Despite extensive investigations into the effects of radiation on normal tissues, there is a dearth of agents for mitigating radiation exposure as might occur as a result of terrorist action. We have developed an effective infrastructure for the discovery and development of novel mitigators. The result is a portfolio of about 30 agents that can significantly mitigate acute radiation syndrome (ARS) in murine models, with at least one active against late effect. The next 5 years will be dedicated to prioritizing and optimizing mitigators and identifying targets and biomarkers that will allow their rational use, singly and in combination. Our Cores have met the challenges of our evolving Program with great flexibility. They have taken products through high throughput screening (HTS), chemoinformatics, synthesis, drug optimization, pharmacokinetics, and animal testing, to patenting and licensing. In acknowledgement of their evolving roles, we have renamed them the Product Development Core (PDC) and Product Testing Animal Core (PTAC). They will retain many of their functions in drug discovery, but will reposition themselves towards more advanced product development. The PDC will perform chemical clustering and toxicoinformatics so as to optimize product development. It will integrate its output with our gnotobiotic PTAC that has highly reproducible models of ARS and a large delayed effects (DEARE) program. Drug discovery will be largely a Core activity that is integrated with projects through the actions of an Executive Committee who will prioritize products for development. Projects will study mitigators within contexts of tissue damage that will promote their rational use through target identification. Project 1 will use mitigators to rebalance immune responses that are critical not only for rescue from ARS but also for preventing DEARE. Its interests are closely allied with those of Project 2 that examines a novel subpopulation of myeloid cells that arises after whole body irradiation (WBI). One of our lead mitigators boosts this response and absolutely requires these cells for activity, as may the case for FDA-approved mitigator G- CSF. Their contribution to DEARE and especially cardiomyopathy will also be investigated. Project 3 focuses on restoration of the hematopoietic stem cell niche by factors released by endothelial cells, following their demonstration that pleiotrophin can mitigate hARS. In this renewal they use genetic and pharmacological models to investigate whether protein tyrosine phosphatase receptor sigma modulates the hematopoietic response to WBI. Project 4 builds on the fact that one of our lead compounds mitigates gut radiation damage by looking at its ability to stimulate gut and CNS stem cells through the Wnt pathway. The level of integration between the projects is high as we seek to obtain a deeper understanding of the interactions between tissue damage, innate immune responses, and stem cell recovery processes after WBI and to exploit these to mitigate ARS and DEARE. The Cores are involved in every project and help drive a reiterative, optimized, and prioritized product development process.
The UCLA-CMCR Program aims to discover novel agents that can be used to mitigate the effects of radiation exposure such as might occur if nuclear materials were to be used for terrorist purposes. We have already discovered about 30 such agents and here we propose to optimize and prioritize these and explore how best to use them to counter the multiple possible effects of radiation exposure. Project-001: Acute and Long Term Immune Responses to Radiation and Mitigation Project Leader: Cheng, Genhong DESCRIPTION (provided by applicant): The long-term goal of this application is to understand the role of immune responses in and the mechanisms responsible for the short and long term diseases caused by exposure to sources of ionizing radiation. One important aspect of radiation injury is the release of both endogenous damage associated molecular patterns (DAMPs) from the damaged tissues and pathogen associated molecular patterns (PAMPs) from the gastrointestinal system. These DAMPs and PAMPs released after irradiation interact with common pattern recognition receptors such as Toll-Like Receptors (TLR) and activate overlapping gene programs to regulate innate and adaptive immune responses as well as tissue damage and repair. In our previous studies, we found that MIS416 - a particle based on the cell wall components of P. acnes decorated with a single stranded TLR9 ligand CpG-A (Vironyx Corp.) - which likely contains multiple PAMPs, can function as a mitigator to rescue lethally irradiated mice. We have further evidence that different TLR agonists induce different profiles of growth factors, cytokines and chemokines, suggesting that multiple innate immune pathways might be required to mitigate radiation damage. Based on our results from multiple tissue damage models, we have recently hypothesized that over reactive innate immune responses to DAMPs and PAMPs released after irradiation can further trigger secondary tissue damages by proinflammatory cytokines and autoantibodies. We have further developed a widely available and easily deliverable DAMP blocking compound, glycyrrhizic acid (GA), as a potent radiation mitigator. In addition, while GCSF has been used as a standard mitigator, we have developed a bivalent GCSF (Bi-GCSF) as a more potent and stable radiation mitigator. Through close collaboration with Dr. William McBride's group, we have found that although many mitigators can effectively rescue lethally irradiated mice during acute radiation syndrome (ARS), many rescued mice often develop delayed effects of acute radiation exposure (DEARE) exhibiting chronic diseases such as heart and kidney failures around a year after WBI. Our preliminary studies indicate that these chronic diseases are associated with proinflammatory responses. Based on these studies, we hypothesize that balanced immune and inflammatory responses are critical not only for rescuing acute phase tissue damages but also for preventing chronic diseases caused by radiation. In this application, we will evaluate the effects of individual mitigators on the short and long term innate and adaptive immune systems and further develop a combination of mitigators that can effectively treat both acute and chronic diseases after radiation.
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