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Principal Investigator: GABOR J TIGYI
Organization: UNIVERSITY OF MARYLAND BALTIMORE
Fiscal Year: 2023
Award: $310,386
Funding agency: National Institute of Allergy and Infectious Diseases
The US population at large, and particularly military personnel and first responders, are at risk of radiation expo-sure due to the explosion of a nuclear device, a nuclear reactor accident, and the threat of radiation terrorism.
There is no radiation medical countermeasure (RCM) drug approved by the FDA that meets the criterion of a
gastrointestinal (GI) radiomitigator – an agent which mitigates the acute GI radiation syndrome (GI-ARS) when
administered after the exposure. Ionizing radiation kills cells that are unable to repair their DNA, primarily via
mitotic catastrophe and apoptotic cell death. Post-irradiation genotoxic stress and cell injury is an unsolved
medical problem. A critical barrier to progress in development of RCM drugs is that a traditional human
clinical trial is not an option. Therefore, FDA approval of a RCM is done under the Animal Rule that requires
detailed understanding of its mechanism of action, demonstration of its safety, and efficacy in animal models,
and its safety in humans. In this transitional research proposal, we propose studies to fully satisfy the mech-anism of action requirement of the Animal rule for Radioprotectin-1 (RP-1) a new radiation mitigator we devel-oped with previous NIAID funding and develop a single-dose extended release formulation that meets CONPOS
requirements of a RCM. Our overall goal is to prepare RP-1 for regulatory approval as a first-in-class synthetic
GI radiation mitigator. RP-1 is the first specific agonist of the lysophosphatidic acid (LPA) receptor subtype 2
(LPA2) with picomolar EC50, which reduces radiation injury-induced mortality in mice. Our central hypothesis
is that RP-1–activated, uniquely long-lasting (> 16h) signaling mediated by the LPA2 G protein-coupled receptor
(GPCR), is responsible for mitigation of genotoxic stress and promotion of cell survival. Our hypothesis predicts
that RP-1 achieves this via 1) obligate stimulation of the LPA2 GPCR, 2) sequential recruitment of supramolecular
signaling interactomes responsible for the long duration of its action, 3) augmentation of DNA repair and 4)
enhanced survival of LGR5 intestinal stem cells (ISC). Our objectives are: 1) determine in detail the unique
molecular mechanism of how RP-1 acts via LPA2 to recruit the interactomes required for overcoming genotoxic
stress, and 2) identify the specific subpopulation of ISC that is protected by RP-1 in vivo using transgenic mice
that express fluorescent protein in the LGR5 marker bearing ISC and 3) develop a single dose extended release
nanoparticle formulation that mitigates the GI-ARS. Although this information is necessary to move RP-1 forward
toward regulatory approval, the body of knowledge we will generate also represents significant and previously
unknown information concerning radioprotective signaling mechanisms.Our expected outcomes will include 1)
establishing that LPA2-dependent recruitment of the IEX-1–TRIP6–ERK1/2-AKT interactome is required for mit-igation of genotoxic stress; 2) defining the role of RP-1 effects that enhance DNA-dependent Protein Kinase-dependent DNA repair and prosurvival signals; 3) demonstrating that RP-1 is an effective mitigator of GI-ARS
by protecting ISC in mice; 4) a single-dose extended-release RP-1 formulation. The impact of our project will
directly affect our first-response options in treating patients with radiation injury. The aims of the project are:
Aim 1. Test the hypothesis that RP-1 via LPA2 mediates long-lasting activation of DNA repair and pro-survival signaling in LGR-5 positive intestinal stem cells.
Aim 2. Develop a nanoparticle-based extended-release RP-1 formulation for the treatment of the GI-ARS
of mice and Rhesus macaques.
All data obtained will be used for a RP-1 Drug Master file and presented to the FDA during our PRE-IND meeting
in the final year of the project and shared with the research community at large.
