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24 grants worth up to $14.9M match your search

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Deconstructing and targeting aneuploidy in human cancer

open

NCI - National Cancer Institute

Summary Aneuploidy—the presence of chromosome gains and losses—is very rare in normal tissues but occurs in more than 80% of human tumors, especially in solid tumors. A high level of aneuploidy in tumors correlates with higher-grade disease, tumor progression, and resistance to therapy. Whether and how aneuploidy contributes to formation and progression of human tumors is not well understood. Whereas genomic and clinical studies in cancer patients suggest that aneuploidy drives tumorigenesis, experimental studies in mouse models and in vitro systems has so far yielded conflicting data on the role of aneuploidy in tumors. Human tumors are often specifically associated with either increases or decreases in the number of specific chromosome(s). One of the main obstacles to progress has been the technical limitation of not being able to engineer the ‘right’ type of aneuploidy in the ‘right’ cell type. Our ultimate goal is to dissect whether and how aneuploidy contributes to initiation and progression or human tumors. Our first objective here is to generate cellular models that faithfully recapitulate the aneuploidy patterns found in tumors in order to study how aneuploidy affects the pathobiology of tumor cells (their ability to grow in vitro or in vivo, to evade cell death pathways, to survive cellular stress and to regulate transcription and translation). Our second objective is to uncover vulnerabilities and synthetic lethal interactions potentially associated with the aneuploid state. The outcomes of the proposed project will represent the foundation to achieve the long-term goal of our lab, which is to develop a better understanding of the causes and consequences of aneuploidy in human tumors in order to uncover aneuploidy-associated biomarkers and therapeutic targets. To accomplish this goal, we will first use a panel of newly generated human cells containing different degrees and types of aneuploidy to compare diploid and aneuploid cells for several tumor-related cellular phenotypes both in vitro and in vivo. Secondly, we will adopt a systematic approach to identify genes and pathways that when blocked, inhibit proliferation and survival of aneuploid tumor cells but not normal cells. Third, we will perform a protein and phospho-protein analysis mainly of colorectal tumor patients’ samples to dissect the consequences of aneuploidy at the level of protein stability and pathway regulation. Our results will fill an important gap of knowledge in our current understanding of how aneuploidy evolves during tumorigenesis and how we might take advantage of this knowledge to improve patient outcomes.

Up to $478K

2028-03-31

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Deconstructing nuclear speckles contribution to muscle stem cell activation across lifespan

open

NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

Abstract Skeletal muscle contains a population of adult stem cells called satellite cells or muscle stem cells (MuSCs) that are responsible for regeneration after injury. MuSCs utilize gene expression programs to maintain quiescence and differentiate after injury and a key regulator of gene expression is splicing, which uniquely changes when transcripts interact with nuclear speckles. Nuclear speckles are membrane-less biomolecular condensates that phase separate proteins, RNAs and chromatin, but how these organelles regulate molecular processes in MuSCs remains unknown. Key experiments from our laboratory provide rigorous support for a role of nuclear speckles and splicing in MuSC function, which were attenuated in old age. The overarching objective of this program is to establish a systems-based approach to understand how nuclear speckles and alternative splicing contribute to MuSC programs of activation and regeneration across lifespan. In Aim 1, we will demonstrate that the loss of a nuclear speckle scaffolding protein, Srrm2, will reduce regenerative potential of muscle stem cells. In Aim 2, we will establish that increases in oxidative stress from old age attenuate nuclear speckles and RNA splicing that regulate muscle stem cell activation and repair of muscle injury. In both Aims, we will use novel transgenic animal models, sophisticated bioinformatics analysis and highly innovative molecular tools to build a comprehensive and new understanding of nuclear speckles influence on alternative splicing and stem cell activity. Successful completion of this program will advance our knowledge of fundamental cell biology for regenerative medicine, and provide a myriad set of insights across molecular, cellular and tissue scales.

Up to $630K

2031-03-31

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Deconstructing RNA polymerase III regulation and function

open

NIGMS - National Institute of General Medical Sciences

Project Summary / Abstract Deconstructing RNA polymerase III regulation and function RNA polymerase III (Pol III) transcription produces a plethora of noncoding (nc)RNAs essential for cell function and frequently dysregulated in contexts relevant to human health, including tRNAs, 5S rRNA, and small nuclear (sn)RNAs. Pol III activity is, itself, directly linked with modulating self-renewal and differentiation, and Pol III- derived ncRNAs individually promote cell proliferation and migration phenotypes via RNA-based mechanisms, altogether linking Pol III transcription dynamics and downstream small RNA landscapes to changes in cellular physiology. However, the full breadth of Pol III transcription and the mechanisms that shape tissue-specific patterns remain gaps in fundamental knowledge due to limited holistic studies of Pol III activity in cells. This proposal leverages a unique combination of genomic and biochemical strategies to systematically profile the breadth of Pol III activity and uncover new regulatory mechanisms - focusing first on a disease-associated Pol III subunit (RPC7a) and the Nucleosome Remodeling and Deacetylase (NuRD) complex. This cross-modality framework applies innovative genomic techniques, such as direct Pol III-4SU-UV-CLIP-nascent-seq and orthogonal analysis of Pol III-centered RNA chaperone protein La (SSB) ncRNA interactions, as well as traditional in vitro transcription tests to characterize both cellular and biochemical mechanisms. Determining the full range of Pol III transcription and the mechanisms contributing to context-specific Pol III regulation will have direct relevance to understanding Pol III dysregulation in cancer, infection, and other diseases, and will open new avenues for research on basic mechanisms of transcription regulation.

