Botannical Extract Library Screeninig with Human ADAS Cells

描述（由申请人提供）：此第一阶段STTR提案已根据研究小组的审查进行了实质性修订。该提案是为了回应美国国立卫生研究院院长新发布的“路线图”，该路线图鼓励企业和学术机构之间的合作，以开发进行研究的替代模式，以及国家人类基因组研究所所长弗朗西斯·柯林斯博士的建议，即“在药物开发的第一步进行学术追求可能特别有价值”。这项STTR I期提案结合了zenbio公司的人才，该公司是用于药物研究的人类脂肪组织来源细胞的领先商业供应商，美国国立卫生研究院资助的彭宁顿生物医学研究中心的植物研究中心，是国际公认的糖尿病和营养研究中心，以及罗格斯大学，是国际公认的植物提取物开发中心。我们的主要假设是，在代谢综合征的发展过程中，植物药物可能影响一种或多种组织类型，而限制脂肪组织中脂肪酸释放量（脂肪分解或TG积累）的提取物将减少异位外周脂肪积累和心血管风险（如烟酸）。在I期提案中，我们假设使用人类脂肪细胞模型的高通量筛选分析将：(1)从现有的植物文库中鉴定出新的先导化合物；(2)补充现有的对肥胖、糖尿病或高血压患者有益的植物提取物的分离分析。作为商业合作伙伴，Zen-Bio带来了现有的高通量人类细胞检测产品组合，用于脂肪生成、脂肪分解和脂肪生成基因表达谱分析。作为学术合作伙伴，PBRC的植物中心与罗格斯大学合作，提供其独特的植物提取物和化学分离专业知识库。此外，植物中心已经从植物中提取出已确定对心血管疾病、糖尿病和肥胖有治疗作用的植物提取物。所有这些工具和试剂将可用于拟议的研究。先前的研究证实了这种方法的实用性和有效性。小鼠3T3-L1前脂肪细胞系已被用于筛选促进或抑制脂肪形成的先导化合物的组合化学文库(2)；然而，众所周知，在小鼠模型中鉴定的化合物往往不能作为人类药理学药物。公共卫生相关性：通过STTR确定的化学物质可能在治疗肥胖、糖尿病和代谢综合征方面有潜在的应用。这项工作的结果将在潜在产品、许可机会和知识产权方面对Zen-Bio和Pennington生物医学研究中心产生直接的商业影响。

DESCRIPTION (provided by applicant): This Phase I STTR proposal has been substantially revised in response to the Study Section review. The proposal was written in response to the NIH Director's newly released }roadmap} that encourages collaboration between corporate and academic institutions to develop alternative models for conducting research and the suggestion by Dr. Francis Collins, Director of the National Human Genome Research Institute, that }academic pursuit of [the] first step in drug development could be particularly valuable}. This STTR Phase I proposal combines the talents of Zen-Bio, Inc., the leading commercial supplier of human adipose tissue-derived cells for pharmaceutical research, with those of an NIH-funded Botanical Research Center at the Pennington Biomedical Research Center, an internationally recognized center for studies of diabetes and nutrition, and Rutgers University, an internationally recognized center for the development of botanical extracts. Our overarching hypothesis is that botanicals may effect one or more tissue types in the development of metabolic syndrome and extracts that limit the amount of fatty acid }release} in adipose tissue (lipolysis or TG accumulation) will reduce the amount of ectopic peripheral fat accumulation and cardiovascular risk (e.g. niacin). In the Phase I proposal, we hypothesize that high-throughput screening assays using human adipose cell models will: (1) Identify novel lead compounds from an existing botanical library and; (2) Complement existing assays in the fractionation of extracts from botanicals with known benefits for obese, diabetic, or hypertensive patients. As the commercial partner, Zen-Bio brings an existing portfolio of high-throughput human cell-based assays for lipogenesis, lipolysis, and adipogenic gene expression profiling. As the academic partner, the Botanical Center at PBRC in collaboration with Rutgers University provides its unique library of botanical extracts and chemical fractionation expertise. In addition, the Botanical Center has already subfractionated botanical extracts from plants with identified therapeutic effects for cardiovascular disease, diabetes, and obesity. All of these tools and reagents will be available for the proposed studies. Prior studies validate the utility and efficacy of this approach. The murine 3T3-L1 pre-adipocyte cell line has been used to screen a combinatorial chemical library for lead compounds promoting or inhibiting adipogenesis (2); however, it is well known that compounds identified in murine models often fail as human pharmacological agents. PUBLIC HEALTH RELEVANCE: The chemicals identified through this STTR may have potential application in the treatment of obesity, diabetes, and metabolic syndrome. The outcome of this work will have direct commercial implications for both Zen-Bio and the Pennington Biomedical Research Center in terms of potential products, licensing opportunities, and intellectual property.