Terms: <AKT><Acceleration><Acute><Acute Radiation Syndrome><Advanced Development><Affect><Agonist><Akt protein><Animal Model><Animal Models and Related Studies><Apoptotic><Armed Forces Personnel><Assay><Benzoic Acids><Bioassay><Biologic Assays><Biological Assay><Blood Precursor Cell><Bone Marrow><Bone Marrow Reticuloendothelial System><Cell Body><Cell Communication and Signaling><Cell Death><Cell Signaling><Cell Survival><Cell Viability><Cells><Cellular injury><Cessation of life><Clinical Trials><Collaborations><Colon><Communities><Complex><DNA><DNA Damage Repair><DNA Integration><DNA Repair><DNA- PKcs protein><DNA-Activated Protein Kinase Catalytic Subunit><DNA-PK><DNA-activated protein kinase><DNA-dependent protein kinase><DNA-dependent protein serine-threonine kinase><Data><Death><Deoxyribonucleic Acid><Development><Devices><Dose><Drug Formulations><Drug Kinetics><Drug Targeting><Drugs><ERK 1><ERK1><ERK1 Kinase><Enzyme Gene><Enzymes><Evaluation><Explosion><Extracellular Signal-Regulated Kinase 1><FDA approved><Formulation><Funding><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GPCR><Generations><Genes><Genotoxic Stress><Goals><Growth Agents><Growth Factor><Growth Substances><Gut Epithelium><HG38><Hematopoietic><Hematopoietic Progenitor Cells><Hematopoietic stem cells><Human><Hyper-Radiosensitivity Of Murine SCID Mutation, Complementing 1><Immunoglobulin Enhancer-Binding Protein><Induction of Apoptosis><Inhibition of Apoptosis><Injury><Intestinal><Intestines><Intracellular Communication and Signaling><Investigational Drugs><Investigational New Drugs><Ionizing Electromagnetic Radiation><Ionizing radiation><Knowledge><LD-50><LD50><LGR5><LGR5 gene><LPA Receptors><Laboratories><Lethal Dose 50><Leucine-Rich Repeat><Lysophosphatidic Acid Receptors><M mulatta><M. mulatta><MAP Kinase 3><MAPK3><MAPK3 Mitogen-Activated Protein Kinase><MAPK3 gene><MOPA><Macaca mulatta><Mediating><Medical><Medication><Mice><Mice Mammals><Military><Military Personnel><Mitogen-Activated Protein Kinase 3><Mitogen-Activated Protein Kinase 3 Gene><Mitotic><Modeling><Modern Man><Molecular><Molecular Mechanisms of Action><Murine><Mus><NF-kB><NF-kappa B><NF-kappaB><NFKB><NIAID><National Institute of Allergy and Infectious Disease><Natural regeneration><Nuclear><Nuclear Factor kappa B><Nuclear Reactor Accidents><Nuclear Transcription Factor NF-kB><Organ><Outcome><P44ERK1><PSTkinase p44mpk><Pathology><Pathway interactions><Patients><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacies><Pharmacokinetics><Pharmacy facility><Phosphoprotein Phosphatase><Phosphoprotein Phosphatase-2C><Phosphoprotein Phosphohydrolase><Population><Pre IND FDA meeting><Pre-IND mtg><Progenitor Cells><Property><Protein Kinase B><Protein Phosphatase C><Protein Phosphatase Gene><Protein Phosphatase-1><Protein Phosphatase-2A><Protein phosphatase><Proteins><Proteins Growth Factors><Proto-Oncogene Proteins c-akt><RAC-PK protein><Radiation><Radiation Dose><Radiation Dose Unit><Radiation Induced DNA Damage><Radiation Induced Genotoxicity><Radiation Injuries><Radiation Protection><Radiation Syndromes><Radiation Toxicity><Radiation exposure><Radiation induced damage><Radiation-Ionizing Total><Radioprotection><Radioprotective><Radiotoxicity><Receptor Protein><Regeneration><Research><Research Proposals><Rhesus Macaque><Rhesus Monkey><Right-Handed Beta-Alpha Superhelix><Role><SCID protein><Safety><Signal Transduction><Signal Transduction Systems><Signaling><Terrorism><Testing><Therapeutic><Toxicokinetics><Transcription Factor NF-kB><Transgenic Mice><Unscheduled DNA Synthesis><XRCC7 protein><analog><animal rule><biological signal transduction><blood stem cell><bowel><c-akt protein><cell damage><cell injury><cell killing><cell regeneration><cellular damage><cellular regeneration><cellular targeting><college><collegiate><damage to cells><developmental><drug candidate><drug development><drug discovery><drug/agent><efficacy study><experience><first responder><gamma irradiation><gastrointestinal><gastrointestinal epithelium><gene product><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic><hemopoietic progenitor><hemopoietic stem cell><in vivo><injuries><injury to cells><ionizing output><irradiation><irradiation injury><irradiation-induced injury><kappa B Enhancer Binding Protein><lipid mediator><lysophosphatidic acid><medical countermeasure><military population><model of animal><monooleylphosphatidate><monooleylphosphatidic acid><mortality><nano particle><nano-sized particle><nanoparticle><nanoparticle drug><nanosized particle><necrocytosis><non-human primate><nonhuman primate><nuclear factor kappa beta><p44 MAPK><p460 protein><pathway><pre-IND consultation><pre-IND discussion><pre-IND meeting><pre-Investigational New Drug meeting><prevent><preventing><progenitor cell survival><programs><proto-oncogene protein RAC><proto-oncogene protein akt><rac protein kinase><radiation countermeasure><radiation damage><radiation damage to DNA><radiation mitigation><radiation mitigator><radiation poisoning><radiation risk><radiation-induced DNA breaks><radiation-induced injury><radio-protection><radio-protective><radiological countermeasure><radiological mitigation><radiological mitigator><radiomitigation><radiomitigator><receptor><recruit><regenerate><regenerative><related to A and C-protein><repair><repaired><response><senescence><senescent><small molecule><social role><stem cell survival><stem cells><terrorist attack><γ-irradiation>