Administrative Supplement to Harnessing the power of p53 with Panaxynol from American Ginseng to suppress colitis and prevent color cancer

利用西洋参中的人参醇 (Panaxynol) 抑制结肠炎和预防彩色癌的 p53 功效的行政补充

基本信息

批准号：
10596870
负责人：
Lorne J Hofseth
金额：
$ 9.12万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2024-12-31
项目状态：
已结题

项目摘要

PROJECT SUMMARY Affecting upwards of 4 million people in North America and Europe, with an economic burden of $30 - $45 billion, Inflammatory Bowel Diseases (IBDs) are debilitating, significantly affect life-style, and carry a high colon cancer risk. Because conventional treatment outcomes are modest with dangerous side effects, about half of IBD patients turn to complementary and alternative medicines (CAMs). Although CAMs have been used for thousands of years, there is a gap in our knowledge of the mechanisms supporting their effectiveness. Understanding these mechanisms will lead to standardized treatment for IBD outside of toxic FDA-approved drugs. This will lower their colon cancer risk. Over the past decade, we have shown that American Ginseng (AG) suppresses colitis and prevents colon cancer in mice. Using scientifically rigorous Bioassay-Guided Fractionation, we have isolated a polyacetylene called panaxynol (PA) that has anti-inflammatory and anti-cancer properties. PA (compared to the100's of other CAMs being tested) comes from a natural source, and is a single ingredient, allowing it to be standardized on its own, or in a cocktail. What makes this molecule particularly interesting and innovative is the mechanism - it is a single molecule extracted from AG, with a unique capacity to target macrophages (mΦ) for apoptosis. Our long-term goal is to identify the primary component(s) of AG responsible for the robust anti-inflammatory and chemopreventive properties of AG we have observed over the past decade; and to determine their mechanism of action. The overall objective of this application is to gain a deeper understanding of both: (a) the broad treatment potential of PA (i.e. multiple pharmacologic and bioengineered animal models of colitis and colon cancer); and (b) the underlying mechanism(s) behind the observation that PA targets mΦ for apoptosis. We focus here on a DNA-damage independent p53 signaling pathway as a mechanism toward mΦ apoptosis. The scientific premise underlying the proposed research is robust. Comparing nine FDA-approved drugs, small molecules, and CAMs, PA is the most efficacious at suppressing colitis in a DSS mouse model. Our central hypothesis is that PA, isolated after a decade of rigorous bioassay-guided fractionation, has anti-inflammatory and anti-cancer activity in the colon because it activates p53- mediated apoptosis in infiltrating mΦ; mitigating colitis; and preventing colon cancer associated with colitis. Furthermore, PA acts as an anti-inflammatory in these models because it induces p53 through a DNA damage- like signaling response in mΦ that is independent of detectable DNA damage. To address this hypothesis, we will test the efficacy of PA in three mouse models of colitis and in genetically engineered mice. Because it appears that PA is taking advantage of a unique p53 mechanism in mΦ, we will test PA in mice with p53 conditionally knocked out in colonic mΦ. A DNA damage-independent mechanism is explored. Results consistent with our hypothesis would identify an innovative, low cost, safe, specific, and natural compound with anti-inflammatory and cancer chemopreventive properties that could quickly be implemented clinically.

项目摘要在北美和欧洲影响400万以上的人，经济伯宁30美元 - 450亿美元的炎症性肠病（IBD）令人衰弱，严重影响了生活方式，并具有较高的结肠癌风险。因为常规的治疗结果是适度的，并且副作用危险，大约一半 IBD患者转向替代药物（CAM）。虽然凸轮已被用于数千年来，我们对支持其有效性的机制的了解存在差距。了解这些机制将导致在有毒FDA批准的IBD的标准化治疗毒品。这将降低其结肠癌风险。在过去的十年中，我们已经证明了美国人参（AG）抑制结肠炎并防止小鼠结肠癌。使用科学严格的生物测定指导分馏，我们已经分离了一种称为Panaxynol（PA）的聚乙炔，具有抗炎和抗癌药特性。 PA（与正在测试的其他凸轮的100相比）来自自然来源，并且是一个成分，可以单独或鸡尾酒中标准化。是什么使该分子特别有趣而创新的是机制 - 它是从Ag中提取的单个分子，具有独特的能力靶向巨噬细胞（Mφ）进行凋亡。我们的长期目标是确定AG的主要组成部分负责我们在过去十年；并确定其作用机理。该应用程序的总体目的是获得对两者的更深入了解：（a）PA的广泛治疗潜力（即多重药理和结肠炎和结肠癌的动物模型）；（b）背后的基本机制观察PA针对Mφ进行细胞凋亡。我们将重点放在DNA破坏独立的p53信号上途径是通向Mφ凋亡的机制。拟议研究的科学前提是强壮的。比较9种FDA批准的药物，小分子和凸轮，PA是最有效的在DSS小鼠模型中抑制结肠炎。我们的中心假设是PA，在严格十年之后孤立生物测定引导的分级，在结肠中具有抗炎和抗癌活性，因为它激活了 p53-浸润Mφ中介导的凋亡；缓解结肠炎；并防止与结肠炎相关的结肠癌。此外，PA在这些模型中充当抗炎药，因为它通过DNA损伤诱导p53 就像在Mφ中与可检测到的DNA损伤无关的信号响应一样。为了解决这一假设，我们将在三种小鼠结肠炎和基因工程小鼠中测试PA的效率。因为它显然，PA正在利用Mφ中独特的p53机构，我们将在P53中测试PA 有条件地在结肠Mφ中淘汰。探索了DNA损伤的机制。结果与我们的假设一致，将确定创新，低成本，安全，特定和自然化合物与可以在临床上迅速实施的抗炎和癌症化学预防特性。