Up to $372K

2031-03-31

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Deconvoluting disparate roles of DDX6 in translational control

open

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY The putative oncogene DDX6 (RCK, p54) has critical roles in the nervous system, embryonic cells, and somatic cells. The importance of DDX6 is further emphasized by rare pathogenic missense mutations in DDX6 that are associated with developmental delays and intellectual disability in children. DDX6 is a member of the DEAD-box RNA helicase family, which are broadly involved in regulation of messenger RNA (mRNA) and translation. Despite its establishment as critical regulator of translation initiation, the molecular mechanisms that underlie DDX6 function remain unclear. Major roadblocks to this include that translation initiation is a heterogenous, multistep process that requires a dozen components and occurs within a minute. Further, the identity of interacting partners in a given DDX6 regulatory complex determines whether DDX6 promotes or inhibits protein synthesis. This complicates cellular study of DDX6, as DDX6 likely forms multiple distinct regulatory complexes on different mRNAs at any given time. To overcome these roadblocks, I will combine biochemical, single-molecule, and biophysical methods to examine my central hypothesis that DDX6 regulates the initial, rate-limiting step of translation initiation and global mRNA conformation in concert with its interaction partners. In Aim 1, I will identify the step of translation initiation that is regulated by DDX6 and its key partner proteins by using in vitro single molecule fluorescence microscopy and a reconstituted human translation initiation system. In Aim 2, I will examine how DDX6 assembles with partner proteins into distinct regulatory complexes and how this impacts mRNA dynamics. In each Aim, I will determine how pathogenic missense mutations in DDX6 disrupt its function. My proposed experiments will uniquely leverage my background in protein biochemistry and enzymology, the Lapointe lab’s expertise in human translation initiation and single molecule fluorescence microscopy, and the Stoddard lab’s expertise in structural biology and enzymology. My collective findings should elucidate which step of translation initiation is controlled by DDX6, how DDX6 assembles into translation inhibiting and translation stimulating complexes, how distinct DDX6 complex assemblies remodel mRNA, and how missense mutations alter DDX6 function. In parallel, my individualized training plan will provide me with opportunities to expand my research skillset into single molecule techniques and human translation initiation, to grow as a leader and mentor within the Lapointe lab, and prepare me for a career as an independent investigator.

Up to $76K

2029-02-28

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Deconvolving Vertebrate Hox Binding Preferences and Activation Properties

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NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY Embryonic development culminates with an astonishing number of terminal differentiation cellular states. Transcription factors (TFs) bind to specific DNA sequences in the genome and are key regulators of gene transcription responsible for generating cell diversity. TFs are grouped in families with similar DNA binding preferences and sometimes similar activation or repression domains, yet they perform different functions during cell differentiation. Consequently, how different TFs of the same family bind and regulate gene expression is poorly understood. Hox genes code for homeodomain (HD) TFs, the second largest TF family in the mammalian genome. Vertebrate HOX TFs are divided into anterior (HOX1-5), central (HOX6-8), and posterior (HOX9-13) paralog groups. In vertebrates, Hox genes pattern various developing tissues. Notably, spinal cord neuronal diversity requires Hox gene activity along its rostro-caudal axis. The role of Hox genes in organizing the spinal cord presents an interesting conundrum. The limb-innervating expression program is controlled by central (HOX6 & HOX8) HOX TFs at the brachial level and posterior (HOX10) HOX TFs at the lumbar spinal cord. Thus, HOX TFs with different DNA sequence preferences induce a similar motor neuron fate. Meanwhile, the posterior HOXC9 induces thoracic fate. Thus, two posterior group genes, Hoxc9 and Hoxc10, induce different spinal cord fates. In agreement with their genomic cluster position, Hox13 paralogs are expressed late during development, distally, and in posterior regions. This application aims to understand how the mammalian posterior group Hox TFs diversify their function to pattern the spinal cord. Aim 1 will dwell more on the protein domain and specific HOX amino acids in Hoxc9 and Hoxc13 that mediate their ability to bind to inaccessible chromatin and DNA residence time. Aim 2 will take a complementary machine learning approach using ChIP-exo data coupled with chromatin features to distinguish individual pioneer Hox binding sites from non-pioneer sites. Aim 3 will investigate how the very variable N-terminus controls the transcriptional output.

Up to $639K

2031-04-30

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Dedicator of Cytokinesis 2 (DOCK2) in Aortic Valve Calcification

open

NHLBI - National Heart Lung and Blood Institute

Summary/Abstract Calcific aortic valve disease (CAVD) is a progressive and life-threatening condition that currently lacks effective pharmacological therapies. Aortic valve calcification (AVC), the central pathological hallmark of CAVD, leads to valve stiffening, reduced cardiac output, and ultimately aortic stenosis, contributing significantly to cardiovascular morbidity and mortality. Despite the clinical burden of AVC, the molecular mechanisms driving calcification remain poorly defined, and no FDA-approved medical therapies exist to halt or reverse disease progression. Key pathological processes in AVC include the osteogenic differentiation of valve interstitial cells (VICs) and the endothelial-to-mesenchymal transition (EndoMT) of valvular endothelial cells (VECs). Emerging evidence identifies Dedicator of Cytokinesis 2 (DOCK2), a guanine nucleotide exchange factor traditionally associated with immune cell signaling, as an important regulator of aortic valve cellular processes. Preliminary data demonstrate that DOCK2 is upregulated in human calcified valves and localizes to both VICs and VECs. DOCK2 deficiency in mouse models significantly reduces AVC, and in vitro knockdown of DOCK2 in VICs and ECs suppresses osteogenic differentiation and EndoMT, respectively. Mechanistic studies implicate two distinct signaling axes: DOCK2 promotes VIC osteogenesis via the PI3K/Akt/GSK3β/β-catenin pathway, and it drives EndoMT through ROS-mediated ERK signaling. The objective of this proposal is to elucidate the cell- specific mechanisms by which DOCK2 contributes to AVC and to evaluate the therapeutic potential of a small molecule DOCK2 inhibitor, cholesterol sulfate. Our central hypothesis is that DOCK2 drives AVC by independently promoting VIC osteogenic reprogramming and EC EndoMT through distinct but targetable signaling pathways. This will be tested through three specific aims: Aim 1 will define the role of DOCK2 in VIC- mediated AVC and determine its signaling mechanism; Aim 2 will establish the contribution of DOCK2 to EndoMT in VECs and elucidate the downstream ROS-ERK pathway; Aim 3 will test whether pharmacologic inhibition of DOCK2 with cholesterol sulfate can prevent or reverse AVC in vivo. The successful completion of this project will identify DOCK2 as a critical molecular driver of AVC, uncover distinct mechanistic pathways in VICs and VECs, and validate a novel small molecule inhibitor as a therapeutic candidate. These studies are expected to significantly advance our understanding of CAVD pathogenesis and provide a foundation for developing targeted, non-surgical interventions to treat or reverse aortic valve calcification.

