Discovery of Novel Anti-Inflammatory Phytochemicals on Human Cell Platforms

在人体细胞平台上发现新型抗炎植物化学物质

• 批准号: 7926261
• 负责人: Erik Mills Schwiebert
• 金额: $ 20万
• 依托单位: DISCOVERYBIOMED, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7926261
• 关键词: Adrenergic Agents; Adverse effects; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Asthma; Biological; Biological Assay; Biological Factors; Botanicals; Breathing; Businesses; Cell model; Cells; Chemotactic Factors; Chronic; Chronic Kidney Failure; Chronic Obstructive Airway Disease; Client; Communities; Complementary and alternative medicine; Complex; Cosmetics; Coupled; Cystic Fibrosis; Cytoprotection; Dendritic Cells; Dermatitis; Development; Diabetes Mellitus; Discipline; Disease; Drug Industry; Drug toxicity; Engineering; Epithelial Cells; Extracellular Matrix; Future; Goals; Grant; Housing; Human; Human body; Immune; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-8; Interstitial Lung Diseases; Irritants; Joints; Kidney; Lead; Life; Light; Lung; Lymphocyte; Maintenance; Marketing; Medical; Medicinal Plants; Medicine; Metabolic Diseases; Methodology; Methods; NF-kappa B; National Center for Complementary and Alternative Medicine; Nephritis; Nephrotic Syndrome; Nose; Nutritional; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phenotype; Physiological; Phytochemical; Plant Extracts; Plant Roots; Plants; Polycystic Kidney Diseases; Population; Process; Property; RNA Interference; Renaissance; Research; Research Infrastructure; Respiratory System; Science; Services; Skin; Small Business Innovation Research Grant; Solutions; Speed; Syndrome; System; Systems Biology; Therapeutic; Time; Tissues; Triage; United States National Institutes of Health; Vision; Work; adrenergic; base; catalyst; cell type; cost; cytokine; cytotoxic; cytotoxicity; design; drug discovery; empowered; high throughput screening; human TSLP protein; in vivo; innovation; interest; keratinocyte; kidney cell; kidney epithelial cell; novel; novel strategies; novel therapeutics; pathogen; programs; public health relevance; research and development; respiratory; skin lesion; small molecule; transcription factor

DESCRIPTION (provided by applicant): Title: "Discovery of Novel Anti-Inflammatory Phytochemicals on Human Cell Platforms" Project Summary Statement The Problems: Complementary and alternative medicine (CAM) is an understudied scientific discipline. It is unappreciated that many biologically active and therapeutically beneficial compounds are derived from botanicals. Moreover, the scientific methods of high-throughput screening (HTS) for drug discovery and drug toxicity with natural product-derived or synthetic small molecules have become entirely based on speed and volume of small molecules examined. More often than not, a heterologous cell that is non-human and is lacking in in vivo-like properties is the chosen cellular platform; more often than not, synthetic small molecules are chosen to develop forward through medicinal chemistry out of expedience. Together, current HTS approaches have resulted in challenged drug discovery processes, pipelines, and programs across "pharma" that are facing significant "slowdowns." Coupled with that, botanically-derived drug toxicity assessment is expensive and is in need of new and appropriate in vitro human cell models from essential tissues to triage hit- to-lead natural product-derived compounds to the essential few, saving in the time, cost and animal lives. The Solution: DiscoveryBioMed, Inc. (DBM) is an emerging human cell-based drug discovery and drug toxicity company that performs its own R&D programs. DBM also provides this expertise and infrastructure as a high content service for academic and commercial clients. For this NCCAM SBIR Catalyst program, DBM is leading a symbiotic commercial partnership with ChromaDex, Inc. (CDex), a botanically-derived natural products company, to breathe new life