processing to achieve a sensing or actuation objective are also funded.

sciencetechnology

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Controlled Clinical Trials on Long-Term Effects of Nutritional Interventions on the Progression of Risk Factors for Age-Related Chronic Conditions Over the Life Span and Their Age of Onset

National Institutes of Health

The National Institute on Aging (NIA) intends to publish a Notice of Funding Opportunity (NOFO) to solicit applications for randomized controlled clinical trials on long-term effects of nutritional interventions on the progression of risk factors for age-related chronic conditions over the life span and their age of onset.Although considerable information is available on health benefits and risks of a variety of nutritional factors (e.g., macronutrients, overall caloric intake, differing nutrient sources) there remains a need for better understanding of long-term benefits and potential risks of differing nutritional factors and dietary practices to maintain health across the full range of the life span. Rigorous understanding of these effects requires long-term controlled clinical trials of preventive interventions in younger and/or older persons. Given the rates of risk factor progression in younger persons and of accumulation of morbidities in later life, many such trials will require long-term intervention durations and follow-up of at least 5 years to provide sufficient power and evidence of their long-term effects.  In order to support projects of sufficient duration to provide for start-up, enrollment, follow-up, and outcome data analyses in such trials, applications in response to this NOFO may propose projects of up to seven years in length.Applications are not being solicited at this time. Notice is being provided to allow potential applicants sufficient time to develop meaningful collaborations and responsive projects. This NOFO intends to utilize the U19 activity code. Investigators with expertise and insights into this area of aging research are encouraged to begin to consider applying for this new NOFO.

2026-09-25

Health

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Controlled Clinical Trials on Long-Term Effects of Nutritional Interventions on the Progression of Risk Factors for Age-Related Chronic Conditions Over the Life Span and Their Age of Onset

National Institutes of Health

The National Institute on Aging (NIA) intends to publish a Notice of Funding Opportunity (NOFO) to solicit applications for randomized controlled clinical trials on long-term effects of nutritional interventions on the progression of risk factors for age-related chronic conditions over the life span and their age of onset.Although considerable information is available on health benefits and risks of a variety of nutritional factors (e.g., macronutrients, overall caloric intake, differing nutrient sources) there remains a need for better understanding of long-term benefits and potential risks of differing nutritional factors and dietary practices to maintain health across the full range of the life span. Rigorous understanding of these effects requires long-term controlled clinical trials of preventive interventions in younger and/or older persons. Given the rates of risk factor progression in younger persons and of accumulation of morbidities in later life, many such trials will require long-term intervention durations and follow-up of at least 5 years to provide sufficient power and evidence of their long-term effects. In order to support projects of sufficient duration to provide for start-up, enrollment, follow-up, and outcome data analyses in such trials, applications in response to this NOFO may propose projects of up to seven years in length.Applications are not being solicited at this time. Notice is being provided to allow potential applicants sufficient time to develop meaningful collaborations and responsive projects. This NOFO intends to utilize the U19 activity code. Investigators with expertise and insights into this area of aging research are encouraged to begin to consider applying for this new NOFO.

2026-09-25

Healthhealthcare

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Controlled Delivery of Adjuvanted Multivalent Fusion Peptide Focused HIV Vaccines