Up to $551K

2031-02-28

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Deep analysis of epitope specific CD4+ T cells before the onset of T1D

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NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY/ABSTRACT Type 1 diabetes (T1D) is an immune-mediated disease in which functional β cells are lost, leading to insulin dependence. HLA class II genotypes are the dominant genetic risk factor, suggesting a key role for CD4+ T cells. Islet-reactive T cells produce inflammatory cytokines and support formation and affinity maturation autoantibodies, the appearance of which accurately predicts disease risk. At-risk individuals develop additional specificities during progression. Therefore, epitope occurs and may be an indicator of impending disease onset. Our preliminary studies show that expanded numbers of CD4+ T cells that target self-antigens are present in individuals with established T1D. Specifically, our preliminary data enabled us to define an array of self-epitopes that are disease relevant and recognized in individuals with two of the highest risk HLA class II genotypes. These include newly discovered conventional and neoepitopes from GAD65 and other beta cell antigens. It is believed that self-reactive T cell responses evolve over time and that beta cell injury elicits neoepitope formation. However, these phenomena have not been directly studied, leaving a significant knowledge gap. Given their important role in orchestrating autoimmunity, understanding the CD4+ T cell responses is a topic of great importance. Indeed, the approval of teplizumab as a therapy to delay the progression of T1D increases the rationale for understanding and monitoring epitope spreading in at-risk individuals. Our work will test the hypothesis that in at-risk subjects there are pivotal shifts in the number, phenotype, and transcriptional programs of autoreactive CD4+ T cells and an expansion of distinct TCR sequences and that these changes reveal important pathways that drive disease progression. Our first aim will characterize longitudinal changes in the number and phenotype of autoreactive T cells in at-risk subjects by performing high dimensional flow cytometry analysis using a robust surface marker panel combined with second generation HLA class II tetramer reagents. Our second aim will utilize the 10X genomics platform to generate rich whole genome RNAseq data sets on antigen specific T cells sorted from IAA positive at-risk individuals. This will allow deep molecular profiling of autoreactive T cells to identify immune cell subsets that contribute to T1D progression and deep analysis of TCR sequences and their structural features, tracking their phenotype trajectories over time and the emergence of key T cell transcriptional states in at-risk subjects. In total, our proposed studies will advance our understanding of T1D, providing important new insights about the T cell specificities, phenotypes, and functional attributes that drive the development of T1D the immunologic changes and mechanisms that promote autoimmune progression.

Up to $2.7M

2030-01-31

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Deep brain stimulation for optimal visual search strategy in Parkinson's Disease

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NIH

PROJECT SUMMARY Parkinson's Disease (PD) constitutes a prevalent neurodegenerative condition affecting approximately 10 million individuals on a global scale. The disorder engenders a range of visual deficits that encompass abnormal eye movements, including fixational saccades — essential for sustaining retinal sensitivity during prolonged fixation — and non-fixational saccades, pivotal for efficient scanning during visual search tasks. The visual navigation impairments in PD transcend mere eye movement dysfunction. They manifest as an impairment in higher visual function, such as the complex interplay of top-down process such as visual reaction time and adaptation of prior knowledge based on contextual cues – referred to as contenxutal visual priors. This constellation of issues results in hindrances across activities such as driving, reading, walking, and navigating through the surrounds – that is impaired visuo-spatial navigation. Despite the far-reaching effects of PD on visual function, treatment options remain limited. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) emerges as a promising PD treatment, particularly for motor symptoms, but its impact on visual navigation remains unclear. The strategic location of the STN near pathways controlling higher-order visual behavior, coupled with its connectivity to the cerebellum and higher order visual areas, enables the modulation of visuo- spatial navigation through the control of saccades and higher-order visual processing. This study hypothesizes that bilateral STN DBS enhances fixational and non-fixational saccades and higher-order visual processing, crucial for visual search and navigation in PD. It suggests that improved saccadic eye movement control relates to active electrode contact near the dorsal STN region and activation of cerebello-thalamic pathway, while better higher-order visual processing correlates with modulation of ansa lenticularis and lenticular fasciculus. Aim 1 focuses on evaluating if STN DBS enhances saccades to target visual navigation issues and identifies STN regions associated with these enhancements. This is done through non-invasive video oculography, measuring eye movement parameters during visual search tasks with STN DBS on and off. Additionally, imaging and DBS modeling guide the identification of beneficial STN regions for saccades. Aim 2 addresses whether STN DBS enhances visual reaction time and contextual priors. This aim investigates whether active electrode contact location near ansa lenticularis and lenticular fasciculus results in these enhancements while preserving motor symptom benefits. Visual parameters during visual search tasks with STN DBS on and off will be analyzed. The study's clinical implications are profound, leading to more effective PD treatments, enhancing Veterans’ independence, well-being, delivering high-quality care to US Military Veterans – closely aligned with the mission of the Veterans Health Administration. Furthermore, the multidisciplinary approach contributes valuable insights into DBS applications beyond PD, potentially benefiting a broader population of Veterans.

