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：“在人类细胞平台上发现新颖的抗炎植物化学物质”项目摘要陈述问题：互补和替代医学（CAM）是一门研究的科学学科。毫无意义的是，许多生物活性和治疗上有益的化合物源自植物性。此外，使用天然产物衍生或合成的小分子的药物发现和药物毒性的高通量筛查（HTS）的科学方法完全基于所检查的小分子的速度和体积。通常，一个非人类的异源细胞是所选的细胞平台。通常，选择合成小分子以出于便捷性而通过药物化学发展。当前的HTS方法共同导致了挑战性的药物发现过程，管道和计划，这些过程正面临着显着的“放缓”。再加上，植物衍生的药物毒性评估很昂贵，需要新的且适当的体外人类细胞模型，从必需组织到分类效果，直到有效的天然产品衍生的化合物到基本的少数物质，从而节省了时间，成本和动物的生命。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，可以执行自己的研发计划。 DBM还为学术和商业客户提供了高度内容服务。对于此NCCAM SBIR催化剂计划，DBM与Chromadex，Inc。（CDEX）（CDEX）的共生商业合作伙伴关系（一家植物上的天然产品公司），将新的生命呼入基于天然产物的药物发现和药物毒性计划的领域。这种伙伴关系是围绕核心科学原则形成的，即主要和永生的人类细胞是必不可少的理想平台，它将推动自然产品衍生和cam友好的基本，应用，翻译，药物发现和药物毒性科学的新型和创新的文艺复兴。这种催化剂的应用说明了NCCAM的特定利益，该催化剂通过找到有效的提取物和纯化的小分子来发现“复杂植物学对复杂的植物学的抗炎生物学作用”，从而保护人类皮肤，呼吸系统和肾细胞免受有害刺激性和病原体的疾病，导致疾病，疾病，疾病，疾病和人类综合体的疾病，并在人类疾病中产生综合症，并具有人类的综合体系。在没有不必要的副作用的情况下，发现与这些不同组织友好的抗炎症的巨大需求。 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）和肾小管系统（近端管，皮质，皮质和肾上腺肾上皮细胞）的深层人类细胞。 DBM将利用源自植物的父母和分离提取物，并从CDEX提供的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以进行潜在发育。将评估，记录和避免有毒提取物和小分子。该方法：DBM将评估植物衍生的提取物和小分子的影响，其具有分泌的炎症介质的高吞吐光基生物测定，源自核因子KAPPA B（NFKAPPAB）激活，中枢和炎症转录因子。 DBM将通过评估其还抑制新近欣赏且重要的人细胞因子，胸腺基质淋巴细胞生成素（TSLP）的分泌能力来巩固命中率提取物和小分子作为全球铅抗炎化合物。 DBM研究了其不朽的人类皮肤，肺和肾上皮细胞在细胞外基质（ECM）涂层的微滴定板上。 DBM使用光基细胞的GLO生物测定法研究了任何潜在的细胞毒性，该生物测定也是HTS和微量磁盘友好的。 DBM和Chromadex将记录植物衍生的原始提取物，提取馏分和纯化的小分子，用于“细胞保护”与“细胞毒性”。最重要的是：我们假设这种以商业为主的伙伴关系将在识别具有抗炎潜力的植物性方面取得成功，并将通知两家公司以及科学和制药群落，总体上，有关免疫和炎症性疾病的潜在潜力。 公共卫生相关性： 公共卫生相关性声明Chromadex，Inc。之间的这种基于人类细胞的药物发现公司与植物衍生的天然产品公司Discovery Biomed，Inc。之间的伙伴关系，试图研究任何疾病和所有疾病系统的抗炎物质的植物化学提取物和小型分子的生物学作用，这些疾病和疾病系统的系统和疾病系统的系统和疾病系统。这些公司共同寻求在不朽的人类皮肤，肺和肾细胞的系统生物学方法中发现和开发植物学的治疗剂，以确定哪些植物衍生的材料是安全和抗炎的，并且可能对人体有毒。这种由DBM领导的合作伙伴关系旨在通过这种长期和紧密的科学和商业视野来领导新的互补和替代医学研究（CAM）研究。