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Grant Abstract: Mechanisms of prostate cancer prevention by Korean Angelica

Grant Number: 5R01AT007395-04
PI Name: Lu
Project Title: Mechanisms of prostate cancer prevention by Korean Angelica

Abstract: In response to PAR-14-201 “Administrative Supplements for Research on Dietary Supplements” in connection with parent award (R01 AT7395 Mechanisms of prostate cancer prevention by Korean Angelica, Lu, PI), we propose experiments to study the efficacy and mechanisms by which Korean Angelica Gigas Nakai (AGN) dietary supplements regulate two types of innate immune cells, neutrophils (phagocytic, bactericidal) and natural killer (NK) cells (kill cancer cells and virus-infected cells) of the myeloid and lymphoid lineages, respectively, using the mouse model. The expansion of the research scope is based on our recently completed human study that suggests the hypothesis that AGN dietary supplement increases and/or activates both neutrophils and NK cells conducive for fighting off opportunistic microbial and viral infections and lowering overall cancer risk to promote organismal health and resilience. To test this novel hypothesis, we propose studies in mice to provide complementary preclinical efficacy data on these innate immune cells and to seek critical mechanistic insights, not yet permissible and obtainable through human trial, into how the immune regulations are achieved. Taking advantage of expertise and reagents developed toward accomplishing the original aims of the parent award, we aim to address 4 questions. A) Does gavage of increasing dosages of AGN extract lead to a dose-dependent increase of the number of peripheral blood neutrophils and NK cells and the peripheral blood mononucleated cell PBMC NKgene expression signatures in mice? B) What is the temporal response patterns of peripheral neutrophils and NK cells to daily gavage of AGN extract? C) Does AGN affect innate immune cell abundance/genesis in immune/hematopoiesis organs such as spleen, thymus, lymph nodes, bone marrow and liver? D) Do AGN compounds decursin and decursinol angelate (D/DA) and/or D/DA-free AGN fraction account for the enhancement action on innate immune cells? Experimentally, we will use a 3x4 factorial design to address questions A & B (vehicle vs. 2 AGN dosages; 4 time points) such that acute vs. chronic AGN supplementation with respect to increasing AGN dosages will be assessed in the same experiment. If positive immune enhancement efficacy is obtained from the factorial studies, we will answer question C by using the optimized AGN dose and time information to analyze blood and those organs. We will address question D by comparing AGN with equi-molar intake of D/DA or D/DA-free fraction using optimal AGN dose and time information as well as target organs. Positive data from these experiments will provide not only an independent validation of the human efficacy outcomes but also an animal model for mechanistic studies concerning how AGN or its active chemicals promote innate immune cell number and functional activities. Such mechanistic insights will better inform future translational studies and practical applications in humans of AGN dietary supplements.

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