Grants

16,469 grants found

24 grants worth up to $11.4M match your search

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High End Laser Scanning Confocal Microscope for the University of Chicago Integrated Light Microscopy Facility

NIGMS - National Institute of General Medical Sciences

Project Summary / Abstract The University of Chicago Integrated Light Microscopy Facility (ILMF) requests funds to purchase a high-end laser scanning confocal microscope. The ILMF currently serves 420 users in 80 labs from across the University. Sixty-seven of those labs use laser scanning confocal microscopy, and 78% of those labs have NIH funding. Usage hours have increased as the ILMF’s microscope capacity has decreased. Two of our confocal microscopes, both Leica SP5 models, are over 14 years old. Leica has designated them end-of-life, meaning they are no longer manufacturing parts for these systems and replacements are not guaranteed. We have already experienced failure of the 488nm Argon and 592nm depletion lasers on one, and failure of the Mai Tai multiphoton excitation laser on the other, with no possibility of replacing any of these components. We expect to decommission at least one SP5 within the next year, making users hesitant to start new projects on those systems. This has stressed our two newer laser scanning confocal systems (purchased with institutional funds in 2016 and 2020), pushing them to use levels averaging 91% of AUT, defined as 3640 hours per year. The system proposed here is the Evident (formerly Olympus) Fluoview 4000 (FV4000), released in 2024. The system will increase the capacity and functionality of laser scanning confocal microscopes in the ILMF, allowing users to collect high-quality data more readily. Several features of the FV4000 will be new to the ILMF, and satisfy a number of outstanding investigator needs. Features include: state-of-the-art, patented, fast signal processing silicon photomultiplier (SiPM, Evident SilVIRTM) detectors, to significantly improve signal-to-noise levels, enhancing detection of Golgi cisternae and other organelle sub-structures; four high magnification, long working distance silicone immersion objectives for detailed, multi-color, 3-dimentional imaging of organoids, thick tissues and tumor samples; and three near-infrared wavelength lasers for excitation of fluorophores beyond the current imaging spectrum, allowing for investigation of a larger number of molecules of interest in a single sample. The FV4000 will also feature full environmental control, allowing users to take advantage of faster imaging speeds to image live samples. This will make it possible to image longer sessions at higher frame rates with less photodamage, resulting in more robust and reliable data from live samples than currently possible. Finally, the FV4000 base is modular in design, allowing for field upgrades with Evident or third-party resources (e.g. a single molecule localization module) as users’ experimental needs grow. In summary, adding an Evident FV4000 laser scanning confocal microscope to the ILMF will make it possible for users to gather information from samples that are currently challenging but valuable research models.

Up to $726K

2027-05-31

health research

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

HIGH PRIORITY / SAFETEA - LU - FEDERAL

open

Chicago Department of Transportation

COLUMBUS AVENUE- FROM KEDZIE AVENUE TO WESTERN AVENUE

Up to $2.4M

Rolling

Business DevelopmentCommunity Development

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

High Priority HIV and Substance Use Research (R01 Clinical Trial Optional)

open

National Institutes of Health

<p>The purpose of this Funding Opportunity Announcement (FOA) is to support high priority research at the intersection of HIV and substance use. This FOA invites innovative research projects with the potential to open new areas of HIV/AIDS research and/or lead to new avenues for prevention, treatment and cure of HIV among people who use drugs (PWUD). Applications submitted under this FOA are required to have a detailed research plan, preliminary data, and a clear description of the nexus with substance use. This FOA is open to both individual researchers and research teams and includes all areas of research from basic science to clinical and implementation research. All studies must focus on NIH HIV/AIDS Research Priorities: NOT-OD-20-018: UPDATE: NIH HIV/AIDS Research Priorities and Guidelines for Determining HIV/AIDS Funding.</p>

2027-03-06

EducationHealth

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

High Priority HIV and Substance Use Research (R01 Clinical Trial Optional)

open

National Institutes of Health

The purpose of this Funding Opportunity Announcement (FOA) is to support high priority research at the intersection of HIV and substance use. This FOA invites innovative research projects with the potential to open new areas of HIV/AIDS research and/or lead to new avenues for prevention, treatment and cure of HIV among people who use drugs (PWUD). Applications submitted under this FOA are required to have a detailed research plan, preliminary data, and a clear description of the nexus with substance use. This FOA is open to both individual researchers and research teams and includes all areas of research from basic science to clinical and implementation research. All studies must focus on NIH HIV/AIDS Research Priorities: NOT-OD-20-018: UPDATE: NIH HIV/AIDS Research Priorities and Guidelines for Determining HIV/AIDS Funding.