2030-06-30

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Deep Learning for Multi-Omics-Based Prediction of Cancer Recurrence and Treatment Non-Response

open

NCI - National Cancer Institute

PROJECT SUMMARY/ABSTRACT Cancer recurrence significantly contributes to increased morbidity, reduced survival, and poor treatment response in patients with solid tumors, including glioma, lung adenocarcinoma (LUAD), and breast invasive carcinomas (BRCA). As such, understanding the factors that drive rapid cancer recurrence and treatment failure, a common cause of early recurrence, is essential to improving patient outcomes. Despite recent advancements in machine learning (ML) and deep learning (DL) approaches to recurrence prediction, current predictive models face limitations, including complex implementation, reliance on manual genomic feature selection, and limited model explainability. Moreover, treatment response models seldom integrate patient-specific protein-protein interaction (PPI) networks despite their critical roles in cancer development and therapeutic resistance mechanisms. To address these significant gaps, this research proposes innovative multi-modal DL architectures that leverage genomic and clinical data from The Cancer Genome Atlas (TCGA) for robust predictions of early cancer recurrence and therapy non-response in glioma, LUAD, and BRCA. The long-term objective of this research is to uncover potential driving factors of recurrence and treatment failure that may aid in the larger scientific community’s effort to improve clinical oncology outcomes. Aim 1 focuses on constructing multimodal attention-based DL architectures to predict early recurrence and incorporates somatic mutation, mRNA expression, and clinical data. The resulting models will undergo rigorous explainability assessments to verify model validity and determine the most informative clinical and genomic features. The final models will be made accessible through a downloadable user-friendly interface, enabling researchers to apply and fine-tune these predictive tools to independent datasets. Aim 2 focuses on constructing DL models integrating patient-specific PPI networks to predict treatment non-response. Using TCGA genomic and clinical data alongside PPI data from Proteinarium, graph neural networks will capture experimentally validated interactions between protein nodes, prioritizing hub genes potentially involved in therapy failure. As before, the models will be subject to rigorous explainability assessment. This research will advance our understanding of the driving factors behind cancer recurrence and treatment failure and yield tools that can identify potential drug targets and mechanisms of action for future research in an unbiased, data-driven manner. I will conduct this research in the Uzun Translational Bioinformatics Lab at Brown University, which specializes in PPI modeling and DL approaches to recurrence prediction, under the guidance of experts in genomics, pathology, oncology, clinical informatics, and ML/DL. Completing the proposed research will significantly contribute to my career goal of utilizing DL methodologies and omics datasets to conduct targeted cancer therapy research and reduce the incidence of cancer relapse.

Up to $50K

2028-05-31

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Deep learning-enabled protein design for targeted depletion of antibiotic resistant bacterial pathogens

open

NIAID - National Institute of Allergy and Infectious Diseases

Proteolysis-targeting chimeras (PROTACs) and Lysosome-targeting chimeras (LYTACs) have emerged as novel and effective therapeutic modalities that leverage targeted protein degradation (TPD) to eliminate disease-associated proteins. However, the preclinical and clinical development of TPD-based therapeutics has largely focused on malignant diseases, where bifunctional chimeric molecules have demonstrated the potential to target and degrade classically “undruggable” proteins. Here, we propose to design and extend the application of such bifunctional chimeric molecules to another class of difficult therapeutic targets, namely the antibiotic-resistant bacterial pathogens. As resistance to frontline antibiotic therapies continues to threaten our ability to combat many infectious organisms, there is a critical need for novel approaches that complement or bypass the traditional direct-acting antibiotics. Our central hypothesis is that rationally designed bacterial targeting chimeras (BacTACs), which specifically bind to a bacterial pathogen of interest and simultaneously engage host immune receptors, can enhance immune-mediated bactericidal activity toward the organism of interest. To achieve this, we will leverage our cutting-edge tools in deep learning-based protein design to generate high-affinity binders to both bacterial surface proteins and key host immune receptors, and then fuse them to create chimeric proteins capable of redirecting immune responses for rapid clearance of the infectious bacterial threats. Specifically, we will pursue the following aims to develop and characterize such BacTACs: In Aim 1, we will design high-affinity binders to surface-accessible proteins of Acinetobacter baumannii and Staphylococcus aureus; in Aim 2, we will develop and characterize designed proteins that engage phagocyte immune receptors; and in Aim 3, we will assess the efficacy of custom-designed BacTACs in tissue culture and murine models of bacterial infection. The validation of designed BacTACs will be conducted using the antibiotic-resistant strains of A. baumannii and S. aureus. The proposed approach to reprogram and redirect immune responses for targeting antibiotic-resistant pathogens addresses several resistance-related and efficacy-related limitations of traditional direct-acting antibiotics. Together, the design methods and BacTACs developed here will provide the basis for a new orthogonal modality to target antibiotic-resistant pathogens.

Up to $804K

2031-06-30

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Deep phenotyping of DR15-restricted CD4+ T cells specific for Epstein-Barr virus epitopes in the spinal fluid and blood of people with multiple sclerosis

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NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY/ABSTRACT Multiple sclerosis (MS) is a debilitating autoimmune disease that affects millions of patients worldwide. While the exact cause remains unknown, two major risk factors have been identified: infection with Epstein-Barr virus (EBV) and presence of the HLA-DR15 genetic variant. This project aims to understand how these risk factors interact to potentially cause MS. Our research focuses on specific immune cells called CD4 T cells that recognize specific EBV proteins in individuals with the HLA-DR15 gene variant. We hypothesize that these cells behave differently in MS patients compared to individuals without MS, potentially driving the disease process. We propose three main objectives: 1. Determine if EBV-specific CD4 T cells are more abundant in the cerebrospinal fluid than in the blood of MS patients compared to individuals without MS. 2. Compare the gene expression patterns of EBV-specific CD4 T cells in the blood and cerebrospinal fluid between MS patients and individuals without MS. 3. Assess to what extent EBV-specific CD4 T cells in patients' blood and cerebrospinal fluid predict clinical biomarkers of disease activity. To achieve these goals, we will use advanced techniques, including cell sorting, gene sequencing, and protein analysis, to study EBV-specific CD4 T cells from blood and cerebrospinal fluid samples of MS patients and controls. This research is significant because it could reveal how EBV infection leads to MS in genetically susceptible individuals. Understanding this process could lead to new ways to diagnose, monitor, and treat MS. It may also help identify individuals at high risk of developing MS before symptoms appear, potentially allowing for early intervention. The public health impact of this research could be substantial. MS affects young adults in their prime working years, causing significant disability and economic burden. By uncovering the mechanisms linking EBV to MS, this project could contribute to the development of more effective treatments or even preventive strategies, ultimately improving the lives of millions affected by this disease.

