Chemical approaches to interrogate neuropeptide and peptide hormone signaling in disease

项目摘要/摘要 靶向神经肽和多肽激素信号转导是一种有前景的治疗广泛的人类 疾病，包括神经退行性疾病、糖尿病、骨质疏松症和癌症。一个严格的分子水平 了解特定的多肽分子如何在疾病中发出信号提供了有价值的信息，可以直接 告知治疗性化合物的设计。然而，仍然有大量的生物活性和疾病- 相关的内源性多肽，其信号通路尚不清楚。因为……的重要性 肽-受体相互作用在正常生理和疾病中，迫切需要新的工具和 完全询问和调制这些信号系统的方法。 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 作为治疗靶点的通路。为了实现这一目标，我的研究项目追求高度跨学科的 方法，在设计、合成和实施新型化学探针和 多肽模拟学、蛋白质和多肽质谱学，以及细胞上多肽-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？ 给予与疾病相关的生物活性多肽？我们的目标是开发和实施新的和无偏见的化学品 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 相互作用前的受体。我们将实施这些方法来识别三个特定的受体 多肽荷尔蒙在肥胖和糖尿病中的作用。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多肽激素之间的相互作用 以造福人类健康为目标。我们正在开发和应用基于质谱学的方法来 在未被研究的疾病相关疾病中发现神经肽和肽激素的全部补充 生理学，包括所有翻译后修饰的特征和严格的量化。我们会 利用我们在化学探针和模拟多肽设计方面的优势，对这些新靶点进行初步评估 身份证明。3)有没有新的“非传统”方法来调制细胞--等待 被揭穿了？我们的目标是探索天然存在的多肽-受体系统，这些系统在 传统的激动剂/拮抗剂范式。将利用从这一研究领域获得的信息来开发 新的化学探针，以更好地了解信号事件，并为设计新的治疗路线提供信息 这可能会提供比传统调制器更多的优势。 总体而言，这项研究计划将开发新的工具和策略来充分理解和调节多肽 信号通路。这项工作将通过以下方式对生物医学研究产生影响：a)显著促进对 疾病中的神经肽和激素，b)识别新的信号通路作为治疗的靶点，以及c) 产生化学探针作为治疗剂的起点。 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