A New Disease Platform Leveraging Complex Drosophila and Mammalian Models

利用复杂果蝇和哺乳动物模型的新疾病平台

• 批准号: 9306960
• 负责人: Ross Leigh Cagan
• 金额: $ 188.87万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9306960
• 关键词: Acute; Address; Adverse effects; Affect; Alpha Cell; Animals; Applied Research; BAY 54-9085; Cardiac Myocytes; Cell model; Cells; Chronic; Colorectal Cancer; Communities; Complex; Data; Databases; Disease; Disease model; Disease remission; Docking; Drosophila genus; Drug Targeting; Emerging Technologies; FDA approved; Generations; Genetic; Genetic Screening; Genomics; Goals; Hereditary Disease; Homeostasis; Human; Hypertrophic Cardiomyopathy; Implant; Industrialization; Lead; Libraries; Malignant Neoplasms; Mendelian disorder; Modeling; Mus; Mutation; Normal tissue morphology; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Procedures; Process; Rare Diseases; Research; Series; Stem cells; Structure; Synapses; Technology; Testing; Therapeutic; Therapeutic Index; Thinking; Tissues; Transgenic Model; Transgenic Organisms; Tumor Initiators; Validation; Variant; Xenograft Model; animal efficacy; base; computational chemistry; cost; cost effective; design; drug discovery; fly; human stem cells; improved; induced pluripotent stem cell; novel; novel strategies; personalized medicine; personalized therapeutic; public health relevance; response; screening; stem-like cell; therapeutic target; therapy development; tool; tumor; tumor xenograft

 DESCRIPTION (provided by applicant): The goal of disease research is to develop therapeutics. While many diseases have been successfully addressed, genetics-based diseases have proven more difficult to develop therapies that bring the disease into remission without significant side effects. Doing so requires addressing both disease complexity and also the complex interactions within the whole body network that affect disease as well as response to therapies. The central theme of this Proposal is to leverage the advantages of the fruit fly Drosophila to build a `functional network platform' designed to identify therapeutics that address disease complexity. We then use stem cell approaches to explore the most promising leads in a human cell context. At each step we make a concerted effort to embrace complexity both in our models and our lead therapeutics. The overall objective of this Proposal is to further develop a platform and pipeline that can be adapted to a broad range of diseases. In the attached Projects, we describe our emerging technologies designed to weave together complementary disease models into a seamless platform designed to build drugs and personalized therapeutics rapidly and at a reasonable cost. We select two diseases-colorectal cancer and RASopathy- to develop and demonstrate the strength of our platform to address both a rare Mendelian disease and one of the most common cancers. The former example tests whether our platform can provide a rapid and cost-effective approach to orphan diseases that require sophisticated therapeutics suitable for long-term treatment. The latter provides an example of how it can embrace disease complexity to build new generation lead therapeutics for a disease that remains a key unmet need in our community. Once developed, we will offer a readily accessible standard operating procedure that will most efficiently bring our platform to the applied science community.

 描述（由申请人提供）：疾病研究的目标是开发治疗方法。虽然许多疾病已被成功地解决，但基于遗传的疾病已被证明更难以开发使疾病缓解而无显著副作用的疗法。这样做需要解决疾病的复杂性以及影响疾病和治疗反应的全身网络内的复杂相互作用。 该提案的中心主题是利用果蝇的优势，建立一个“功能网络平台”，旨在确定解决疾病复杂性的治疗方法。然后，我们使用干细胞方法来探索人类细胞背景下最有前途的线索。在每一步，我们都齐心协力，在我们的模型和领先疗法中拥抱复杂性。 该提案的总体目标是进一步开发一个可适用于各种疾病的平台和管道。在所附的项目中，我们描述了我们的新兴技术，这些技术旨在将互补的疾病模型编织成一个无缝平台，旨在以合理的成本快速构建药物和个性化治疗。我们选择了两种疾病-结直肠癌和RASopathy-来开发和展示我们的平台的优势，以解决罕见的孟德尔疾病和最常见的癌症之一。前一个例子测试了我们的平台是否可以为需要适合长期治疗的复杂疗法的孤儿疾病提供快速和具有成本效益的方法。后者提供了一个例子，说明它如何能够拥抱疾病的复杂性，为我们社区仍然存在的一个关键的未满足需求的疾病建立新一代的领先疗法。 一旦开发完成，我们将提供一个易于访问的标准操作程序，这将最有效地将我们的平台带到应用科学界。