Up to $248K

2028-05-31

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Deep phenotyping of sleep and symptoms in adolescents with psychosis-spectrum conditions

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NIMH - National Institute of Mental Health

PROJECT SUMMARY Adolescents experiencing psychosis-spectrum (PS) symptoms are at high risk for lifelong mental illness and impairment, including conversion to schizophrenia. Mechanisms influencing the onset or persistence of PS symptoms in adolescence are unclear. Sleep is altered in youth at clinical high risk for psychosis (CHR) compared to controls, and sleep problems may predict the transition to full-threshold psychosis and persist in first episode psychosis (FEP). Studies of sleep and PS symptoms in youth suffer from three main gaps. First, extant studies are overly correlational, with few studies using dense sampling across days to understand temporal fluctuations between PS symptoms and sleep in youth. Second, nonspecific behavioral indices of sleep (from self-report and actigraphy) may reveal the clinical presentation of sleep deficits but not the root mechanistic cause of these difficulties. Finally, studies of sleep in this population have omitted measurement of important co-occurring processes such as stress, which may mediate or moderate the sleep-psychosis relationship in ways important for treatment development. This study seeks to address these three critical gaps by investigating daily fluctuations in PS symptoms, sleep at behavioral and neurobiological levels, and psychological stress in adolescents with PS conditions (n = 40, aged 14-17 years). Across a 3-week sampling period, this study will measure PS symptoms (hallucinations and paranoia), subjective ratings of stress, and objectively measured sleep characteristics, including behavioral (actigraphy-estimated sleep duration, fragmentation, efficiency, timing, rhythmicity, and regularity) and biological (simultaneous PSG/EEG-indexed sleep spindle density, amplitude, duration) markers. Participants will first complete a baseline interview to assess eligibility, PS symptoms, sleep, and stress. For the subsequent 21 days, adolescents will (1) wear a patch-based actigraphy monitor to assess sleep and 24h rest-activity rhythms; (2) complete twice-daily digital diaries probing sleep, stress, as well as PS symptom type (e.g., hallucinations and paranoid thoughts), severity, impairment, and timing; and (3) wear PSG and wearable EEG for 2 consecutive nights to index sleep spindles. This measurement supports 2 specific aims: 1) Examine how subjective ratings of PS symptoms and stress fluctuate with respect to sleep on a daily basis, and 2) Examine the feasibility of collecting at-home EEG data from adolescents with early phase psychosis and establish early links among spindles, PS symptoms, and stress. This study aligns with NIMH objectives to 1) define brain mechanisms underlying complex behavior by characterizing sleep spindles in early psychosis, and 2) examine mental illness trajectories across the lifespan by exploring these mechanisms in an understudied adolescent population. If successful, this will be the first study to employ deep phenotyping of sleep in adolescents with early phase psychosis.

Up to $399K

2028-06-30

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Deep River

open

State of Connecticut

Deep River

Up to $2.1M

Rolling

general

Free to search & build · $99 one-time to unlock the application pack · No subscription

Deep River

open

State of Connecticut

Deep River

Up to $2.0M

Rolling

general

Free to search & build · $99 one-time to unlock the application pack · No subscription

Deep templates for longitudinal morphometry in Alzheimer's disease

open

NIA - National Institute on Aging

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) affects one in eight Americans over 65 and is among the leading causes of death in the United States. Despite its prevalence, the accurate clinical diagnosis of AD remains challenging due to non-specific clinical tests and symptom overlap with other types of dementia. Except at top medical centers, the resulting misdiagnosis rates in excess of 15% relative to “gold-standard” neuropathologic analysis at autopsy negatively impact the efficacy of care, patient outcomes, and clinical trial efficiency. Although there are biomarkers that correlate with the neuropathology of AD, many are either invasive or largely inaccessible in routine clinical practice, such as PET imaging. One in-vivo marker that could be largely accessible is morphological metrics derived from non-invasive T1-weighted structural brain magnetic resonance imaging (MRI). These scans are already routinely acquired for individuals presenting with age-related cognitive decline, but integration barriers hamper the clinical accessibility of derived metrics. The fundamental goal of this project is to enable hospitals with limited access to AD biomarkers to achieve the diagnostic accuracy of top-performing institutions. We aim to improve the sensitivity and accessibility of structural MRI metrics by improving longitudinal, within-subject approaches that drive the morphometric analysis of MRI scans using a subject-specific reference image—a template—constructed from time points after rigid registration correcting for differential head positioning. We will build upon recent image-synthesis techniques and cutting- edge deep learning to develop anatomy-aware registration tools that generalize to medical imaging data across different MRI scanners and hospitals, without retraining or preprocessing. First, we will incorporate randomized, synthetic atrophy of AD-specific structures, ventricular expansion, and MRI distortions into a generative model. We will use this model to develop a deep neural network for rigid brain regis- tration that is robust to localized change and irrelevant intensity variations common in clinical imaging. Second, we will develop a deformable registration network that differentiates session-specific MRI distortions from disease effects. We will leverage AD-aware registration networks to construct individualized deformable templates across time to enhance the sensitivity of longitudinal morphometry, making it compatible with the clinical workflow. The project will result in deep-learning tools for longitudinal brain registration and template construction that are fast, accurate, and easy to use without machine-learning expertise or high-end computational resources. They will increase the power to detect disease effects with fewer subjects and dramatically reduced runtimes.

