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）： 职务名称：“在人类细胞平台上发现新型抗炎植物化学物质”项目概要问题：补充和替代医学（CAM）是一门研究不足的科学学科。许多生物活性和治疗有益的化合物来源于植物，这是不被理解的。此外，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）的科学方法已经完全基于所检查的小分子的速度和体积。通常情况下，非人类且缺乏体内样特性的异源细胞是所选择的细胞平台;通常情况下，出于方便，选择合成小分子通过药物化学向前开发。总之，目前的HTS方法导致了整个“制药”面临重大“放缓”的药物发现过程、管道和计划的挑战。“再加上，植物源性药物毒性评估是昂贵的，需要新的和适当的体外人类细胞模型，从基本组织中筛选出命中导致天然产品衍生化合物，以节省时间，成本和动物生命。公司名称：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，执行自己的研发计划。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催化剂计划，DBM正在领导与ChromaDex，Inc.的共生商业合作伙伴关系。（CDex），一家植物源性天然产品公司，为基于天然产品的药物发现和药物毒性项目的竞技场注入新的活力。这种伙伴关系是围绕核心科学原则形成的，即原代和永生化的人类细胞是必不可少的理想平台，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创新复兴。该催化剂应用程序说明了NCCAM的具体利益，即通过寻找有效的提取物和纯化的小分子来发现“具有系统生物学方法的复杂植物药的抗炎生物学作用”，这些提取物和纯化的小分子可以保护人类皮肤，呼吸道和肾脏细胞免受有害刺激物和病原体的侵害，这些刺激物和病原体会导致人类患者的无数疾病，病症和综合征。仍然存在巨大的未满足的需求，以找到对这些不同组织友好而没有不必要的副作用的抗炎药。DBM将利用来自皮肤（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）的永生化人类细胞作为本CAM研究的平台。DBM将利用源自植物的亲本和分级提取物以及来自CDex提供的植物提取物的纯化小分子植物化学物质。抗炎提取物和保护皮肤、肺和肾的小分子将被提出来进行潜在的开发。有毒提取物和小分子将被评估、记录和避免。方法：DBM将评估植物提取物和小分子的作用，并对分泌的炎症介质白细胞介素-8（IL-8）进行高通量基于光的生物测定，白细胞介素-8（IL-8）来源于核因子κ B（NF κ B）活化，是一种中枢免疫和炎症转录因子。DBM将通过评估其抑制一种新认识到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，寻求巩固命中提取物和小分子作为全球领先的抗炎化合物，TSLP是一种淋巴细胞化学引诱物和树突状细胞激活剂，也被NF κ B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，该生物测定法也是HTS和微量滴定板友好的。DBM和ChromaDex将记录植物来源的原始提取物、提取物组分和纯化的小分子的“细胞保护”与“细胞毒性”。‘底线：我们假设，这种商业驱动的伙伴关系将成功地鉴定具有抗炎潜力的植物药，并将告知两家公司以及科学和制药界关于CAM药物治疗免疫和炎症疾病的潜力。 公共卫生相关性： 公共卫生相关性声明这是一家基于人类细胞的药物发现公司Discovery BioMed，Inc.，和一家植物源性天然产品公司，ChromaDex，Inc.旨在研究植物化学提取物和小分子作为抗炎物质对引起皮肤、呼吸系统和肾脏系统炎症的任何和所有疾病和病症的生物效应。这些公司共同寻求以系统生物学方法在不朽的人类皮肤，肺和肾细胞中发现和开发植物源性疗法，以确定哪些植物源性材料是安全和抗炎的，哪些可能对人体有毒。DBM领导的这一合作伙伴关系旨在引领全球新型抗炎药物的补充和替代医学（CAM）研究的新复兴，以这种长期和密切的科学和商业愿景。