2027-03-06

Education

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

High Priority HIV and Substance Use Research (RM1 Clinical Trial Optional)

open

National Institutes of Health

Up to $1.5M

2027-03-05

Education

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

High Priority HIV and Substance Use Research (RM1 Clinical Trial Optional)

open

National Institutes of Health

Up to $1.5M

2027-03-05

EducationHealth

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

High Quality Force Field Models for Biased Ligand Design

open

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY High Quality Force Field Models for Biased Ligand Design Molecular simulation (MS) plays an essential role in biochemical and biophysical research. A key element to successful applications of MS is the quality of a practical molecular mechanics force field (MMFF). The central mission of the Wang lab is to develop a set of MMFF models to accurately model the structures, dynamics, energetics, and functions of biomolecular systems. We aim to reduce the root-mean-square error of free energy prediction to be < 0.6 kcal/mol. To achieve this mission, we will first develop the 3rd generation of GAFF (GAFF3). GAFF3 development will be based on ABCG2, a new physical charge model which has demonstrated superior performance in large scale solvation free energy calculations. New force field parameterization techniques, such as applying machine learning potentials to fast detect “bad” torsional parameters, will be extensively applied in GAFF3 development. Special versions of GAFF3 which utilize a double exponential (DE) functional form for van der Waals interactions and new versions of GAFF2 with extended chemical space coverage will be developed in parallel. We will then critically evaluate the performance of newly developed GAFF force fields in studying biomolecule-ligand interactions using both pathway-based and endpoint free energy methods. Advanced sampling techniques including alchemical enhanced sampling and orthogonal space tempering will be applied for this evaluation effort. We believe that GAFF3 will be able to approach the performance limit an additive model can achieve. The successful development of GAFF3 will provide us with an advanced framework for addressing three challenges in the current drug design: (1) to efficiently and effectively describe the heterogenous environment where ligand-receptor binding occurs; (2) to rationally design a ligand which biasedly elicits a certain cellular signal but does not affect other pathways. A biased ligand is an attractive drug candidate as it can minimize unwanted or adverse effects; (3) to expand the druggable chemical space for those very promising drug targets. Artificial intelligence (AI) techniques will be utilized to power our biased ligand design. We have developed and evaluated a novel GAFF3-based scoring function, ligand-receptor interaction profile (LRIP) scoring function (LRIP-SF) to tackle the first challenge. LRIP-SF has achieved superior performance in both drug lead identification and optimization. As an accurate and efficient scoring function, LRIP-SF can fill the big gap between two widely used virtual screening methods, docking and alchemical free energy filters. We believe that the function and signaling pathways elicited by a ligand are encoded in the LRIP, and machine learning algorithms can learn the key attributes of the LRIP and generate scoring functions, LRIP-SFs, to recognize similar ligands in a screening library. Moreover, LRIP-SFs can be implemented into a generative modeling framework, such as generative adversarial networks (GAN) or diffusion models, to biasedly de novo design chemical structures. Thus, the AI-powered algorithms and DRUG-GAN models / diffusion models will be able to tackle the second and third challenges and likely revolutionize future drug discovery.

