Grants

Louisiana Office of Cultural Development

Louisiana Main Street supports downtown revitalization through preservation-based economic development strategies.

$5K – $50K

downtown revitalizationeconomic developmenthistoric preservation

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Louisville Arts Commission — Project Grant

artsculturecommunity arts

Louisville Arts Commission

Project and operating grants for arts organizations and individual artists from Louisville Arts Commission. Supports visual, performing, literary, and media arts.

$2K – $50K

2026-12-31

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Louisville Forward Grants

Louisville Forward / Louisville Metro Government

Economic development grants and incentives supporting business attraction, retention, expansion, and entrepreneurship in Louisville Metro, including forgivable loans and tax incentives.

$10K – $250K

Business DevelopmentCommunity Development

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Louisville Neighborhood Development Grants

Louisville Metro Government

Grants for neighborhood improvement, community building, and commercial revitalization in Louisville neighborhoods.

$5K – $75K

community developmentneighborhood revitalizationeconomic development

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Louisville Small Business Assistance

Louisville Metro Government

Grants, microloans, and technical assistance for small businesses in Louisville, with focus on underserved neighborhoods and minority-owned businesses.

$3K – $50K

Business DevelopmentEquity & Access

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Low - Field MR Fingerprinting for Myocardial Tissue Characterization in Patients with Cardiac Implantable Electronic Devices

NIBIB - National Institute of Biomedical Imaging and Bioengineering

PROJECT ABSTRACT/SUMMARY Over two million Americans have a cardiac implantable electronic device (CIED) to manage arrhythmias, often secondary to cardiomyopathies, and prevent sudden cardiac death. Magnetic Resonance Imaging (MRI) is a powerful tool for non-invasive detection of myocardial tissue abnormalities—including inflammation, edema, and fibrosis—using late gadolinium enhancement (LGE) imaging and quantitative T1, T2, and extracellular volume fraction (ECV) mapping. However, MRI remains widely underutilized in patients with CIEDs, as metallic components in these devices distort the magnetic field and create off-resonance artifacts that severely degrade image quality. Although 16% of patients with CIEDs will develop a clinical indication for cardiac MRI at some point, they are 40% less likely to undergo an MRI exam than non-CIED patients, leaving clinicians to rely on alternative modalities that lack detailed tissue characterization capabilities. This project aims to address this unmet need by developing MRI technology for robust myocardial tissue characterization specifically tailored for CIED patients, providing quantitative tissue property maps (T1, T2, proton density, and ECV) and multi-contrast LGE images from a single imaging platform. Our solution is based on Magnetic Resonance Fingerprinting (MRF), an innovative framework that measures temporal changes in magnetization (“fingerprints”) to achieve rapid multiparametric mapping. We propose a novel cardiac MRF technique that is separately optimized for conventional 1.5T scanners, given that most CIED patients are currently imaged at this field strength, as well as emerging low-field 0.55T scanners, which offer inherent advantages for imaging near metallic implants, such as reduced off-resonance artifacts. In Aim 1, we will develop the proposed technique in parallel for 1.5T and 0.55T by integrating robust data collection strategies, such as center-out radial sampling and wideband excitation pulses, with a physics-informed deep learning reconstruction that further suppresses off-resonance artifacts and residual motion. We will evaluate accuracy, precision, and repeatability in phantoms and healthy subjects with an externally positioned CIED scanned at both field strengths compared to conventional cardiac mapping methods. In Aim 2, we will assess MRF for native and post-contrast mapping in cardiomyopathy patients with CIEDs at 0.55T and 1.5T and validate methods for detecting myocardial fibrosis, given its prognostic importance in many conditions. To this end, we will generate synthetic multi-contrast (bright- and dark-blood) LGE images from post-contrast MRF maps, which we expect to simplify the exam and enhance detection of fibrosis compared to conventional bright-blood wideband LGE scans. Furthermore, we will develop a clustering algorithm that directly analyzes tissue property maps to identify fibrosis, serving as a semi-automated and operator- independent alternative to LGE. This project has the potential to have a significant and immediate impact on public health by expanding access to advanced MRI techniques for myocardial tissue characterization in CIED patients, who are at high risk of adverse cardiovascular events yet are underserved by current MRI technology.