NIAID - National Institute of Allergy and Infectious Diseases

Controlled Delivery of Adjuvanted Multivalent Fusion Peptide Focused HIV Vaccines Project Summary The development of a safe and effective vaccine against HIV-1 continues to be a global health priority and has posed a formidable scientific challenge. Recent advances in vaccinology and immunology highlight great promise in enhancing potency of vaccine-induced immunity using prolonged delivery of vaccine immunogens and adjuvants. Striking increases in the induction and persistence of germinal centers produced by such regimens in rodents and non-human primates highlight the enormous benefit in affinity maturation of vaccine-specific B cells, which is critical for HIV-1 targeted vaccines. Notably, we have recently found that the SOSIP+3M-052 combination induced antigen-specific long-lived plasma cells that successfully trafficked to the bone marrow in non-human primates (NHPs) and were found to be stable for 2-3.5 years in independent studies. We seek to capitalize on these insights with five mutually reinforcing components: (i) safe and injectable hydrogels, based on unique chemistry of tunable bond formation and disconnection, that provide uniquely tunable extended release properties; (ii) safe and highly immunogenic virus-like particle platforms for multivalent antigen display; (iii) platform-switching heterologous immunization to focus the immune response on the HIV-1 fusion peptide; (iv) state-of-the-art SOSIP-based envelope glycoprotein (Env) immunogens; and (v) a nanoparticle-based form of the TLR7/8 targeted adjuvant 3M-052. These tools will be used to generate vaccine-induced durable and protective HIV-1 specific immunity, and to study responses at the cellular, molecular, and antibody-epitope levels in NHPs to maximize the changes of clinical success. Our three specific aims blend innovative chemistry, immunogen display, and delivery (Finn lab) with optimization of vaccination strategies coupled with deep immunological and vaccinological analyses in rodents and NHPs (Kasturi Lab). Upon successful completion of the program, we will have validated a modular class of vaccine formulations and identified key determinants of vaccine-induced durable and protective humoral immunity. This work will enable rapid future optimization of candidate vaccines against HIV-1, and potentially other pathogens, to elicit broad and long-lasting protection.

Up to $725K

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Controlling and Preventing STIs in US Health Departments (CAP-STIs)

Centers for Disease Control - NCHHSTP

CDC is funding programs that track, prevent, and control sexually transmitted infections (STI) in state, district, territorial, and city or county health departments.The purpose of this NOFO is to track, prevent, and control three common STIs: syphilis, gonorrhea, and chlamydia.The NOFO supports the goals of the Sexually Transmitted Infections National Strategic Plan 2021-2025:Prevent new STIs.Improve the health of people by reducing adverse outcomes of STIs.Implement STI prevention technology and innovations more quickly.Reduce the impact of STIs in areas or populations disproportionately impacted by STIs.Achieve integrated, coordinated efforts that address the STI epidemic.Local surveillance data will determine the priority populations for this NOFO. Each program should focus on populations that are disproportionately impacted by STI transmission. To be successful with this NOFO, you will need to collaborate with partners to address interconnected comorbidities and sexual health.

2026-10-31

Healthhealthcare

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Controlling and Preventing STIs in US Health Departments (CAP-STIs)

Centers for Disease Control - NCHHSTP

CDC is funding programs that track, prevent, and control sexually transmitted infections (STI) in state, district, territorial, and city or county health departments.The purpose of this NOFO is to track, prevent, and control three common STIs: syphilis, gonorrhea, and chlamydia.The NOFO supports the goals of the Sexually Transmitted Infections National Strategic Plan 2021-2025:<ul style="list-style-type:circle;"><li data-list-item-id="e79cf983ba39763c23eda8aed158102f8">Prevent new STIs.</li><li data-list-item-id="e437a644cc861328b27303eb97c3183d7">Improve the health of people by reducing adverse outcomes of STIs.</li><li data-list-item-id="eafa674f30590fa4a2b36407909366a38">Implement STI prevention technology and innovations more quickly.</li><li data-list-item-id="ed171c07ec21ab10e660bc91b6d331024">Reduce the impact of STIs in areas or populations disproportionately impacted by STIs.</li><li data-list-item-id="e29b7cb9079311e0a57a0f69863d650b6">Achieve integrated, coordinated efforts that address the STI epidemic.</li></ul>Local surveillance data will determine the priority populations for this NOFO. Each program should focus on populations that are disproportionately impacted by STI transmission. To be successful with this NOFO, you will need to collaborate with partners to address interconnected comorbidities and sexual health.