Up to $660K

2029-02-28

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Deeply subwavelength near infrared imaging with avalanching nanoparticles

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NIGMS - National Institute of General Medical Sciences

PROJECT ABSTRACT Optical microscopy is ubiquitous in cell biology and is well-suited for studying cell signaling in live cells and animals, offering minimally invasive in situ monitoring, subcellular and millisecond resolution, and probes for specific receptors or other biomolecules. However, live cell imaging is constrained by the diffraction limit, by temporal limits of most super-resolution techniques, by probe stability, and by the UV or visible lasers used in most microscopy. These common microscopy lasers can be phototoxic, give rise to autofluorescent background, photobleach fluorophores to generate harmful free radicals, and lack the ability to penetrate to subsurface sites. Here, we address all of these limitations with unique new optical probes, avalanching nanoparticles (ANPs), that show the most nonlinear emission of any reported nanoscale material. ANPs upconvert incident light, which enables them to be imaged without autofluorescent background or photobleaching, and to be excited by near infrared (NIR) wavelengths, which are far less phototoxic than the lasers most common in bioimaging. The steep nonlinearity of ANP emission enables experimental realization of a revised Abbe equation of the diffraction limit, achieving real-time sub-70 nm spatial resolution without the need for special optics, computation, or imaging processing. To enable live-cell ANP imaging, we propose synthesis of biocompatible and antibody-functionalized ANPs for receptor targeting, as well as construction of a modified laser scanning confocal microscope, which addresses the innate slow kinetics of photon avalanching. Both breast cancer cells and neural microglia will be imaged to determine spatial localization and dynamics of cell surface receptors critical to their respective functions. ANPs may also be photoswitched indefinitely between bright and dim states entirely with NIR light, enabling sub-nanometer localization accuracies with the superresolution technique INPALM. Because ANPs do not measurably photobleach, collection of unlimited photons with controlled NIR toggling between bright and dim states is possible, leading to this exceptional precision. While these optical breakthroughs have the potential to fundamentally alter how high-resolution bioimaging is approached, ANPs have not been imaged in live cells and only in limited cases in fixed cells. We propose imaging of microglial receptors in live cells at 70-nm resolution and INPALM imaging of fixed cells at sub-nanometer precision with a confocal microscope customized for ANP imaging. The combination of receptor-targetable ANPs with a microscope designed for fast, high-resolution ANP imaging and for ANP superresolution leads to the ultimate goal of bringing these radical advances in nanoparticle optics into the realm of bioimaging.

Up to $430K

2030-03-31

health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

DeepRAP: Deep Reasoning, Abstraction & Planning towards trustworthy Cognitive AI Systems

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European Commission - HORIZON

DeepRAP: Deep Reasoning, Abstraction & Planning towards trustworthy Cognitive AI Systems. Call: EIC Pathfinder Challenges 2026. Programme: HORIZON. Open call from the EU Funding & Tenders Portal.

$50K

2026-10-28

technology

Free to search & build · $99 one-time to unlock the application pack · No subscription

Deepwater Horizon Oil Spill Louisiana and Open Ocean Trustee Implementation Groups; Draft Joint Restoration Plan and Environmental Assessment #1: Wetlands, Coastal, and Nearshore Habitats, Federally Managed Lands, Fish and Water Column Invertebrates, Sea Turtles, Submerged Aquatic Vegetation, and Birds Restoration of the Chandeleur Islands

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Interior Department

The natural resource trustee agencies for the Louisiana and Open Ocean Trustee Implementation Groups (the TIGs) have prepared the Draft Joint Restoration Plan and Environmental Assessment #1: Wetlands, Coastal, and Nearshore Habitats, Federally Managed Lands, Fish and Water Column Invertebrates, Submerged Aquatic Vegetation, Sea Turtles, and Birds Restoration of the Chandeleur Islands (Draft RP/EA). The Draft RP/EA analyzes projects to partially restore resources injured in the Deepwater Horizon (DWH) oil spill. The Draft RP/EA evaluates a reasonable range of six action alternatives under the Oil Pollution Act (OPA), including criteria set forth in the OPA natural resource damage assessment (NRDA) regulations, and the National Environmental Policy Act (NEPA). A No Action alternative is also analyzed. The total cost to implement the TIGs' two preferred alternatives is approximately $360,000,000. The TIGs are proposing to allocate approximately $247,000,000 in DWH NRDA funds to implement the preferred alternatives and the State of Louisiana is actively pursuing additional funding sources. The TIGs invite comments on the Draft RP/EA.

See notice

environment

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Deer Island Ecosystem Restoration, Phase 1 Deer Island, MS (Harrison County)

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DEPT OF DEFENSE.DEPT OF THE ARMY.US ARMY CORPS OF ENGINEERS.ENGINEER DIVISION SOUTH ATLANTIC.ENDIST MOBILE.W074 ENDIST MOBILE

Deer Island Ecosystem Restoration, Phase 1 Deer Island, MS (Harrison County)

Rolling

general

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Defective HIV-1 proviral abundance and their immune effects in children and adolescents living with perinatal HIV-1

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NIAID - National Institute of Allergy and Infectious Diseases