Up to $75K

2027-11-30

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Low disturbance prefabrication approaches for deep renovation of multi-storey buildings (Built4People Partnership)

European Commission - HORIZON

Low disturbance prefabrication approaches for deep renovation of multi-storey buildings (Built4People Partnership). Call: BATTERIES and ENERGY. Programme: HORIZON. Open call from the EU Funding & Tenders Portal.

$50K

2026-09-15

clean_energy

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Low Income Taxpayer Clinic Grant Program; Availability of 2026 Grant Application Package

Treasury Department

This document contains a notice that the IRS has provided a grant opportunity in www.grants.gov for organizations interested in applying for a Low Income Taxpayer Clinic (LITC) matching grant. The IRS is authorized to award multi-year LITC grants not to exceed three years. Grants may be awarded for the development/start up, expansion, or continuation of programs providing qualified services to eligible taxpayers. The budget and the period of performance for the grant will be January 1, 2026-December 31, 2026. The application period runs from May 15, 2025, through July 14, 2025.

See notice

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Low Income Taxpayer Clinic Grant Program; Availability of 2027 Grant Application Package

Treasury Department

This document contains a notice that the IRS has provided a grant opportunity in www.grants.gov for organizations interested in applying for a Low Income Taxpayer Clinic (LITC) matching grant. The IRS is authorized to award multi-year LITC grants not to exceed three years. Grants may be awarded for the development/start up, expansion, or continuation of programs providing qualified services to eligible taxpayers. The budget period for the grant will be January 1, 2027- December 31, 2027. For new grantees, the Period of Performance is generally one year (January 1, 2027-December 31, 2027.) The application period runs from May 6, 2026, through July 6, 2026.

See notice

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Low intensity focused ultrasound for posttraumatic stress disorder

NIH

PTSD is highly prevalent in Veterans and is associated with significant psychiatric and medical comorbidity and healthcare utilization. Most importantly, PTSD prevents Veterans from reintegrating into society and is associated with significant disability and psychosocial dysfunction. Despite its prevalence and devastating impact, even the most efficacious treatments have modest success in improving either symptoms or functioning in Veterans with PTSD. One reason for this limited efficacy is the inability for current treatments to directly target and engage deep brain regions which are directly involved in PTSD psychopathology. However, recent advances in the areas of neuroscience, psychiatry and technology allow, for the first time, development of new technologies that can non-invasively and reversibly modulate deep brain structures through the use of low intensity focused ultrasound (FUS). This application is targeting the amygdala, which is a core region involved in PTSD and many other psychiatric disorders. To date, cleared uses of focused ultrasound are high-intensity sonication to irreversibly ablate tissue, therapeutically for movement disorders and cancer-related pain. Effects are highly focal (i.e., millimeter-scale), and occur without adjacent tissue damage. In contrast, FUS as it is proposed here uses acoustic energy at the same precision but within safety limits for diagnostic ultrasound. Although therapeutic use of FUS remains largely unexplored, several groups demonstrated that FUS can safely modulate neural activity in mice, rabbit, swine, and non-human primates. Even more recent data indicates FUS can safely modulate human cortical activity, including that of somatosensory and motor cortex as well as the subcortical thalamus in healthy individuals. Our group has been leading the effort to evaluate the use of FUS, by delivering a single dose of FUS inside the bore of an MRI scanner to a group of depressed Veterans. However, FUS has not yet been developed for PTSD, and before rigorous clinical trials of FUS for PTSD can be initiated, several key questions remain and are the focus of this study. Using a phase II-style proof of concept/dose-finding study, investigators will characterize the effects of sham-controlled FUS administrations. Veterans with chronic PTSD first receive an MRI scan to facilitate high- precision targeting using out-of-scanner stereotactic neuronavigation. After targeting, Veterans are randomized to receive sham FUS, or one, two, or three FUS administrations per week over a month, and then Veterans will be followed for up to three months to evaluate longer-term effects. Neuroimaging MRI will be obtained prior to and following completion of FUS to explore neural effects. Thus, this study will evaluate the short-term durability of any effects on symptoms and function, and the design will provide important insight into the potential use of repeated administrations over time. The significance of this project lies in the potential to develop non-invasive deep brain stimulation for PTSD, with lessons learned that will be applicable for broader implementation; this goal can be realized through this careful and programmatic phase II study.