2026-10-31

Health

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Controlling epilepsy symptoms with precisely timed inhibition and circuit editing

NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY/ABSTRACT Temporal lobe epilepsy (TLE) is a complex neurological disorder that is characterized by spontaneous, reoccurring seizures and often presents with debilitating cognitive comorbidities including learning and memory deficits. Current treatments for TLE are ineffective at managing cognitive comorbidities and often exacerbate these symptoms. The mechanisms underlying cognitive impairments in TLE are poorly understood, but learning and memory deficits are thought to arise when TLE pathologies disrupt the normal function of hippocampal circuits that support these cognitive processes. Circuits in the hippocampal dentate gyrus (DG) are known to support learning and memory and have been shown to be disrupted in TLE patients and in animal models of TLE. Recently, Dr. Shuman showed that the spike timing of DG interneurons is disrupted in TLE. Additionally, he showed that restoring proper spike timing of DG interneurons with closed-loop optogenetic stimulation decreased seizure susceptibility in TLE mice. Because proper spike timing in the hippocampus is an important mechanism that supports learning and memory computations, I hypothesize that DG interneuron spike timing is also important for behavior. In aim 1, I will test this hypothesis by using closed- loop optogenetic stimulation to alter the spike timing of DG interneurons relative to ongoing theta oscillations. I predict that disrupting DG interneuron spike timing in non-epileptic mice will impair learning and memory while restoring the disrupted spike timing of DG interneurons in TLE mice will restore learning and memory deficits. While optogenetic approaches are great for assessing the causal relationships between physiological processes and behavior, there are a number of barriers that limit the translational potential of optogenetics. In aim 2, I will employ a novel circuit-editing tool to increase connectivity between DG interneurons and their upstream inputs in the medial entorhinal cortex (MEC) with the goal of increasing feedforward inhibition in the DG. I hypothesize that increasing connectivity to DG interneurons will decrease seizure susceptibility. Additionally, I predict that this approach will restore the proper spike timing of DG interneurons because inputs fire at the same preferred phase of theta as DG interneurons and are not disrupted in TLE. Circuit-editing is a novel technique that has never been applied to epilepsy. Successful implementation of this approach could result in a transformative gene therapy for epilepsy patients and will inform how feedforward inhibition in the DG normally supports hippocampal physiology. The following research project and training plan were designed to help me grow both scientifically and professionally, and support from this grant will be invaluable as I continue to work towards my goal of becoming an independent researcher. The outstanding opportunities provided by the Shuman lab and Mount Sinai provide the ideal training environment for me as I pursue my postdoctoral fellowship and ultimately a career in academic research.

Up to $76K

2029-03-04

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Controlling Invasive Plants

National Park Service

This Announcement is NOT a request for applications. This announcement is to provide public notice of the National Park Service's intention to award financial assistance.

$15K – $45K

Education

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Controlling tumor-infiltrating regulatory T cell function by the IL-17-Ybx1 signaling pathway

