Microbial Metabolite Mimics, PXR and Colitis-Induced Colorectal Cancer

微生物代谢物模拟物、PXR 和结肠炎诱发的结直肠癌

基本信息

批准号：
10459272
负责人：
Sridhar Mani
金额：
$ 37.46万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-14 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10459272
关键词：
Acids Acute Adenocarcinoma Adopted Affinity Agonist Animal Model Azoxymethane Bile Acids Binding Biochemical Biological Biological Assay Calorimetry Cell Line Cells Chemicals Colitis associated colorectal cancer Colon Carcinoma Computer Models Crystallization Data Development Disease Dysplasia Functional disorder Generations Goals Histology Human Hybrids Immunity In Vitro Inbred BALB C Mice Indoles Indomethacin Inflammation Intestines Laboratories Lead Libraries Ligand Binding Ligands Modeling Molecular Mucous Membrane Mus Nuclear Orphan Receptor Nuclear Receptors Periodicity Pharmaceutical Preparations Physiological Principal Investigator Property Reproducibility Rifampin Sampling Series Signal Pathway Signal Transduction Sodium Dextran Sulfate Source Specificity Structure TLR4 gene Testing Time Tissues Transactivation Tryptophan United States Food and Drug Administration Validation adenoma analog base carcinogenicity clinical development clinical translation colon cancer prevention cytotoxicity design dextran sulfate sodium induced colitis drug discovery drug structure efficacy evaluation enthalpy experimental study fatty liver disease gut inflammation gut microbiome human disease improved in vitro testing in vivo inflammatory marker insight intestinal barrier intestinal homeostasis intestinal injury lead optimization microbial mimicry molecular modeling mouse model mutant non-alcoholic fatty liver disease novel novel strategies novel therapeutics pharmacophore potency testing pregnane X receptor programs rational design receptor receptor binding scaffold screening side effect small molecule small molecule therapeutics symbiont therapeutic target translational medicine treatment group tumorigenesis

项目摘要

The project proposed directly targets the vexing problem of controlling aberrant inflammation-induced carcinogenic signals (e.g., TLR4) in the intestine by understanding the biological properties of adopted orphan nuclear receptors (ONRs). One of these receptors, Pregnane X Receptor (PXR), is abundantly expressed in the intestines and is a potential therapeutic target for colitis –associated colon cancer (CRC). Since existing treatments for colitis-associated CRC are limited and have significant side effects, non-toxic targeting of validated biological targets to prevent colon cancer is warranted. Based on our novel observations that IPA abrogates murine intestinal inflammation (IBD) directly through the non-hematopoietic Pregnane X Receptor (PXR)/Toll-like Receptor 4 (TLR4) signaling pathway, the goal of this project is to test the hypothesis that intestinal PXR can be uniquely modulated by small molecules designed to mimic the gut indole metabolites as a novel approach to treat IBD. Based on the indole/IPA chemical scaffold mimicry, this project will generate novel PXR ligands that can therapeutically target intestinal inflammation and colon cancer in humans, and will provide mechanistic insights into how these molecules binds to PXR. Our preliminary studies have shown that IPA derived from symbionts significantly reduces indomethacin-induced intestinal injury in mice in a PXR and TLR4 dependent manner. IPA regulates intestinal barrier function through PXR. An inverse relationship between PXR and TLR4 as well as IPA and inflammation in human intestinal samples and cell lines, supports our findings in mice. In mice, IPA is a potent activator of PXR, while the human receptor is effectively activated when combined with base indole at a physiologically relevant level. Human PXR LBD mutants were insensitive to activation by indole and IPA. Both Indole and IPA bind to PXR protein in solution. IPA protects against colitis-induced CRC in mice. Small molecule mimics (FKK) of indole/IPA chemical scaffold potently activate PXR and are non-toxic to cells and tissues. Thus, as PXR is a relevant target for intestinal inflammation, we hypothesize that microbial metabolite mimicry will allow for the design of novel, potent and most of all safe compounds that activate PXR and abrogate colitis-associated CRC. To achieve our goals we will (1) synthesize and validate in vitro FKK drug-like lead compounds targeting PXR using rational structure based design; (2) optimize lead FKK candidates based on binding affinity and specificity; (3) evaluate the in vivo efficacy of the lead FKK compounds in abrogating CRC using chemical hPXR mouse models of intestinal inflammation/CRC. In the short-term, we hope to have validated a single novel therapeutic lead based on their likelihood to safely abrogate CRC in mice. These studies can serve as the basis for further validation in human disease-specific animal models in the laboratory prior to embarking on clinical translation. Since PXR has been shown to significantly modulate barrier function in mice, our IPA-like leads could potentially have broader impact on other diseases propelled by a dysfunctional intestinal barrier.