2030-03-31

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Low-Cost Chip-Scale Atomic Clock (LC CSAC)

Dept of the Army -- Materiel Command

**PLEASE REVIEW FULL SPECIAL NOTICE** Funding Opportunity Title: Low-Cost Chip-Scale Atomic Clock (LC CSAC) Funding Instrument Type: Technology investment agreement The aim of this Special Notice under the ARL BAA (W911NF-17-S-0003), under Grants.gov Opportunity W911NF-17-S-0003-SPECIALNOTICE-LC-CSAC, is to fund a team or multiple teams to design, manufacture, and deliver a battery-powered atomic clock that achieves identical (or better) size, weight, and power (SWaP) and performance to the commercially available chip-scale atomic clock (CSAC) with a selling price goal of < $300/unit in high volume. Precise timing is critical for numerous Army applications such as navigation, communications, surveillance, and synchronization of sensors and systems. Assured PNT solutions currently rely on acquiring GPS signals, which may not be readily available in increasingly contested environments. Commercially available silicon MEMS and quartz oscillators (TCXO, OCXO) are unable to provide GPS holdover in the event of a GPS outage, except for high-end OCXOs that may be considered large and power hungry for certain applications. To ease reliance on GPS, long-holdover clocks with SWaP-C appropriate for various DoD platforms are necessary to enable mission-critical functions even in contested environments. Current high-performance atomic clocks (maser, laser-cooled cesium fountain) serve as standards and are large, expensive, and require regular monitoring and exquisite environmental control. Since the early 2000s, the chip-scale atomic clock (CSAC) has been developed and successfully matured into a commercial product with DARPA and industry investment. While an Army/Air Force/OSD Manufacturing Technology effort further reduced the manufacturing cost1, the current selling price is still prohibitive for high-volume, low-SWaP DoD platforms. There is an opportunity to leverage the many advances in MEMS, photonics, and atomic physics over the past two decades to develop state-of-the-art, high-performance, battery-powered atomic clocks with improved manufacturability, significantly reduced cost, and improved performance. This special notice seeks proposals from one or more for-profit firms in accordance with 32 CFR 37.210. A consortium, led by a for-profit firm, is also encouraged. Points of Contact: Jonathan Hoffman jonathan.e.hoffman.civ@mail.mil Jenna Chan Jenna.f.chan.ctr@mail.mil

sciencetechnology

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Low-Cost Chip-Scale Atomic Clock (LC CSAC)

Dept of the Army -- Materiel Command

Low-Cost Chip-Scale Atomic Clock (LC CSAC)

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Lowe's Foundation Community & Skilled Trades Grants

Lowe's Foundation

Supports community improvement, skilled trades education, and workforce development in construction and building trades.

$10K – $500K

community developmentworkforce developmentskilled trades

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Lowell Folk Festival and Summer Music Series Support for 2017 Season

National Park Service

The objective of this Agreement is to provide ethnic and cultural events based on NPS themes at Lowell National Historical Park. Lowell National Historical Park was established to preserve and interpret the nationally significant historical and cultural sites, structures and districts in Lowell, Massachusetts, for the benefit and inspiration of present and future generations by implementing the recommendations of the report of the Lowell Historic Canal District Commission. The report of the Lowell Historic Canal District Commission calls for the Lowell National Historical Park to be a vital and contributing part of the Lowell community accomplishing its mission through active public/private partnerships.

