Role of LITAF in Inflammatory Disease

LITAF 在炎症性疾病中的作用

基本信息

批准号：
9344787
负责人：
Salomon Amar
金额：
$ 40.45万
依托单位：
NEW YORK MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9344787
关键词：
Adverse effects Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Applications Grants Atherosclerosis Binding Biochemical Biological Biological Availability Biological Products Blood Circulation Blood Vessels Bone Marrow CCL2 gene Cells Cellular Assay Clinical Clinical Trials Complex Control Animal Crohn&apos s disease Cytokine Gene Data Defense Mechanisms Development Disease Dose Drug Kinetics Drug Targeting Eicosanoids Endotoxic Shock Exhibits Funding Gene Expression Gene Expression Regulation Goals Homeostasis Human Immune system In Vitro Infection Inflammation Inflammatory Inflammatory Arthritis Inflammatory Bowel Diseases Inflammatory Response Injection of therapeutic agent Injury Insulin-Dependent Diabetes Mellitus Interleukin-1 Interleukin-6 Investigation Kava Knowledge Laboratories Leukocytes Libraries Lipopolysaccharides Marketing Maximum Tolerated Dose Mediating Mediator of activation protein Modification Molecular Target Mus Names Natural Products Natural regeneration Necrosis Nutraceutical Oral Outcome Pathogenesis Pathway interactions Periodontal Diseases Periodontitis Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phosphotransferases Plant Roots Positioning Attribute Process Production Property Protein Kinase Proteins Rattus Recombinant Proteins Regulation Research Rheumatoid Arthritis Role Sepsis Series Signal Transduction Signal Transduction Pathway Site Solubility Structure Survival Rate TNF gene Testing Tissues Toxic effect United States National Institutes of Health Variant Vascular Endothelial Growth Factors base chemical stability cost cytokine design dietary supplements experience granulocyte improved in vitro activity in vivo inhibitor/antagonist interest macrophage mouse model novel patient subsets pre-clinical programs reactive oxygen intermediate research clinical testing response scaffold screening small molecule tool transcription factor upstream kinase

项目摘要

DESCRIPTION (provided by applicant): The inflammatory response protects the body against infection and injury but can itself become dysregulated with deleterious consequences to the host. In recent years the inflammatory cytokine TNF-α has been clinically validated as a primary driver of several inflammatory diseases, and biopharmaceutical drugs have been marketed that block TNF-α action. These drugs, however, are effective in only a subset of patients, and can cause severe and even fatal side effects. Moreover, because they are recombinant proteins these drugs must be administered perenterally, thus requiring repeated injections. There is a continued critical need for novel anti-inflammatory drugs that possess improved efficacy/toxicity profiles, and in particular for small molecule drugs that can be taken orally. We have recently screened a small molecule compound library in an attempt to identify compounds capable of interfering with a TNF-α transcription factor that we cloned in our laboratory 12 years ago named LITAF. The screening library, comprising in part dietary supplements and established nutraceuticals, contained at least one class of natural products that displayed TNF-α suppression activity. In particular, several compounds isolated from kava root extract were found to mediate substantial reduction of TNF-α secretion in a cellular assay. Moreover, specific kava-derived compounds were found to protect mice against lethal doses of LPS or experimental periodontitis, compared to control animals. Importantly, a representative compound from this series was shown to possess promising pharmaceutical properties including oral bioavailability in rats, and a preliminary medicinal chemistry effort has identified regions on the molecule that can be modified to optimize the compound's properties. A key objective of our over-arching research program is to identify the molecular target(s) by which kava compounds elicit their biological effect, and to elucidate their mechanism of action. However the potency of the compounds must be improved to enable these goals. The present application outlines 3 Aims: First, a comprehensive medicinal chemistry approach will be taken to design, synthesize and test compounds with the goal of delivering 2-3 biochemically well- characterized and validated tool compounds optimized for potency and for in vivo exposure. Second, these optimized, kava-derived compounds will be tested in animal models of inflammation to validate them in vivo for target identification and mechanism of action studies, and to establish their potential as a new class of anti-inflammatory drugs. Third to determine the molecular target(s) in the signal transduction pathway by which kava compounds mediate LITAF inhibition of LPS-induced cytokine secretion. Our goal is the elucidation of the mechanism of action of optimized kava compounds, a step towards identifying novel anti-inflammatory compounds suitable for clinical development.