Up to $109K

2031-04-30

health research

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

High throughput screening and machine learning for discovery of next generation chemicals for cryopreservation

open

NIBIB - National Institute of Biomedical Imaging and Bioengineering

PROJECT SUMMARY This project aims to develop cryopreservation methods to extend organ viability from hours to years. This would improve transplantation by allowing more effective organ allocation, lower discard rates, improved immunological matching, reduced chronic rejection, and more flexible surgery scheduling. Current efforts to cryopreserve organs use cryoprotective agents (CPAs) to prevent ice formation, but these efforts are limited by the toxicity of existing CPAs. Previous research has mainly focused on <10 molecules out of the ~40 that have been tested as CPAs. However, the number of potential molecules is in the millions. This project leverages novel high throughput screening methods and machine learning to explore this vast chemical space to identify new CPA mixtures with reduced toxicity. The central hypothesis is that high throughput screening of CPAs for cell membrane permeability, toxicity, and promotion of glass formation can be combined with machine learning and decision-making algorithms to enable discovery of novel low toxicity compositions for organ cryopreservation. The project has four specific aims: Aim 1: Screen for chemicals with high membrane permeability and low toxicity. High throughput experiments will be combined with virtual screening using machine learning models to discover new molecules with promising properties for cryopreservation. Aim 2: Identify CPA interactions that reduce toxicity. To uncover synergistic CPA interactions, high throughput experiments will be performed to compare the toxicity of binary CPA mixtures to single-CPA solutions. The resulting data will be used to train a model for predicting the toxicity of CPA mixtures. Aim 3: Quantify the glass forming abilities of CPA mixtures. A high throughput approach will be used to determine the concentration required to form a glass upon cooling for each CPA mixture. Aim 4: Optimize CPA mixtures for organ cryopreservation. An iterative approach combining mathematical optimization, high throughput testing, and model retraining will be used to identify CPA compositions that can prevent ice with minimal toxicity. Overall, this work will establish high throughput screening and machine learning as a platform for discovery of novel CPA mixtures with reduced toxicity, laying the groundwork for future efforts to cryopreserve human organs.

Up to $560K

2029-05-31

health research

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

High Throughput Tools for Brain and Behavior (SBIR [R43/R44])

open

National Institutes of Health

-Purpose. This purpose of this Funding Opportunity Announcement (FOA) solicits Small Business Innovation Research (SBIR) grant applications from small business concerns (SBCs) that propose to develop and commercialize technologies for high throughput data acquisition and analysis that could aid the research fields of basic behavioral science, neuroscience or neuroAIDS relevant to the missions of the National Institute of Mental Health (NIMH) and National Institute of Neurological Disorders and Stroke (NINDS). -Mechanism of Support. This FOA will utilize the SBIR (R43/R44) grant mechanisms for Phase I, Phase II, and Fast-Track applications and runs in parallel with a FOA of identical scientific scope, PA-08-002, that solicits applications under the Small Business Technology Transfer (STTR) (R41/R42) grant mechanisms. -Funds Available and Anticipated Number of Awards. For this FOA, budgets up to $300,000 total costs per year and time periods up to 2 years for Phase I may be requested. Budgets up to $500,000 total costs per year and up to 3 years may be requested for Phase II. Awards issued under this FOA are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications.

rolling

Healthhealthcare

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

High Throughput Tools for Brain and Behavior (STTR [R41/R42])

open

National Institutes of Health

-Purpose. This purpose of this Funding Opportunity Announcement (FOA) solicits Small Business Technology Transfer Program (STTR) grant applications from small business concerns (SBCs) that propose to develop and commercialize technologies for high throughput data acquisition and analysis that could aid the research fields of basic behavioral science, neuroscience or neuroAIDS, relevant to the missions of the National Institute of Mental Health (NIMH) and the National Institute of Neurological Disorders and Stroke (NINDS). -Mechanism of Support. This FOA will utilize the STTR (R41/R42) grant mechanisms for Phase I, Phase II, and Fast-Track applications and runs in parallel with a FOA of identical scientific scope, PA-08-001, that solicits applications under the Small Business Innovation Research (SBIR) (R43/R44) grant mechanisms. -Funds Available and Anticipated Number of Awards. For this FOA, budgets up to $300,000 total costs per year and time periods up to 2 years for Phase I may be requested. Budgets up to $500,000 total costs per year and up to 3 years may be requested for Phase II. Awards issued under this FOA are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications.

rolling

Healthhealthcare

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

High-end endo-atmospheric interception

open

European Commission - EDF

High-end endo-atmospheric interception. Call: Development actions implemented through actual cost grants (accelerated call). Programme: EDF. Open call from the EU Funding & Tenders Portal.

