Chemical approaches to interrogate neuropeptide and peptide hormone signaling in disease

项目总结/摘要 靶向神经肽和肽激素信号传导是治疗多种人类疾病的有前景的策略。 疾病，包括神经退行性疾病、糖尿病、骨质疏松症和癌症。严格的分子水平 了解特定肽分子在疾病中的信号传递方式提供了有价值的信息， 为治疗化合物的设计提供信息。然而，仍然存在大量的生物活性和疾病- 相关内源性肽，其信号传导途径尚不清楚。由于重要性， 肽-受体相互作用在正常生理学和疾病中的研究，迫切需要新的工具和 方法来充分询问和调节这些信号系统。 我的研究计划的长期目标是严格识别和评估新的分子信号 作为治疗靶点的途径。为了实现这一目标，我的研究计划追求高度跨学科 方法，具有设计，合成和实施新型化学探针的专业知识， 肽模拟物、蛋白质和肽质谱以及细胞上肽-受体相互作用的分析。 在接下来的五年里，我们的动机是三个广泛的研究问题。1)a的受体是什么 给予疾病相关的生物活性肽？我们的目标是开发和实施新的和公正的化学 直接检测肽-受体相互作用而不需要遗传或化学修饰的方法 在相互作用之前，我们将实施这些方法来识别三种特定的受体， 在肥胖和糖尿病中起作用的肽激素。2)多肽丰度和翻译后 加工影响疾病？我们的目标是确定神经肽和肽激素的相互作用， 以造福人类健康为目标。我们正在开发和应用基于质谱的方法， 揭示神经肽和肽激素在未充分研究的疾病相关的完整补充 生理学，包括所有翻译后修饰的表征和严格的定量。我们将 利用我们在化学探针和肽模拟物设计方面的优势， 识别. 3)是否有新的“非传统”方法来调节细胞间信号传导， 被发现？我们的目标是探索自然发生的肽受体系统，功能以外的 传统的激动剂/拮抗剂范例。从该研究领域获得的信息将用于开发 新的化学探针，以更好地了解信号事件，并为新的治疗途径的设计提供信息 其可以提供优于传统调制器的优点。 总的来说，这项研究计划将开发新的工具和策略，以充分了解和调节肽 信号通路这项工作将通过以下方式影响生物医学研究： 疾病中的神经肽和激素，B）鉴定治疗靶向的新信号传导途径，和c） 产生化学探针作为治疗剂的起始点。 项目摘要/摘要第6页

PROJECT SUMMARY/ABSTRACT Targeting neuropeptide and peptide hormone signaling is a promising strategy to treat a wide range of human diseases, including neurodegenerative diseases, diabetes, osteoporosis, and cancer. A rigorous molecular-level understanding of how specific peptide molecules signal in disease provides valuable information that can directly inform the design of therapeutic compounds. However, there remain a large number of bioactive and disease- relevant endogenous peptides whose signaling pathways are not understood. Because of the importance of peptide-receptor interactions in normal physiology and disease, there is a critical need for new tools and approaches to fully interrogate and modulate these signaling systems. The long-term goal of my research program is to rigorously identify and evaluate novel molecular signaling pathways as therapeutic targets. To achieve this goal, my research program pursues a highly interdisciplinary approach, with expertise in the design, synthesis, and implementation of novel chemical probes and peptidomimetics, protein and peptide mass spectrometry, and analysis of peptide-receptor interactions on cells. Over the next five years, we are motivated by three broad research questions. 1) What are the receptors for a given disease-related bioactive peptide? Our goal is to develop and implement new and unbiased chemical approaches to directly detect peptide-receptor interactions without the need to genetically or chemically modify the receptor prior to interaction. We will implement these approaches to identify receptors for three specific peptide hormones with roles in obesity and diabetes. 2) How does peptide abundance and post-translational processing influence disease? Our goal is to identify neuropeptide and peptide hormone interactions that can be targeted to benefit human health. We are developing and applying mass spectrometry-based methods to uncover the full complement of neuropeptides and peptide hormones in understudied disease-relevant physiologies, including characterization of all post-translational modifications and rigorous quantitation. We will use our strengths in chemical probe and peptidomimetic design to evaluate these new targets after initial identification. 3) Are there new “non-traditional” approaches to modulating cell-cell signaling waiting to be uncovered? Our goal is to explore naturally occurring peptide-receptor systems that function outside of the traditional agonist/antagonist paradigm. Information gained from this research area will be utilized to develop new chemical probes to better understand signaling events, and to inform the design of novel therapeutic routes that may provide advantages over traditional modulators. Overall, this research program will develop new tools and strategies to fully understand and modulate peptide signaling pathways. This work will impact biomedical research by a) significantly advancing understanding of neuropeptides and hormones in disease, b) identifying novel signaling pathways to target for treatment, and c) generating chemical probes as the starting point for therapeutic agents. Project Summary/Abstract Page 6