权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

利用 p53 与西洋参中的人参醇 (Panaxynol) 的功效抑制结肠炎并预防结肠癌

基本信息

批准号：
10524156
负责人：
Lorne J Hofseth
金额：
$ 5.2万
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 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10524156
关键词：
Ablation Address Affect American Animal Model Animals Anti-Inflammatory Agents Apoptosis Area Autoimmune Diseases Biological Assay Biomedical Engineering Cells Chemicals Chemoprevention Chemopreventive Agent Clinical Clinical Trials Coculture Techniques Colitis Colon Colon Carcinoma Combined Modality Therapy Complementary and alternative medicine Crohn&apos s disease DNA DNA Damage Dangerousness Disease Dose Drug Kinetics Economic Burden Effectiveness Europe Exposure to FDA approved Fractionation Functional disorder Genetically Engineered Mouse Genome Ginseng Preparation Goals Immune Inflammatory Inflammatory Bowel Diseases Intestines Knowledge Lead Life Style Malignant Neoplasms Mediating Modeling Molecular Mus Myeloid Cells Nature North America Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacology Plants Prevalence Property Research Resveratrol SIRT1 gene Sepsis Signal Pathway Signal Transduction Source Standardization TNF gene TP53 gene Testing Toxic effect Treatment outcome Treatment-related toxicity Ulcerative Colitis anti-cancer anticancer activity base cancer chemoprevention cell type cellular targeting colon cancer prevention colon cancer risk conditional knockout conventional therapy cost dextran sulfate sodium induced colitis efficacy testing experimental study improved in vivo innovation macrophage microbiota murine colitis novel p53 Signaling Pathway replication stress response sex side effect single molecule small molecule sound treatment strategy

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.

项目总结