$50K

2026-09-29

research

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

High-End Instrumentation (HEI) Grant Program (S10 Clinical Trial Not Allowed)

open

National Institutes of Health

The High-End Instrumentation (HEI) Grant Program encourages applications from groups of NIH-supported investigators to purchase or upgrade a single item of high-end, specialized, commercially available instruments or integrated systems. The minimum award is $750,001. There is no maximum price limit for the instrument; however, the maximum award is $2,000,000. Instruments supported include, but are not limited to, nuclear magnetic resonance spectrometers, X-ray diffractometers, mass spectrometers, high throughput robotic screening systems, DNA and protein sequencers, biosensors, electron and light microscopes, flow cytometers, and biomedical imagers.

2027-06-01

Healthhealthcare

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

High-energy human milk diets in the first two weeks after birth to reduce the severity of respiratory morbidity in extremely preterm infants

open

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY This hypothesis-driven, patient-oriented pilot randomized clinical trial will evaluate whether providing a high- energy human milk diet during the first two weeks after birth reduces respiratory morbidity in extremely preterm (EPT) infants. EPT infants, born at 28 weeks of gestation or earlier, have immature lungs and a high risk of developing bronchopulmonary dysplasia (BPD)—a chronic lung disease that increases mortality and long-term developmental complications. Early enteral nutrition is critical for lung development, yet most EPT infants receive insufficient energy during the first 14 days after birth. Docosahexaenoic acid (DHA) and arachidonic acid (ARA) supplementation is a promising strategy to increase energy intake through human milk, but there is no consensus on whether fat- enriched or protein-enriched diets are more beneficial for improving lung function. Building on findings from our recent NIH-funded trial, which demonstrated that protein-enriched diets improved growth and potentially reduced BPD severity, we will now assess whether a DHA/ARA-enriched exclusive human milk diet can achieve superior benefits. In this trial, we will randomize 150 EPT infants to receive either an exclusive human milk diet enriched with a commercially available DHA/ARA supplement or a standard, exclusive human milk diet during the first 14 days after birth. The primary outcome is the severity of respiratory morbidity at term equivalent age. We will also evaluate the feasibility of using non-invasive oscillometry to measure lung function in this population. This study will inform the design of a larger clinical trial and may establish that early enteral energy provision— unlike parenteral nutrition—provides measurable respiratory benefits. The findings could reshape neonatal nutrition strategies and optimize care for preterm infants at risk of BPD.

Up to $181K

2029-03-31

health research

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

High-performance energy systems

open

European Commission - EDF

High-performance energy systems. Call: Development actions implemented via actual cost grants. Programme: EDF. Open call from the EU Funding & Tenders Portal.

$50K

2026-09-29

clean_energy

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

High-performance, circular-by-design, bio-based thermosets

open

European Commission - HORIZON

High-performance, circular-by-design, bio-based thermosets. Call: HORIZON-JU-CBE-2026. Programme: HORIZON. Keywords: Composites (including laminates, reinforced plastics, cermets, combined natural and synthetic fibre fabrics filled composites), Materials engineering (biomaterials, metals, ceramics, polymers, composites, etc.), New materials: oxides, alloys, composite, organic-inorganic hybrid, nanoparticles, Polymers and plastics. Open call from the EU Funding & Tenders Portal.

$50K

2026-09-22

research

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

High-Priority Research in Tobacco Regulatory Science (Clinical Trial Optional)

upcoming

National Institutes of Health

High-Priority Research in Tobacco Regulatory Science (Clinical Trial Optional)