$1 – $152K

artshumanities

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Lower Airway Microbial Sulfur Metabolism and Oxidative Stress in Inflammatory Lung Disease

NIAID - National Institute of Allergy and Infectious Diseases

Abstract. Oxidative stress is a key factor in many inflammatory airway diseases, driven by redox dysregulation. Cigarette smoke, a major contributor, induces reactive oxygen species (ROS) accumulation, disrupting redoex homeostasis and upregulating pro-inflammatory pathways. While the gut microbiome’s influence on host redox status and antioxidant capacity is well documented, the role of the lung microbiome in oxidative stress has been less clear, despite observed lower airway dysbiosis in many inflammatory diseases. Recent research, including data from us, indicates that the lung microbiome is functionally active and can directly influence the metabolic landscape of the lower airways. Enrichment of anaerobic bacteria such as Veillonella and Actinobacteria, along with metabolites like glutathione disulfide, is associated with worsening pulmonary function and symptoms in inflammatory lung diseases, such as chronic obstructive pulmonary disease (COPD). This suggests that microbial metabolites contribute to disease pathophysiology. Many oral commensal bacteria utilize sulfur-containing compounds, and their enrichment in the lower airways, observed in early-stage COPD patients, may impact the local sulfur pool. This can alter crucial sulfur compounds, including sulfur-containing amino acids, reactive sulfur species, and thiol antioxidants, which are vital for redox signaling and oxidative stress modulation. Our central hypothesis is that the aspiration of oral commensals alters sulfur metabolism and shifts sulfur compound abundance in the lungs, contributing to redox dysregulation and increased susceptibility to oxidative stress, leading to inflammation. To investigate this, we propose two specific aims: 1.) Assess if altered sulfur metabolism is associated with the enrichment of oral commensals and increased oxidative stress in the lower airways, using samples already collected from a human cohort; and 2.) Evaluate the microbial contribution to lower airway sulfur compounds and oxidative stress in a preclinical mouse model. We hypothesize that introducing these bacteria will decrease lower airway abundance of sulfate, increase total sulfide, and cause heightened oxidative stress and subsequent inflammation. This research aims to provide proof of concept for the role of the lower airway microbiome in oxidative stress injury, potentially present in early inflammatory airway diseases. Our findings will support larger prospective and longitudinal studies, which will be key to proving that these microbial metabolic pathways are active in the lower airways and amenable to targeted interventions.

Up to $254K

2028-04-30

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Lower B500 Road Removal in Redwood National Park

National Park Service

United States Department of the Interior, National Park Service (NPS) Notice of Intent to Award. This is not a request for applications. This posting is to provide public notice of NPS' intention to fund the following project activities without full and open competition: Project Statement P19AC01047 under Annual Funding Agreement G848017001 with the Yurok Tribe, for the project titled, "Lower B500 Road Removal in Redwood National Park."

$189K

natural resources

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Lower Columbia Watershed Restoration Cooperative Agreement with Columbia River Estuary Studey Taskforce

National Park Service

This is not a request for application. This serves as public notice of the National Park Services intention to fund project activities with full and open competition. The broad goals of this agreement include restoring habitat for federally listed threatened and endangered salmon and steelhead restoring National Park Service and adjacent lands within the Columbia River estuary and restoring the historic scene at the NPS and adjacent lands within the Columbia River estuary by restoring the natural setting

$200K – $500K

natural resources

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LOYALISTS & LIBERTY: SAVANNAH IN THE AMERICAN REVOLUTION [IN ANTICIPATION OF THE NATION?S SEMIQUINCENTENNIAL, COASTAL HE...

