Human Adipocyte Platform for Discovery of Novel Adiponectin Secretagogues

用于发现新型脂联素促分泌剂的人类脂肪细胞平台

• 批准号: 8251015
• 负责人: ERIC CLINTON SEALES
• 金额: $ 22.19万
• 依托单位: DISCOVERYBIOMED, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8251015
• 关键词: Adipocytes; Adult; Adverse effects; Alabama; Atherosclerosis; Attenuated; Automation; Biological Assay; Biological Markers; Body Weight decreased; Botanicals; Businesses; Cells; Child; Collection; Critical Pathways; Development; Diabetes Mellitus; Diet; Disease; Epidemic; Failure; Future; Goals; Health; Human; Lead; Libraries; Life Style; Marketing; Mediator of activation protein; Medicinal Plants; Metabolic Diseases; Methodology; Methods; Mission; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Overweight; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phytochemical; Plasma; Process; Research; Screening procedure; Site; Small Business Innovation Research Grant; Societies; Talents; Therapeutic; Validation; Visceral; Work; adiponectin; analog; base; combat; cost; design; diabetic patient; drug candidate; drug discovery; drug market; experience; fighting; human disease; in vivo; innovation; novel; pandemic disease; programs; sedentary; stem; trend

DESCRIPTION (provided by applicant): Small business concerns, DiscoveryBioMed, Inc. (DBM) and Chromadex, Inc. (CDex), have designed an innovative automation-friendly drug discovery program to screen medicinal plant-derived phytochemicals and extract fractions on an immortalized human adipocyte platform to discover novel, selective secretagogues of adiponectin, an established biomarker and causative mediator in obesity-related diseases. Obesity and obesity-related diseases including Type 2 diabetes and atherosclerosis have reached epidemic proportions in the US and the developed world and are causing huge morbidity and cost burdens on society. As such, there is a huge, unmet need for new drugs to combat these diseases. Drug pipelines in metabolic diseases are experiencing problems, and many "new drugs" for obesity-related diseases are simply re-branded or combined pharmaceuticals with an undefined weight loss side effect. Plasma concentrations of the adipokine, adiponectin, are reduced in vivo in obese and diabetic patients. Furthermore, reduced circulating adiponectin is well-established as both a biomarker of and a causative agent in metabolic diseases. Accordingly, up-regulating adiponectin expression has been proposed as a high-priority therapeutic strategy for obesity-related diseases. This Phase 1 SBIR-driven partnership and program will integrate the greatest strengths of these two small business concerns into one highly innovative drug discovery platform: the physiologically-relevant immortalized human visceral adipocyte platform and cell-based targeted and phenotypic screening methodology provided by DBM and a screening library of medicinal plant-derived extract fractions, phytochemicals, and phytochemical derivatives/analogs provided by CDex. DBM will first differentiate immortalized human preadipocytes derived from visceral depot sites. Mature adipocytes will be challenged with CDex"s medicinal plant-derived compound library to discover novel adiponectin secretagogues. Throughout the process, we will apply a carefully designed Critical Path of primary, secondary and tertiary discovery and validation steps to identify "high value" hit-to-lead compounds. DBM proposes the following milestones and will show progress achieved to date: (1) Design and optimize an automation- friendly immortalized 'pooled donor' human visceral adipocyte-based drug discovery platform to detect secreted adiponectin; (2) Screen our platform with CDex's diverse collection of 10,000-12,000 medicinal plant-derived botanical extract fractions, purified phytochemicals, and phytochemical analogs/derivatives to discover and validate novel selective adiponectin secretagogues; and (3) Begin to establish parallel tracks of continued non-directed (random) screening and directed (targeted) screening based on lead compounds, structurally-similar compounds and medicinal chemistry derivatives. The ultimate goal of this proposed program is to discover hit-to-lead phytochemicals and phytochemical analogs that acutely enhance endogenous (natural) adiponectin secretion in differentiated adipocytes that can be developed into future drugs to slow the development of obesity and diabetes worldwide. PUBLIC HEALTH RELEVANCE: Obesity, diabetes and related metabolic disorders are epidemics in danger of becoming pandemics. The combination of increasingly unhealthy diets and a sedentary lifestyle have contributed significantly to cause 2 billion adults and millions of children worldwide to be overweight or obese as of 2010. The future human health burden is immense and potentially catastrophic. The cost for the US and the world is estimated to exceed $1 trillion by 2015. When DiscoveryBioMed, Inc. and Chromadex, Inc. formed our partnership, our initial and first target markets or foci were obesity and diabetes. We seek to combine our talents in a synergized effort to discover new drugs that stem this alarming tide and attenuate these profound metabolic diseases. For DBM, this is a local mission, given the dangerous obesity and diabetes trends in Alabama and in our region.