Rolling

research

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

High-Resolution In Vivo MicroCT Imaging to Advance Translational Musculoskeletal and Multidisciplinary Research

open

OD - NIH Office of the Director

We request support for the acquisition of the Bruker SkyScan 1276 CMOS Edition High-Resolution In Vivo MicroCT System to serve a large, diverse, and NIH-funded research community at the University of Rochester School of Medicine and Dentistry (URSMD). The instrument will be housed in the Biomechanics and Multimodal Tissue Imaging (BMTI) Core of the Center for Musculoskeletal Research (CMSR), which supports over 60 NIH-funded investigators across 12 departments. The SkyScan 1276 will replace an obsolete 21-year- old scanner and expand our capabilities in longitudinal and cross-sectional imaging of murine and larger animal models. The SkyScan 1276 provides true spatial resolution down to 6 µm, with voxel sizes as low as 2.8 µm, and enables high-throughput imaging with helical scanning, slip-ring gantry, and physiological monitoring. It supports a large field of view (75 mm × 310 mm), allowing full-body imaging of small animals and complex 3D constructs in a single scan. The SkyScan’s robust software suite will ensure reproducible, high- quality data analysis in alignment with ASBMR standards. These capabilities are vital for a broad range of applications, including skeletal biology, tumor progression, vascular imaging, implant osseointegration, and regenerative medicine. This shared instrument will be accessible to NIH-funded investigators in the CMSR, Wilmot Cancer Institute, Aab Cardiovascular Research Institute, Department of Oral and Craniofacial Sciences, Allergy/Immunology and Rheumatology unit, and Environmental Health Sciences Center. Collectively, these groups have ongoing projects funded by P30, P50, R01, and U grants that require the SkyScan’s resolution, throughput, and physiological imaging features. Major users collectively project over 1,600 annual usage hours, representing 83% of estimated available time. The system will be operated by a dedicated and experienced technician and overseen by a seasoned core director and a previous S10 recipient. The core will be supervised by an internal Advisory Oversight Committee comprised of intuitional leaders and experts. Training plans include on-site and vendor-led education, annual workshops, and on-demand hands-on sessions. The acquisition of the SkyScan 1276 will transform imaging capabilities at URSMD by enabling precise, minimally invasive, and translational research. This investment will significantly enhance productivity, innovation, and impact across multiple NIH-funded programs and catalyze new discoveries at the interface of basic science and clinical translation.

Up to $466K

2027-05-14

health research

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

High-resolution phenotyping of the hemodynamic consequences of thoracic aortic aneurysm repair

open

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY In adults with descending thoracic aortic aneurysm (TAA), vascular repair (grafting) reduces the ~20% yearly rate of rupture and/or mortality but is associated with negative perioperative consequences. Currently, thoracic endovascular aortic repair (TEVAR) has become the standard treatment for descending TAA due its lower in and out of hospital morbidity and mortality. While repair is essential, there are known negative consequences of TEVAR related to the graft material’s stiffness. Notably, the non-physiological properties of the graft may attenuate the long-term benefit of TAA repair by reducing end-organ function. Indeed, age-related stiffening of the native aorta is known to increase arterial pressure, wave reflections and the associated adverse end-organ remodeling related to greater transmission of pressure and flow pulsatility in key pressure and flow sensitive organs, such as the heart, brain, and kidneys. Despite these well-known effects of native aortic stiffening, no study has comprehensively and directly assessed the hemodynamic consequences of descending TAA repair (i.e. stiffening) locally on the aorta or on the heart, brain and kidneys. It is known that placement of grafts in the ascending aorta elicits increased aortic flow velocity, local aortic stiffness, downstream descending aortic dilation, increased wall shear stress, and likely increases pressure and flow pulsatility, arterial wave reflections and aortic pressure that, together, elicit pathological vascular and end-organ remodeling associated with reductions in function and end-organ damage. Importantly, no study has performed high-resolution assessments of the hemodynamic (pressure, wave reflection and pulsatility) and end-organ consequences of descending TEVAR at rest, but also importantly not during exercise where the consequences of aortic grafting may be exaggerated. Thus, the overall aim of the K99/R00 proposal is to perform high-resolution phenotyping of the central hemodynamic consequences of TAA pre- and post-TEVAR at rest and during exercise and determine the magnitude of associated effects on end-organ structure and function. Our project will begin to fill the large unmet gap in understanding aortic and aortic aneurysmal physiology at rest and during exercise, the impact of the standard treatment for descending TAA, and point the way towards better recommendations in practice and for design of future therapies. Furthermore, these data will encourage medical device companies to design more compliant grafts so that the positive effects of aortic grafting in terms of reducing aortic rupture risk are not offset by inducing reductions in cardiac, brain and renal function. Completion of the proposed project will provide me with a unique skillset, different from that of my mentoring team, rendering me highly competitive for future NIH funding related to the study of hemodynamics and end-organ function in health and disease.