National Endowment for the Humanities

LOYALISTS & LIBERTY: SAVANNAH IN THE AMERICAN REVOLUTION [IN ANTICIPATION OF THE NATION?S SEMIQUINCENTENNIAL, COASTAL HERITAGE SOCIETY WILL OPEN THE EXHIBITION ?LOYALISTS & LIBERTY: SAVANNAH IN THE AMERICAN REVOLUTION? IN JULY 2026. AS A CENTERPIECE OF SAVANNAH HISTORY MUSEUM, THE 3,000-SQUARE-FOOT EXHIBITION WILL TELL THE STORY OF SAVANNAH?S ROLE IN AMERICA?S FOUNDING AND FIGHT FOR INDEPENDENCE WHILE PROVIDING A FOCAL POINT OF COMMUNITY ENGAGEMENT. IT WILL SHOWCASE RARE ARTIFACTS FROM THE 18TH CENTURY THAT REPRESENT LIFE DURING THE PERIOD, INCLUDING NEVER-BEFORE-EXHIBITED ARTILLERY THAT WILL SERVE AS THE CENTERPIECE OF THE EXHIBITION. CHS RESPECTFULLY REQUESTS SUPPORT FOR THE MOUNTING AND EXHIBITION OF THESE ARTIFACTS CRITICAL TO THE STORY OF SAVANNAH AND GEORGIA?S ROLE IN THE WAR FOR INDEPENDENCE.]

Up to $25K

2026-08-31

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Loyola Foundation Jesuit Mission Grants

Loyola Foundation

Supports Jesuit missions and ministries worldwide including education, healthcare, social services, and spiritual formation in underserved communities.

$5K – $75K

Jesuit missionsEducationhealthcare+1

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LPS Qubit Collaboratory (LQC)