描述(申请人提供)：小型企业DiscoveryBioMed，Inc.(DBM)和ChromaDex，Inc.(CDex)设计了一种创新的自动化友好型药物发现计划，以筛选从药用植物中提取的植物化学物质，并在永生化的人类脂肪细胞平台上提取部分，以发现脂联素的新的、选择性的分泌物，脂联素是肥胖相关疾病的公认生物标志物和致病介质。肥胖和肥胖相关疾病，包括2型糖尿病和动脉粥样硬化，在美国和发达国家已经达到流行的程度，并正在给社会造成巨大的发病率和成本负担。因此，对抗击这些疾病的新药有着巨大的、尚未得到满足的需求。代谢性疾病的药物管道遇到了问题，许多治疗肥胖相关疾病的“新药”只是简单地更名或联合用药，具有不明的减肥副作用。在肥胖和糖尿病患者体内，血浆中脂肪因子--脂联素的浓度降低。此外，循环脂联素的减少被公认为是代谢性疾病的生物标志物和致病因子。因此，上调脂联素的表达被认为是肥胖相关疾病的高度优先的治疗策略。这一由SBIR驱动的第一阶段合作和计划将把这两家小型企业的最大优势整合到一个高度创新的药物发现平台中：DBM提供的与生理相关的永生化人类内脏脂肪细胞平台和基于细胞的靶向和表型筛选方法，以及CDex提供的药用植物提取物部分、植物化学物质和植物化学衍生物/类似物的筛选资料库。DBM将首先区分来自内脏储存库的永生化人类前脂肪细胞。成熟脂肪细胞将被CDex S药用植物衍生化合物文库挑战，以发现新的脂联素促分泌剂。在整个过程中，我们将应用精心设计的一次、二次和三次发现和验证步骤的关键路径来识别“高价值”点击到铅的化合物。DBM提出了以下里程碑，并将展示迄今所取得的进展：(1)设计和优化一个自动化友好的永生化“混合供体”人体内脏脂肪细胞药物发现平台，以检测分泌的脂联素；(2)利用CDex收集的10,000-12,000个药用植物植物提取物提取物、纯化植物化学物质和植物化学类似物/衍生物的多样化集合筛选我们的平台，以发现和验证新型选择性脂联素分泌剂；以及(3)开始基于先导化合物、结构相似化合物和药物化学衍生物建立持续非定向(随机)筛选和定向(靶向)筛选的平行轨道。这项拟议计划的最终目标是发现能够显著增强分化脂肪细胞内源性(天然)脂联素分泌的命中型植物化学物质和植物化学类似物，这些物质可以被开发成未来的药物，以减缓全球肥胖和糖尿病的发展。 公共卫生相关性：肥胖、糖尿病和相关代谢紊乱是有可能成为流行病的流行病。截至2010年，越来越不健康的饮食和久坐不动的生活方式在很大程度上导致了全球20亿成年人和数百万儿童超重或肥胖。未来的人类健康负担是巨大的，可能是灾难性的。据估计，到2015年，美国和世界的成本将超过1万亿美元。当DiscoveryBioMed，Inc.和ChromaDex，Inc.建立合作伙伴关系时，我们最初和第一个目标市场或焦点是肥胖和糖尿病。我们寻求将我们的才华结合在一起，共同努力发现阻止这一令人震惊的浪潮并减轻这些深刻的代谢性疾病的新药。对于DBM来说，考虑到阿拉巴马州和我们地区危险的肥胖和糖尿病趋势，这是一项当地的任务。