During suppressive antiretroviral therapy (ART), HIV-1 persists in long-lived resting memory CD4+ T cells of children and young adults with perinatal HIV-1 as both intact and defective proviral genomes. The intact, replication-competent proviruses contribute to the latent reservoir and are a lifelong barrier to cure. In perinatal HIV-1, the reservoir is established early and shaped by unique immunologic factors. A growing body of evidence suggests that while defective proviruses cannot contribute to rebound in the absence of ART, these proviruses are transcriptionally and translationally active, potentially leading to adverse immune effects. However, the frequency, composition, and potential immunologic effects of defective proviruses across pediatric age groups remain poorly understood. In this proposal, we aim to characterize the defective proviral reservoir in children and young adults living with perinatal HIV-1 by determining the abundance and sequences of proviruses that are maintained for years despite ART and assessing their ability to produce viral mRNA and proteins. This project leverages well-characterized, bio-banked peripheral blood mononuclear cell (PBMC) and plasma specimens from pediatric HIV-1 cohorts to systematically characterize the landscape of defective proviruses in perinatal infection from infancy through adolescence. Our hypothesis is that in longstanding treated perinatal HIV-1, defective proviruses are transcriptionally and translationally active and drive persistent residual HIV-1 viremia during ART, promoting immune activation and exhaustion despite replication incompetence. Defective proviruses may also serve to produce decoy viral proteins that elicit autologous neutralizing antibodies, thereby reducing the efficacy of autologous neutralization of the latent reservoir. We propose three specific aims. In Aim 1, we will quantify and characterize intact and defective proviruses across pediatric age groups using near full-length single genome sequencing. In Aim 2, we will assess the transcriptional activity of defective proviruses following ex vivo stimulation in co-culture for HIV-1 mRNA analyses and their correlation with immunologic and clinical measures, including markers of immune activation and exhaustion. We will then compare it to sequences from low level plasma viremia to determine whether defectives are the source. In Aim 3, we will perform the quantitative viral outgrowth assay (QVOA) with the ultrasensitive p24 Simoa assay to identify if high- and low-level p24 producing wells are harboring intact or defective proviruses. We will then determine whether env-pseudotyped virus derived from intact or defective proviral sequences can be neutralized with autologous plasma IgG. By integrating molecular virology and immunology profiling in a pediatric context, this study will generate novel insights into the role of defective proviruses in HIV-1 persistence in children. Our findings will inform the design of age-specific cure strategies and contribute to the broader goal of ART-free remission in children with perinatal HIV-1 towards a life free of co-morbidities.

Up to $780K

2031-03-31

health research

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Defense Security Cooperation University - Research Grants

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Washington Headquarters Services

The Defense Security Cooperation Agency s (DSCA) Defense Security Cooperation University (DSCU) promotes access to and production of knowledge on security cooperation. Security cooperation refers to all Department of Defense (DoD) interactions with foreign security establishments that build and develop allied and partner security capabilities and capacity for self-defense and multinational operations, provide the Armed Forces of the United States with access to the foreign country during peacetime or a contingency operation, and build relationships that promote specific United States security interests (Joint Publication 3-20, Security Cooperation, 1-2; see also 10 USC 16, Security Cooperation ). Evidence-, theory, and data-building activities that contribute to the body of knowledge on security cooperation or irregular warfare, and that result in lessons that can be applied to practice, are the primary focus of this notice of funding opportunity (NFO). Research products sponsored through this NFO must be unclassified and publicly accessible. DSCU expects awardees to participate in conferences, seminars, focus groups and events, and to make final research products and supporting data (if applicable) easily accessible to the public, in order to enhance dissemination of research findings and facilitate application of lessons learned in areas of policy, practice, and workforce professionalization.The DSCU research grant program, conducted pursuant to 10 USC 4001 and 10 USC 384(g), is generally open to a broad range of researchers, although individual DSCU components may have restrictions on who may receive grants.Please see the full NFO for complete details.

$3K – $800K

2028-08-07

sciencetechnology

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Define regulatory T cell repertoire sustainability

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NIAID - National Institute of Allergy and Infectious Diseases

SUMMARY Regulatory T cells (Tregs) actively suppress effector T cells that not only cause autoimmune diseases but also mount anti-tumor immune response. A diverse repertoire of T cell antigen receptors (TCRs) is conferred upon Tregs during their selection and development. We previously demonstrated that Treg repertoire diversity is essential for immune regulatory function. However, Treg repertoire is not static, but rather undergoes dynamic changes, involving continuous new Treg generation, incorporation, and likely turnover of aged Tregs. This raises questions about the nature of Treg repertoire dynamics, sustainability, and immunological roles. Despite the substantial advancements in Treg research, the answers to these questions remain largely speculative due to technical challenges in tracking and controlling specific Treg repertoire without introducing adverse effects. To address this critical knowledge gap, we developed novel mouse genetic tools. Rag1CreER knock-in mice were engineered to perform timestamp tracing of thymic T cells. In the presence of a Rosa reporter, such as RosaLSL-tdTomato (LSL, loxP-Stop-loxP), tamoxifen treatment labeled newly derived thymic T cells, allowing us to investigate the dynamics of thymic Treg generation, egression, and incorporation into the peripheral Treg repertoire in lymphoid and non-lymphoid organs at various stages of life. When integrated with advanced analytical platforms, this will enable us to resolve the developmental heterogeneity of Treg repertoire. We also developed Foxp3LSL mice to seamlessly switch Treg fate in an inducible manner via its master regulator Foxp3. When combined with CreER lines, such as Rag1CreER or available Cd4CreER, these Foxp3LSL mice, upon tamoxifen treatment, would restore normal Foxp3 regulation in precursor cells or Treg cells, depending on the timing of CreER expression. In preliminary experiments, we demonstrated the reliability and feasibility of these methods and unveiled unexpected findings of the activity of Tregs with a finite repertoire. In this study, based on preliminary results, we propose that existing Tregs undergo “exhaustion-like” deterioration over time or upon immune challenges. Consequently, continuous new Treg generation is required to maintain Treg repertoire integrity. To test this hypothesis, we will first rigorously define the exhaustion-like nature of Tregs with a finite repertoire in non-competitive conditions with or without immune challenges. We will then use these innovative genetic tools to determine the causal role of continuous thymic Treg generation. Finally, we will test the hypothesis that excessive stimulation via TCR signaling drives the exhaustion-like activity of Tregs in lineage stability and Foxp3-dependent gene regulation. Overall, we will utilize innovative approaches to define Treg deterioration in the resting state over time or after immune challenges, addressing a long-standing question in the field. Successful completion of our study would lead to a significant conceptual advancement and potential novel strategies to improve Treg-based treatment of cancer and autoimmune diseases.