描述（由申请人提供）：炎症反应可以保护身体免受感染和损伤，但其本身可能会失调，从而对宿主产生有害后果。近年来，炎症细胞因子 TNF-α 已被临床验证为多种炎症疾病的主要驱动因素。，并且已经上市的阻断 TNF-α 作用的生物制药药物，然而，这些药物仅对一小部分患者有效，并且可能导致严重甚至致命的副作用，而且，因为它们是重组的。这些蛋白质药物必须肠外给药，因此需要重复注射，因此迫切需要具有改善的功效/毒性特征的新型抗炎药物，特别是我们最近筛选的可口服的小分子药物。一个小分子化合物库，试图识别能够干扰 TNF-α 转录因子的化合物，该化合物是我们 12 年前在实验室克隆的，名为 LITAF。该筛选库部分由膳食补充剂和已建立的营养保健品组成。至少一类天然产物具有 TNF-α 抑制活性。特别是，在细胞测定中发现从卡瓦根提取物中分离出的几种化合物可显着减少 TNF-α 的分泌。此外，还发现了特定的卡瓦衍生化合物。与对照动物相比，该系列的代表性化合物被证明具有良好的药物特性，包括大鼠的口服生物利用度，并且初步的药物化学工作已经确定了该分子的区域。那我们总体研究计划的一个关键目标是确定卡瓦化合物引发其生物效应的分子靶标，并阐明其作用机制。为了实现这些目标，必须对化合物进行改进。本申请概述了 3 个目标：首先，将采用综合药物化学方法来设计、合成和测试化合物，目标是提供 2-3 种经过生物化学充分表征和验证的优化工具化合物。其次，这些优化的卡瓦衍生化合物将在炎症动物模型中进行测试，以验证它们的体内靶标识别和作用机制研究，并确定它们作为新型抗氧化剂的潜力。第三，确定卡瓦化合物介导 LITAF 抑制 LPS 诱导的细胞因子分泌的分子靶点。我们的目标是阐明优化卡瓦化合物的作用机制，这是朝着这一目标迈出的一步。鉴定新型抗炎药适合临床开发的化合物。

项目成果

期刊论文数量（33）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Novel regulation of CCL2 gene expression by murine LITAF and STAT6B.

DOI：
10.1371/journal.pone.0025083
发表时间：
2011
期刊：
PloS one
影响因子：
3.7
作者：
Tang X;Yang Y;Amar S
通讯作者：
Amar S

Kava-241 reduced periodontal destruction in a collagen antibody primed Porphyromonas gingivalis model of periodontitis.

DOI：
10.1111/jcpe.12784
发表时间：
2017-11
期刊：
Journal of clinical periodontology
影响因子：
6.7
作者：
Alshammari A;Patel J;Al-Hashemi J;Cai B;Panek J;Huck O;Amar S
通讯作者：
Amar S

LITAF mediation of increased TNF-α secretion from inflamed colonic lamina propria macrophages.

LITAF 介导发炎的结肠固有层巨噬细胞 TNF-α 分泌增加。

DOI：
10.1371/journal.pone.0025849
发表时间：
2011
期刊：
PloS one
影响因子：
3.7
作者：
Bushell KN;Leeman SE;Gillespie E;Gower AC;Reed KL;Stucchi AF;Becker JM;Amar S
通讯作者：
Amar S

Kavain Reduces Porphyromonas gingivalis-Induced Adipocyte Inflammation: Role of PGC-1α Signaling.

Kavain 减少牙龈卟啉单胞菌引起的脂肪细胞炎症：PGC-1α 信号传导的作用。

DOI：
10.4049/jimmunol.1800321
发表时间：
2018
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Singh,ShailendraP;Huck,Olivier;Abraham,NaderG;Amar,Salomon
通讯作者：
Amar,Salomon

Deep sequencing of the oral microbiome reveals signatures of periodontal disease.

DOI：
10.1371/journal.pone.0037919
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Liu B;Faller LL;Klitgord N;Mazumdar V;Ghodsi M;Sommer DD;Gibbons TR;Treangen TJ;Chang YC;Li S;Stine OC;Hasturk H;Kasif S;Segrè D;Pop M;Amar S
通讯作者：
Amar S