Up to $143K

2028-03-31

health research

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

High-resolution structural analysis of native amphotericin megasynthases

open

NCCIH - National Center for Complementary and Integrative Health

Project Summary. Polyketide natural products have provided critical therapeutics, and they will remain an important component of new drug discovery and manufacturing. This program aims to develop new technologies to enable the high resolution cryo-EM structural elucidation of Type I polyketide synthases (PKSs) isolated directly from natural producer organisms. To date these megasynthase proteins have proven challenging for structural biology studies due to significant technical challenges, including extremely large molecular weights, difficult heterologous expression and highly dynamic structural features. As such, very few structures have been reported, and most are at low resolution and do not represent full synthases. We have recently developed tools for dual site-selective crosslinking of PKSs that enforces dynamic constraint and has led to the collection of high- resolution cryo-EM structures in single-modular Type I PKSs. Here we propose the development of two key tools. The first will convert native holo-PKSs to their cognate apo- forms to enable crosslinking within native PKSs. The second is the development protein isolation methodologies for very large megasynthases (500 kDa to 2 MDa) from within native producer proteomes, such that the resulting isolated forms can be structurally elucidated by cryo-EM. The amphotericin synthase pathway from producer bacterium Streptomyces nodosus will serve as a model system for high-resolution structural analysis. Together these tools will offer a fundamental step-change in access to molecular detail of PKS megasynthase structure.

Up to $440K

2028-03-31

health research

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

High-Risk Research in Biological Anthropology and Archaeology

open

U.S. National Science Foundation

Anthropological research may be conducted under unusual circumstances, often in distant locations. As a result the ability to conduct potentially important research may hinge on factors that are impossible to assess from a distance and some projects with potentially great payoffs may face difficulties in securing funding. This program gives small awards that provide investigators with the opportunity to assess the feasibility of an anthropological research project. It is required that the proposed activity be clearly high risk in nature. The information gathered may then be used as the basis for preparing a more fully developed research program. Investigators must contact the cognizant NSF Program Director before submitting an HRRBAA proposal. This will facilitate determining whether the proposed work is appropriate for HRRBAA support.

Up to $35K

rolling

sciencetechnology

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

High-throughput and Machine Learning Optimization of Fluorescent Sensors for Multiplexed Imaging in vivo

open

NIMH - National Institute of Mental Health

PROJECT SUMMARY / ABSTRACT Monitoring neuronal activity modulation is pivotal for elucidating brain functionality and addressing neurological disorders. Despite the advancements brought by green fluorescent calcium indicators like GCaMP and neuromodulator sensors, a considerable gap persists in the development of red fluorescent sensors that match the properties of their green counterparts. This gap, characterized by limitations in dynamic range, photostability, and kinetics, restricts a more comprehensive exploration of neuronal interactions, especially in multiplexed, dual-imaging imaging scenarios. Additionally, the iterative engineering approach for new sensor development is notoriously slow and labor-intensive. Our central goal is to leverage our sensor screening platform, Opto-MASS, as well as our recent successes in using machine learning to expedite the optimization of fluorescent sensors. This project aims to engineer red fluorescent calcium and neuromodulator sensors that match the kinetics and dynamic range of green sensors and further enhance their properties. Our objectives include the rigorous benchmarking of these sensors against the best-in-class for properties such as dynamic range, kinetics, and photostability, followed by comprehensive in vivo validation across multiple laboratories and application scenarios using fiber photometry and two and 3-photon imaging. Our project is innovative because it utilizes a high-throughput screening assay capable of evaluating over 10,000 sensor variants from library collections in under an hour, a significant advancement over current methods. Coupled with pioneering machine learning models that identify key residues affecting sensor performance, we will significantly accelerate fluorescent sensor development, particularly for red calcium and GPCR-based sensors. Importantly, we aim to achieve these goals while reducing time and resource commitments. Our project directly addresses critical needs outlined in this FOA, including a broader range of reliable sensors in neuroscience research that facilitate nuanced, multidimensional studies of brain activity. By developing sensors with improved dynamic ranges, kinetics, and photostability, we aim to overcome existing barriers to multiplexed imaging of neuronal dynamics in vivo. Ultimately, the successful completion of this project would not only fill a vital gap in neuroscientific research tools but also align with the NIH BRAIN Initiative's objectives to advance neurotechnology and set new standards for molecular tool development and in vivo validation in neuroscience.