into the arena of natural product-based drug discovery and drug toxicity programs. This partnership is formed around the core scientific principle that primary and immortalized human cells are essential and ideal platforms that will drive a new and innovative renaissance in natural product- derived and CAM-friendly basic, applied, translational, drug discovery and drug toxicity sciences. This Catalyst application speaks to specific interests of the NCCAM that seek to discover "the anti-inflammatory biological effects of complex botanicals with a systems biology approach" by finding potent extracts and purified small molecules that protect human skin, respiratory, and kidney cells from harmful irritants and pathogens that cause a myriad of diseases, disorders and syndromes in the human patient. There remains an enormous unmet need to find anti-inflammatories friendly to these different tissues without unwanted side effects. DBM will utilize a deep panel of immortalized human cells derived from skin (keratinocytes), respiratory system (nasal, airway and lung epithelial cells) and renal system (proximal tubule, cortical, and medullary kidney epithelial cells) as platforms for this CAM research. DBM will utilize parental and fractionated extracts derived from botanicals and purified small molecule phytochemicals from plant extracts provided by CDex. Anti- inflammatory extracts and small molecules that protect skin, lung and kidney will be brought forward for potential development. Toxic extracts and small molecules will be assessed, documented, and avoided. The Approach: DBM will assess the effects of botanically-derived extracts and small molecules with high- throughput light-based bioassays of a secreted inflammatory mediator, interleukin-8 (IL-8) that derives from nuclear factor kappa B (NFkappaB) activation, a central immune and inflammatory transcription factor. DBM will seek to solidify hit extracts and small molecules as global lead anti-inflammatory compounds by assessing their ability to also inhibit the secretion of a newly appreciated and important human cytokine, thymic stromal lymphopoietin (TSLP), a lymphocyte chemoattractant and dendritic cell activator that is also upregulated by NFkappaB action. DBM studies its immortal human skin, lung and kidney epithelial cells on extracellular matrix (ECM)-coated microtiter plates. DBM studies any potential cytotoxicity using a light-based CellTiter GLO bioassay that is also HTS- and microtiter plate-friendly. DBM and ChromaDex will document botanically- derived raw extracts, extract fractions, and purified small molecules for 'cytoprotection' versus 'cytotoxicity.' The Bottom Line: We hypothesize that this commercial-driven partnership will be successful in the identification of botanicals with anti-inflammatory potential and will inform the two companies and the scientific and pharma communities at large about the potential of CAM medicines for immune and inflammatory disorders. PUBLIC HEALTH RELEVANCE: Public Health Relevance Statement This partnership between a human cell-based drug discovery company, Discovery BioMed, Inc., and a botanical-derived natural products company, ChromaDex, Inc. seeks to study the biological effects of phytochemical extracts and small molecules as anti-inflammatory substances for any and all diseases and disorders that cause inflammation in the skin, the respiratory system and the renal system. Together, these companies seek to discover and develop botanically-derived therapeutics in a systems biology approach across immortal human skin, lung and kidney cells to determine which plant-derived materials are safe and anti-inflammatory and which may be toxic to the human body. This DBM-led partnership seeks to lead a new renaissance in complementary and alternative medicine (CAM) research for new global anti-inflammatory drugs with this long-term and closely held scientific and commercial vision.