Dept of the Army -- Materiel Command

The U.S. Army Research Office (ARO) in partnership with NSA s Laboratory for Physical Science (LPS) is soliciting Incubator, Collaboration, and Fellowship research proposals for participation in the LPS Qubit Collaboratory (LQC). The mission of the LQC can be captured in three broad goals: 1) pursue disruptive fundamental research and enabling technologies with a focus on qubit development for quantum computing and other applications (such as sensing); 2) grow deep, collaborative partnerships to tackle the most difficult and relevant long-term problems in quantum information science and technology; and 3) build a quantum workforce of tomorrow through research experiences in government at LPS and at LQC partners. The LQC will offer a mechanism for collaborative research between LPS and academia, industry, FFRDCs, and Government Laboratories to advance foundational and transformative research on challenging problems that have hindered progress in quantum information processing and associated technologies.The goal of this BAA is to seek proposals that bring together expertise from the public and private sectors and their respective research infrastructures to advance solutions that may be best approached as a collaborative team. A Collaboratory is a center without walls, in which the nation s researchers can perform their research without regard to physical location, interacting with colleagues, accessing instrumentation, sharing data and computational resources, [and] accessing information in digital libraries. This BAA introduces LQC Research Thrusts (A.1.1) which are the technical areas of interest which will be updated periodically where partners of the LQC will pursue joint research with LPS through Incubator (A.1.2) and Collaboration (A.1.3) collaborative agreements. The LQC BAA also fulfills the Government s overarching interest--through the proposed research and on-site research experiences--in creating and training a workforce in quantum science and technology, generating pathways of solutions that feed technology development, establishing partnerships, and creating transition opportunities. In further support of training through research, Section A.1.4 calls for Quantum Computing Research (QuaCR) Graduate and Postdoctoral Fellowships for US citizens working in areas of interest.Substantial progress on solving the most difficult and long-term Quantum Information Science & Technology (QIST) research problems that unleash further rapid progress in the field will constitute LQC success. Examples of such research problems include (but are not limited to): limits of performance due to device design, material selection, and/or control, the exploration of alternative qubit physics (e.g., different approaches to qubit encoding or types of gates) and lowering of barriers to such approaches, advances in materials that improve qubit gate fidelity, reducing the overhead of classical components in quantum information technology and optimizing classical performance, and the exploration of applications of quantum technologies to new domains.Three categories of proposals are sought for this BAA:1.Incubator opportunities seek partnership proposals from single investigators and small research groups, including teaching colleges, who may have unique skillsets to contribute toward the pursuit of the research thrusts presented in A.1.1. Incubator proposals may also be the development of concepts into a detailed technical research approach to advance solution of problems of high interest to quantum information science research. Incubator proposals would avail themselves of the collaboration opportunities with LPS research staff and infrastructure made available at the Laboratory for Physical Sciences (LPS) to lay the groundwork for concepts that may be suitable for a Collaboratory proposal or responses to other DoD quantum information science research opportunities.2.Collaboratory proposals seek research proposals that bring together a strong significant collaboration--researchers from academia, industry, FFRDCs, and/or Government Laboratories--to pursue long-term projects focused on fundamental problems of interest to qubit development and/or associated science and technology. These collaborative groups will propose to work together in a focused manner for a period of time expected to be one to three years in order to demonstrate a proof-of-concept experiment and/or theory exploration to determine the feasibility of their creative idea.3.QuaCR Research Fellowship proposals seek to support talented U.S. citizen graduate students and postdoctoral researchers in the field of quantum information processing (primary interest) and quantum sensing (secondary interest). Applicants with a background from either within or outside QIS are encouraged. The proposed research areas are described in this BAA and must enhance active Quantum Information Science research efforts being supported by the Army Research Office and/or LPS. Research fellows are encouraged to complete an LPS Internship during their graduate career or visit during their postdoctoral fellowship.Funding Opportunity Title: LPS Qubit Collaboratory Special Research Topics Announcement: W911NF21S0009-SPECIALNOTICE-1The U.S. Army Combat Capabilities Development Command (DEVCOM), Army Research Laboratory (ARL)-Army Research Office (ARO) is looking for proposed research and development solutions under the Broad Agency Announcement (BAA) W911NF21S0009-2 for Basic and Applied Scientific Research in Quantum Computing. The title for this Special Notice is LPS Qubit Collaboratory Special Topics. Upon receipt, compliant proposals will be reviewed through a technical and programmatic process in accordance with the evaluation criteria referenced in the W911NF21S0009-2 LQC BAA to determine which proposal may be awarded Grant, Cooperative Agreement, or Procurement Contract under this topic.

2027-04-30

sciencetechnology

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LPS Qubit Collaboratory (LQC)

Dept of the Army -- Materiel Command

LPS Qubit Collaboratory (LQC)

2027-04-30

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LRRK2 signaling in the progression of Parkinson's disease and dementia

