The purpose of this grant is to develop novel therapeutic approaches for radiological/nuclear medical countermeasures. Very few medical products have been shown to counter the acute and long-term injuries that can result from a nuclear or radiological accident or attack. Medical products and regimens that mitigate and/or treat radiation injury post-exposure (i.e., administration of first dose to start at least 24 hours after radiation exposure), with emphasis on ease of administration in a mass casualty and emergency scenario; safety; and long shelf-life are still to be developed and are thus of high priority. Therapeutic administration of a drug that inhibits the activity of the protein latexin in hematopoietic stem cells (HSCs) resulted in mitigation of HSC function. These findings suggest that pharmacologic augmentation of the activity of such a drug, in combination with additional mitigators currently developed, might offer a rational approach to the mitigation of tissue injury and lethality caused by ionizing radiation that especially affects hematopoiesis.
Public Health Relevance Statement: Very few medical products have been shown to counter the acute and long-term injuries that can result from a nuclear or radiological accident or attack. Recent non-terrorist related accidents have also increased global and national attention to the need for medical countermeasures. This proposal seeks to test whether a chemical compound that targets a specific protein and that shows radio-mitigation for hematopoietic stem cells might be further developed into a full radiation mitigation compound and ultimately a drug.
Project Terms: Accidents; Acute; Affect; analog; Animals; Attention; base; Binding; Binding Proteins; Biological Assay; Biology; Blood; Blood Cells; Bone Marrow; Carboxypeptidase; Cell Count; Cell physiology; Cessation of life; Chemicals; design; Dose; effective therapy; efficacy study; Emergency Situation; experimental study; FDA approved; functional disability; genetic regulatory protein; Goals; Gold; Grant; Granulocyte Colony-Stimulating Factor; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hemorrhage; Hour; improved; In Vitro; in vivo; Infection; inhibitor/antagonist; Injury; Ionizing radiation; irradiation; knock-down; Lead; Life; mass casualty; Medical; medical countermeasure; Metabolic; Mus; Natural regeneration; novel; novel therapeutic intervention; novel therapeutics; Nuclear Accidents; Nuclear Radiology; Pancytopenia; Pathology; Pathway interactions; PC3.1 antigen; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Proteins; pyridine; Radiation; Radiation Accidents; Radiation exposure; Radiation induced damage; Radiation Injuries; radiation mitigation; radiation response; Radiation Toxicity; radiation-induced injury; Radio; radiological attack; Reagent; Regimen; Risk; Role; Safety; screening; self-renewal; System; Testing; Therapeutic; Tissues; Toxic effect; Transplantation; Up-Regulation; Whole-Body Irradiation; Work