Up to $880K

2031-01-31

health research

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Define the mechanisms through which STK33 regulates multiciliated cells

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NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY/ABSTRACT The following proposal outlines a 5-year career training plan that will prepare Dr. Andrew Berical to be an independent physician-scientist and leader in the field of airway epithelial functional genomics. Motile cilia are found throughout the human body, most notably on multiciliated cells (MCCs) in the conducting airway. Individuals with primary ciliary dyskinesia (PCD) have inherited variants in any one of more than 50 genes that regulate the structure or function of cilia, leading to a lifetime of chronic cough, recurrent infections and respiratory failure. Due to the complexity of the MCC molecular program and limited disease-relevant platforms, there are no targeted therapies available for PCD. An improved understanding of fundamental MCC biology and the availability of a human-based platform would have enormous implications for the PCD field. Dr. Berical’s long-term vision is to utilize pluripotent stem cell-based techniques to understand how specific genes regulate airway epithelial homeostasis and how gene variants lead to the initiation of airway diseases such as PCD, CF, asthma, COPD and IPF. Dr. Berical presents preliminary data suggesting a recently described serine-threonine kinase (STK33) has a fundamental role in the MCC developmental program. STK33 deletion results in 1) fewer MCCs, 2) fewer cilia per cell, 3) an abnormal ciliary structure and 4) reduced ciliary beat frequency. In this proposal, Dr. Berical aims to understand the mechanism by which STK33 effects the MCC molecular program to create this highly irregular phenotype. Leveraging key training opportunities through his collaborators and scientific advisory committee, he will 1) precisely characterize the STK33-dependent MCC defects using time course single cell RNA-sequencing to pinpoint when, during MCC differentiation, STK33 exerts its effect, 2) identify STK33 downstream targets and effector molecules and 3) determine the in vivo ramifications of STK33 loss on the engraftment, differentiation and function of airway epithelial cells. Following this investigation of the STK33-dependent regulation of MCC biology, Dr. Berical then expands these methods to probe the functions of a curated list of high priority ciliary kinases of unknown function. This work will provide much needed insight into the MCC molecular program and develop an essential platform for the interrogation of genes of unknown function in the airway epithelium, applicable to the genetically heterogeneous PCD, as well as other airway diseases. Dr. Berical has 80% protected time from his department to accomplish these aims under the guidance of his mentors Drs. Finn Hawkins and Darrell Kotton at the Center for Regenerative Medicine at Boston University/Boston Medical Center. He has assembled a remarkable team of advisors with diverse expertise to assist in his career development and scientific research. Dr. Berical details a comprehensive training plan that includes experiential training, didactic coursework, attendance and presentation at scientific meetings, preparation of manuscripts and acquiring additional grant support culminating in an R01. Dr. Berical has the commitment of his department to accomplish these goals and transition to an independent physician-scientist position by the end of the award.

Up to $167K

2031-02-28

health research

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Defining a mechanism for inner nuclear membrane protein SUN2's mechanical regulation of skin fibrosis

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NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases

PROJECT SUMMARY/ABSTRACT In progression of skin fibrosis, the pathological stiffening of skin, both pro-fibrotic biochemical signaling and mechanical signals from the stiffening extracellular environment drive hyper-activated fibroblasts to secrete excess extracellular matrix (ECM) proteins. However, how these two inputs are integrated to drive fibrosis remains poorly understood, posing a barrier for treatments that can effectively reverse the fibrotic process. Our lab’s preliminary work provides new insight to this unanswered question, having identified a novel role for SUN2, an inner nuclear membrane protein, in driving fibrosis, potentially by regulating both mechanical and biochemical signaling. We have found that SUN2 responds to fibrotic stimuli in vivo, increasing in fibrotic patient and mouse skin samples, and in fibroblasts cultured on stiff substrates modeling fibrotic tissue. Additionally, depleting SUN2 decreases expression of pro-fibrotic TGFβ pathway target genes necessary for driving excess ECM deposition, as well as chromatin accessibility at the promoters of these genes. In vivo, loss of SUN2 is protective against injury-induced skin fibrosis. Given SUN2’s well-characterized function as a Linker of Nucleoskeleton and Cytoskeleton (LINC) complex component, which transduces bi-directional force from the cytoskeleton to the nuclear interior, a compelling hypothesis is that mechanical signals from the stiffening, fibrotic ECM increases SUN2 levels at the nuclear envelope, which amplifies force transduction to the nucleus necessary for upregulation of pro-fibrotic TGFβ target genes. The goal of this proposal is to investigate this hypothesis and define a molecular mechanism for how mechanical signals alter the composition and function of the nuclear envelope to regulate pro-fibrotic biochemical signaling. To accomplish this, I will first recapitulate the mechanical conditions of skin fibrosis in vitro, culturing dermal fibroblasts on substrates of relevant stiffnesses. Then, I will define how ECM stiffness regulates SUN2 levels by performing a series of RT-qPCR and cycloheximide chase experiments, utilizing inhibitors and a CRISPR Cas9 approach to disrupt cellular degradation pathways and further probe this mechanism. To determine how biological SUN2 levels alter the mechanical environment of the nucleus I will perturb SUN2 expression via siRNA or alteration of SUN2’s phosphorylation state and utilize our lab’s Nesprin molecular tension sensor, created to measure tension on LINC complexes. Lastly, to identify how SUN2 regulates pro-fibrotic TGFβ target gene expression in response to ECM stiffness, I will perform various genomics experiments including ATAC-Seq, RNA-Seq, and CUT&RUN to determine how ECM stiffness alters chromatin accessibility and gene expression of TGFβ target genes, and the activity of TGFβ pathway effectors SMAD 2/3. This proposal will address fundamental aspects of cell biology and mechanobiology and will define a novel mechanism for how mechanical signaling and biochemical signaling are integrated to drive fibrosis. Additionally, successful completion of this proposal will provide new therapeutic targets for reversing the fibrotic process in skin.

Up to $50K

2028-11-15

health research

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