NCI - National Cancer Institute

Project Summary/Abstract: Regulatory T cells (Tregs) play key roles in immune homeostasis, tumor development, and cancer therapy through suppression of inflammation. How the inflammatory tumor environment shapes the behavior of Tregs in turn, is less known. This knowledge gap precludes our ability to selectively block the activity of tumor infiltrating Tregs, while leaving systemic Treg function intact. One of the prominent inflammatory pathways involves interleukin-17 (IL-17), which has been shown to promote tumor development in multiple tissues including the gut. IL-17 family cytokines promote inflammation that drives the development of colorectal neoplasia, which eventually lead to colorectal cancer (CRC). Thus far, the underlying mechanism has largely been attributed to IL-17’s impact on tumor cells and myeloid cells. Our preliminary studies show that targeted ablation of IL-17 signaling on Treg cells increased colonic tumor development in mice, demonstrating a previously unknown protective role of IL-17 in CRC. We found that IL-17 directly signals to Tregs to promote their immune suppressive signature and more importantly, alternative splicing of RNAs in these cells. We also found that IL-17 promotes the expression of the RNA binding protein (RBP), Ybx1, and enhances the splicing of RNAs whose protein products are critical for Treg function. These genes (Foxp3, IL-27RA, and Stat3) also contain RNA motifs that can be recognized by Ybx1, whose role in Treg is unknown. Ablation of Ybx1 in both human and mouse Tregs resulted in reduced Treg immune suppression function, and reduced expression of immune suppressive protein Galactin-1. We demonstrate that proper splicing of Galactin-1 mRNA depends on Ybx1. These findings lead to our hypothesis that IL-17 promotes Treg function and suppresses CRC development through Ybx1 mediated alternative RNA splicing, and that a similar IL-17-Ybx1 pathway promotes Treg activity in established tumors and impedes cancer immunotherapy. Given the critical roles of both Tregs and Th17 cells in tumor development and cancer therapy, along with the knowledge gap relating to the impact of RBPs on Treg biology, we propose the following studies: 1) delineate the mechanism by which the IL-17-Ybx1 pathway regulates alternative RNA splicing and function of Tregs; 2) test if the IL-17-Ybx1 pathway in CRC can be manipulated to prevent gut tumorigenesis; and 3) test the feasibility of targeting IL-17-Ybx1 pathway for the enhancement of cancer immunotherapy. These investigations will provide new insights into the mechanisms by which the inflammatory tumor microenvironment (TME) controls Treg function, and guide the invention and use of novel therapies for the treatment of CRC in humans. For example, based on a role for Ybx1 in promoting immune suppressive function of Tregs in CRC, we may employ targeted therapy by degrading Ybx1 in tumor infiltrating Tregs to foster an immunologically “hot” environment for enhanced cancer immunotherapy. Justification for the use of animal models We propose to use multiple animal models of cancers in this project. These models closely mimic human colorectal cancers by simulating tumor cell mutation process, microbiota interaction, and tumor environment evolution, allowing us to interrogate the mechanism of Ybx1-controlled Treg cell function in cancers. These models cannot be replaced with non-animal studies such as in vitro cell culture or organs-on-a-chip systems.

Up to $485K

2031-05-31

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Conversations About Race & Equality-A Foundation

Mount Baker Community Club

The Mount Baker Community Club will host a three-hour facilitated workshop about race on Sunday, November 18, 2-5pm, at the Mount Baker Community Club, 2811 Mt. Rainier Dr. S. Free and open to public, the workshop will lay the foundation for talking about race, particularly with children. 30-50 participants are expected.

Up to $700

Rolling

general

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Converting wound scar into healing with regeneration

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

Summary The goal of this grant is to understand the regulation of SHH-driven hair follicle neogenesis (HFN) in adult wounds. While much research focuses on wound healing, scarring, particularly from burns, trauma, and surgeries, remains largely overlooked. Scarring affects over 50% of the U.S. population, with 50 to 80 million new scars formed annually, resulting in significant cosmetic, psychological, and social burdens. Yet, no effective anti-scarring therapy currently exists. We previously developed a model in which large wounds in mice can lead to efficient hair follicle regeneration, opening the door to understanding the molecular mechanisms of HFN. Our lab has identified Sonic Hedgehog (SHH) as a critical factor in determining whether wounds heal with hair follicle regeneration or fibrosis and how SHH interacts with WNT and BMP signaling pathways for successful HFN. These findings raise new possibilities about the roles of SHH in the unresolved issue of wound scar remodeling: Can SHH remodel existing scars? If so, how long after wounding is it effective? And can this approach be applied to human scars? Furthermore, a longstanding question is how a developmental signal like SHH can be induced after wounding and what prerequisites are necessary for this signal to occur. This project aims to investigate the effect of SHH on old scars long after healing (Aim1), explore one of the upstream mechanisms we’ve identified as essential for SHH induction in large wounds (e.g., angiogenesis) (Aim 2), and examine how SHH signaling can similarly induce HFN using human fibroblasts (Aim 3).

Up to $595K

2031-02-28