Up to $2.3M

2030-12-31

health research

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

High-Throughput Automated Patch Clamp Instrument

open

OD - NIH Office of the Director

PROJECT SUMMARY Ion channels control the membrane potential and electrical properties of a myriad of excitable cells, making them critical components required for the physiological function of numerous organ systems including heart, brain, smooth muscle and skeletal muscle. The function of these channels and resulting electrical properties of the membrane are often evaluated using patch-clamp electrophysiology. However, as the number of variables underlying channel function has grown with increasing knowledge of normal and disease states, conventional manual patch-clamp methods have become increasingly insufficient to support the research. At the University of Maryland, Baltimore (UMB) our faculty includes a broad group of researchers focused on understanding the normal and pathophysiological mechanisms of ion channels and membrane electrical properties. The goal of this proposal is to support those scientists in their study of the electrophysiological characteristic of excitable cells, enabling enhanced mechanistic understanding of ion channel function and disease, and facilitating pharmacologic and therapeutic studies aimed at targeting ion channel function for therapeutic effect. This will be achieved through the purchase of an automated patch-clamp system, the Nanion Technologies SyncroPatch 384. The capability of the instrument to simultaneously patch up to 384 cells will dramatically increase the throughput of biophysical studies currently in process at UMB, enabling new resolution of genotype correlation with electrical phenotypes and promoting the development of new therapies. The Nanion SyncroPatch 384 is capable of recording in either voltage-clamp or current-clamp mode from a wide array of cell types, with data quality comparable to manual patch-clamp techniques, but with significantly greater throughput and reduced reliance on specialized user skills. The instrument will comprise the University of Maryland High -Throughput Ion Channel (HTIC) core and will be housed in the Department of Pharmacology and Physiology, where multiple faculty with electrophysiological expertise are available to support the instrument. Strong financial, administrative and facilities support will be provided by the University to ensure the success of the instrument, which will support a varied array of NIH-funded research projects. In summary, the SyncroPatch 384 offers significant advantages over conventional manual patch clamp techniques, including higher throughput, greater consistency and reproducibility, advanced temperature control, comprehensive data acquisition and analysis, versatility, and access to patch clamp techniques for a broader array of researchers.

Up to $750K

2027-04-30

health research

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

High-throughput Characterization of Genetic Mechanisms of Traditional and Paired Prime Editing

open

NHGRI - National Human Genome Research Institute

Abstract The development of prime editing has allowed for genome manipulation with user-defined insertions, deletions, or single-nucleotide conversions, without installing harmful double-stranded breaks in the genome.5 This has revolutionized the genomic medicine field, with companies like Prime Medicine, Inc. now using prime editing in human clinical trials. Despite its versatility, prime editing often results in lower editing efficiencies for larger edits, and the nuances of how insertion and deletion edits are installed by prime editors are not well understood. 5,6,7,8 Past genomic mechanistic studies of prime editing have identified DNA mismatch repair (MMR) as a negative regulator of point mutation introduction9; however, MMR does not process loops or bulges larger than 16 nucleotides, which would be utilized to install large insertions and deletions by prime editing.10,11,12 Therefore, the mechanism(s) by which the cell processes prime edits larger than 16-nt is unexplored. While traditional prime editing often becomes hindered by longer edits, “paired” prime editing techniques can facilitate larger genome modifications by replacing a sequence between two nick sites. 8,13 More thorough understanding of the DNA repair pathways will improve both traditional and paired prime editing. Aim 1 of this proposed project will develop a “dead” fluorescent reporter that is corrected by a large genomic modification by either traditional or paired prime editing. The reporter will be utilized in Aim 2, in which a high-throughput Cas12 knockout screen will be used to identify the repair pathways involved in processing large edits by traditional and paired prime editing. DNA damage repair genes will be knocked out, and K562 cell lines constitutively expressing the developed reporter and prime editor system will be separated by editing efficiency via fluorescent activated cell sorting (FACS), high-throughput sequencing (HTS), and large-scale bioinformatics data processing. In Aim 3, the results from the genomic screen will be validated through testing at multiple endogenous sites and in various cell types to ensure reproducibility and rigor in identifying hit genes. With an increased understanding of traditional and paired prime editing, the resulting gene hits will be incorporated into novel prime editor systems to increase editing efficiency for longer edits, which can fill gaps on treating all genetic disease. Additional knowledge of what repair pathways process large edits will also add to the DNA damage repair field, enriching understanding on structure and biology of genomes. Ultimately, the proposed training plan is set to advance the PI’s technical foundation of genomic, high-throughput screening methods, as well as provide steps to develop professional skills, leadership, and scientific independence for a future in academic research. It will be supported by the sponsor Dr. Alexis Komor and UCSD’s Chemistry and Biochemistry department, in consortium with the many UCSD and Sanford core research facilities that will provide the necessary FACS, HTS, and supercomputing instruments.