该项目提出的直接针对控制异常炎症引起的烦恼问题通过了解所采用的孤儿的生物学特性，肠中的致癌信号（例如TLR4）核受体（ONRS）。这些受体之一，即怀孕X受体（PXR），在肠道是结肠炎相关结肠癌（CRC）的潜在治疗靶标。由于存在结肠炎相关的CRC治疗受到限制，具有显着的副作用，无毒的靶向有必要确保预防结肠癌的生物学靶标。根据我们的新颖观察IPA的观察直接通过非杂型妊娠X受体消除鼠肠注射（IBD）（PXR）/Toll样受体4（TLR4）信号通路，该项目的目的是检验以下假设。肠道PXR可以由旨在模仿肠吲哚代谢物的小分子来独特地调节一种新颖的治疗IBD的方法。基于吲哚/IPA化学脚手架模仿，该项目将产生可以在人类中靶向肠道注射和结肠癌的新型PXR配体，并将提供机械洞察这些分子如何与PXR结合。我们的初步研究表明源自符号的IPA显着降低了PXR中小鼠吲哚美辛诱导的肠损伤 TLR4依赖性方式。 IPA通过PXR调节肠道屏障功能。逆关系在PXR和TLR4以及IPA和人类肠样品和细胞系中的注射之间，支持我们在老鼠中的发现。在小鼠中，IPA是PXR的潜在激活剂，而人体受体有效激活与基本吲哚结合在物理相关水平上时。人PXR LBD突变体不敏感通过吲哚和IPA激活。吲哚和IPA都与溶液中的PXR蛋白结合。 IPA预防结肠炎诱导的小鼠CRC。吲哚/IPA化学支架的小分子模拟物（FKK）可能激活 PXR，对细胞和组织无毒。这是PXR是肠道注射的相关目标，我们假设微生物代谢产物模仿将允许设计新颖，潜力和最安全的设计激活PXR并消除结肠炎相关的CRC的化合物。为了实现我们的目标，我们将（1）合成和验证使用基于理性结构的PXR靶向PXR的体外FKK药物样铅化合物设计; （2）根据结合亲和力和特异性优化铅FKK候选者；（3）评估铅FKK化合物在使用肠道化学HPXR小鼠模型中废除CRC中的体内效率在短期内，我们希望基于他们安全地消除小鼠CRC的可能性。这些研究可以作为进一步验证的基础在实验室的人类疾病特异性动物模型中，在开始临床翻译之前。自从已显示PXR显着调节小鼠的屏障功能，我们的IPA样线索可能可能对功能失调的肠道屏障推动的其他疾病产生更广泛的影响。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

An expanding bacterial colony forms a depletion zone with growing droplets.

DOI：
10.1039/d0sm01348j
发表时间：
2021-03-04
期刊：
Soft matter
影响因子：
3.4
作者：
Ma H;Bell J;Chen W;Mani S;Tang JX
通讯作者：
Tang JX

Drug Mimicry: Promiscuous Receptors PXR and AhR, and Microbial Metabolite Interactions in the Intestine.

DOI：
10.1016/j.tips.2020.09.013
发表时间：
2020-12
期刊：
Trends in pharmacological sciences
影响因子：
13.8
作者：
Dvořák Z;Sokol H;Mani S
通讯作者：
Mani S

The Pregnane X Receptor and Indole-3-Propionic Acid Shape the Intestinal Mesenchyme to Restrain Inflammation and Fibrosis.

DOI：
10.1016/j.jcmgh.2022.10.014
发表时间：
2023
期刊：
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
影响因子：
7.2
作者：
Flannigan, Kyle L.;Nieves, Kristoff M.;Szczepanski, Holly E.;Serra, Alex;Lee, Joshua W.;Alston, Laurie A.;Ramay, Hena;Mani, Sridhar;Hirota, Simon A.
通讯作者：
Hirota, Simon A.

Enterobacter sp. Strain SM1_HS2B Manifests Transient Elongation and Swimming Motility in Liquid Medium.

DOI：
10.1128/spectrum.02078-21
发表时间：
2022-06-29
期刊：
MICROBIOLOGY SPECTRUM
影响因子：
3.7
作者：
Zhang, Zhiyu;Liu, Haoming;Karani, Hamid;Mallen, Jon;Chen, Weijie;De, Arpan;Mani, Sridhar;Tang, Jay X.
通讯作者：
Tang, Jay X.

Confinement discerns swarmers from planktonic bacteria.