NINDS - National Institute of Neurological Disorders and Stroke

Summary Genetic studies implicate pathogenic missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene as a common cause of familial Parkinson's disease (PD). Independently, genome-wide association studies identify LRRK2 promoter variants important in idiopathic PD risk. LRRK2 protein signals within the endolysosomal system through phosphorylating Rab protein substrates, altering their function in different pathways and cell responses. Phosphorylation of the prominently expressed Rab10 substrate is absent in LRRK2 knockout mice, diminishes with LRRK2 kinase inhibition, and is upregulated with pathogenic LRRK2 mutations and LRRK2 activation. Genetic variants in non-coding regions in Rab10 are tied to Alzheimer's disease (AD) resilience, and pRab10 upregulation may be associated with tau aggregation in the brain. Post- mortem studies find most LRRK2 carriers harbor 3R/4R tauopathy and Aß changes, often with Lewy pathology. Evidence in models suggests LRRK2 signaling may promote α-synuclein and tau pathology and related inflammation responses. However, there is a paucity of data from humans related to the role of LRRK2 signaling in disease progression. The main goals of this application are to learn whether LRRK2 signaling changes in PD and AD predict disease severity, discover pathways tied to these changes, and how LRRK2 signaling changes in the brain manifest with progressive pathological depositions of α-synuclein and tau. To accomplish these goals, our work in the last decade has culminated in the development of ultra- sensitive single molecule array assays, capable of assessing, with great specificity and sensitivity, LRRK2 signaling in biobanked tissues and fluids. Our recent results, starting from cross-sections of PD patients and controls, suggest a possible association between high pRab10 levels and worse PD severity. Preliminary results in post-mortem brain tissues have identified possible aberrant pRab10 accumulations in PD and AD. Here we propose to fully leverage deeply phenotyped longitudinal cohorts of PD and AD patients, and neurologically normal controls, to measure LRRK2 signaling changes as they occur with disease progression, in both serum and CSF. These measures will provide some of the first well-powered insights into how LRRK2 signaling changes might predict disease outcomes. Whole blood transcriptomic profiles and genomic data will be interrogated for factors critical in driving LRRK2 signaling. In complement, pathologically staged PD and AD brain tissues will be analyzed for LRRK2 signaling changes, together with powerful mouse models that have predictable progressive tau and α-synuclein pathology. Through the proposed work, the first large-scale effort to understand LRRK2 signaling changes in the progression of PD and AD, we expect to uncover new pathobiological mechanisms that further implicate LRRK2 in idiopathic neurodegenerative diseases, and begin to define idiopathic patient populations more likely to benefit from LRRK2-targeted therapeutic approaches.

Up to $1.8M

2029-04-30

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LRRK2-specific DARPins as tools to investigate kinase activation and regulation in Parkinson's Disease

NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY Parkinson’s disease (PD) is the second fastest growing aging-related neurodegenerative disease in the world. One of the most commonly mutated genes in PD is Leucine Rich Repeat Kinase 2 (LRRK2). LRRK2 mutations that are linked to PD result in hyperactive kinase activity, but unmutated LRRK2 can also be hyperactive in idiopathic forms of PD, making its kinase the most actionable target for PD therapeutics. Thus, it is critical to understand how LRRK2’s kinase activity is regulated, something that remains poorly understood. LRRK2 encodes a multi-domain protein, whose N-terminal half is comprised of three protein-protein interaction repeat domains that form an arm-like structure that drapes across its kinase and GTPase domains, to dock at the C- terminal WD40 domain. When these arm-like repeats are docked on the WD40 domain, LRRK2’s kinase is autoinhibited. Here, I will use LRRK2-specific Designed Ankyrin Repeat Proteins (DARPins), which I was involved in developing, to determine how LRRK2’s kinase activity is regulated. We identified three DARPins, E11, C12 and G10, which bind tightly to LRRK2 at partially overlapping sites on its WD40 domain, yet have distinct effects on LRRK2’s kinase activity. Our data suggest that DARPin C12 activates LRRK2’s kinase activity, while DARPin E11 and G10 inhibit it. Our preliminary cryo-EM data support the hypothesis that DARPin C12 relieves autoinhibition by blocking binding of LRRK2’s repeat domains to the WD40 domain. My preliminary data also supports the hypothesis that some PD alleles outside of the kinase active site effectively act like C12: they activate the kinase by relieving autoinhibition. Based on the binding sites of E11 and C12, we hypothesize that E11 may be blocking binding of an activating factor, while C12 maybe stabilizing the autoinhibited conformation of LRRK2. Thus, DARPin E11 is an excellent tool to identify novel activators of LRRK2, as well as to screen existing small molecule libraires to identify allosteric inhibitors of LRRK2’s kinase. I expect to determine how mutations in LRRK2 that are distal to the kinase domain increase kinase activity. In addition, my goal to identify novel activators of LRRK2’s kinase and allosteric inhibitors of its kinase will lead to new therapeutic strategies for targeting LRRK2 for the treatment of PD.

Up to $43K

2028-09-29