描述（由申请人提供）： 标题：“在人体细胞平台上发现新型抗炎植物化学物质”项目摘要声明问题：补充和替代医学（CAM）是一门尚未得到充分研究的科学学科。人们没有意识到许多具有生物活性和治疗有益的化合物都源自植物。此外，利用天然产物衍生或合成小分子进行药物发现和药物毒性的高通量筛选（HTS）的科学方法已完全基于所检查的小分子的速度和体积。通常，选择的细胞平台是非人类且缺乏体内样特性的异源细胞；通常，出于权宜之计，选择合成小分子通过药物化学进行发展。总之，当前的 HTS 方法给“制药”领域的药物发现流程、管道和项目带来了挑战，面临着严重的“放缓”。除此之外，植物源药物毒性评估费用昂贵，并且需要新的、合适的体外人体细胞模型，从基本组织到将天然产物衍生化合物分类到必要的少数，从而节省时间，成本和动物生命。解决方案：DiscoveryBioMed, Inc. (DBM) 是一家新兴的基于人类细胞的药物发现和药物毒性公司，开展自己的研发项目。 DBM 还为学术和商业客户提供这种专业知识和基础设施作为高内容服务。对于这个 NCCAM SBIR Catalyst 项目，DBM 正在与植物源天然产品公司 ChromaDex, Inc. (CDex) 建立共生商业合作伙伴关系，为基于天然产品的药物发现和药物毒性项目领域注入新的活力。这一合作伙伴关系是围绕核心科学原则而形成的，即原代和永生化人类细胞是必要和理想的平台，将推动天然产物衍生和 CAM 友好的基础、应用、转化、药物发现和药物毒性科学的新的和创新的复兴。该 Catalyst 应用体现了 NCCAM 的特定兴趣，即通过寻找有效的提取物和纯化的小分子来保护人类皮肤、呼吸系统和肾细胞免受有害物质的侵害，从而发现“采用系统生物学方法的复杂植物药的抗炎生物效应”。引起人类患者多种疾病、紊乱和综合症的刺激物和病原体。寻找对这些不同组织友好且没有不良副作用的抗炎药仍然是一个巨大的未满足的需求。 DBM 将利用源自皮肤（角质形成细胞）、呼吸系统（鼻、气道和肺上皮细胞）和肾脏系统（近端小管、皮质和髓质肾上皮细胞）的永生化人类深层细胞作为 CAM 研究的平台。 DBM 将利用 CDex 提供的植物源亲本和分馏提取物以及植物提取物中纯化的小分子植物化学物质。抗炎提取物和保护皮肤、肺和肾脏的小分子将被提出潜在的开发。将评估、记录并避免有毒提取物和小分子。方法：DBM 将通过高通量光基生物测定来评估植物提取物和小分子的作用，对分泌性炎症介质白细胞介素 8 (IL-8) 进行评估，该介质源自核因子 kappa B (NFkappaB) 激活，中枢免疫和炎症转录因子。 DBM 将寻求将热门提取物和小分子巩固为全球领先的抗炎化合物，方法是评估它们抑制新近受到重视的重要人类细胞因子胸腺基质淋巴细胞生成素 (TSLP) 分泌的能力，TSLP 是一种淋巴细胞趋化剂和树突状细胞激活剂，也可通过 NFkappaB 作用上调。 DBM 在细胞外基质 (ECM) 包被的微量滴定板上研究其永生的人类皮肤、肺和肾上皮细胞。 DBM 使用基于光的 CellTiter GLO 生物测定法研究任何潜在的细胞毒性，该生物测定法也适用于 HTS 和微量滴定板。 DBM 和 ChromaDex 将记录植物来源的原始提取物、提取物级分和纯化小分子的“细胞保护”与“细胞毒性”。底线：我们假设这种商业驱动的合作伙伴关系将成功识别具有抗炎潜力的植物药，并将让两家公司以及整个科学界和制药界了解 CAM 药物治疗免疫和炎症性疾病的潜力。 公共卫生相关性： 公共健康相关性声明 人类细胞药物发现公司 Discovery BioMed, Inc. 与植物源性天然产品公司 ChromaDex, Inc. 之间的合作旨在研究植物化学提取物和小分子作为抗衰老药物的生物效应。炎症物质，用于治疗引起皮肤、呼吸系统和肾脏系统炎症的任何及所有疾病和病症。这些公司共同寻求通过系统生物学方法在永生的人类皮肤、肺和肾细胞中发现和开发植物源疗法，以确定哪些植物源材料是安全且抗炎的，哪些可能对人体有毒。这一由 DBM 主导的合作伙伴关系旨在凭借长期且密切关注的科学和商业愿景，引领全球新型抗炎药物补充和替代医学 (CAM) 研究的新复兴。