Up to $43K

2029-04-30

health research

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

High-throughput tools to track the fate of prematurely terminated transcripts in cancer cells

open

NCI - National Cancer Institute

Post-transcriptional gene regulation plays a critical but understudied role in cancer development. The genetic basis of cancer has been extensively characterized; yet, alterations in RNA processing mechanisms, such as alternative polyadenylation (APA) events, can also drive oncogenesis independent of DNA mutations. In chronic lymphocytic leukemia, APA inactivates tumor suppressor genes by generating intronically terminated transcripts that produce truncated proteins lacking tumor-suppressive domains. Similar APA-driven oncogenic mechanisms have been observed in glioblastoma and lung adenocarcinoma. APA events in 3’ UTRs are prevalent in many cancer types, leading to changes in stability, localization, and translation of these transcripts, with widespread ramifications including increased cell proliferation, angiogenesis, and metastasis. Despite the recognition that APA events play a significant role in cancer, technological limitations have hampered our ability to track the dynamic fate and functional impact of alternatively processed transcripts across the cell in different cancer types. Current methods that identify APA events cannot simultaneously monitor the nuclear export, translation efficiency, or degradation patterns of APA transcripts to understand their movement and fate in the cell. A better understanding of the dynamics of APA transcripts, and how they differ in cancer cells versus healthy cells, will help us to define critical regulatory nodes for these transcripts, and uncover cellular processes that promote the usage of oncogenic APA transcripts across different cancer types. To quantify RNA flow rates across subcellular compartments, from synthesis to export, translation, and degradation, we developed subcellular TimeLapse-seq (TL-seq). While this technology establishes a foundation for investigating RNA dynamics, it has not yet been engineered to track the fate of transcripts that are alternatively polyadenylated (APA transcripts). Here, we propose to integrate subcellular TL-seq with 3'-end sequencing to create powerful new tools for comprehensively studying the flow and fate of alternatively polyadenylated transcripts in cancer cells. Aim 1: To map the fate of APA transcripts, we will develop 3prime-TLseq, a novel method that combines subcellular TimeLapse-seq with 3'-end sequencing to quantify APA transcript dynamics. To demonstrate the utility of our approach, we will apply the developed protocol to investigate how JTE-607 – a small molecule that interferes with cleavage and polyadenylation machinery and shows promising activity against various cancer types– affects the dynamics of APA transcripts. Aim 2: To determine whether and how well APA transcripts are translated, we will develop 3primeTL-polysome profiling, which combines TimeLapse-seq and 3'-end sequencing with polysome profiling to quantitatively measure both the rate of RNA loading onto polysomes and the half-life of associated RNAs. By overcoming the limitations of current methods, which can identify global APA events but cannot track their dynamic flow and fate through subcellular compartments, we will enable researchers to study previously inaccessible aspects of RNA regulation in cancer, and potentially identify novel therapeutic vulnerabilities.

Up to $237K

2029-02-28

health research

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