Mechanism of Neuropilin and TM inhibitor peptides in AD/angiogenesis

Neuropilin 和 TM 抑制肽在 AD/血管生成中的作用机制

• 批准号: 8788404
• 负责人: MATTHIAS BUCK
• 金额: $ 19.42万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8788404
• 关键词: Affect; Age related macular degeneration; Antibodies; Binding; Blindness; Blocking Antibodies; Blood Vessels; Cell Proliferation; Cell Survival; Cell membrane; Cells; Cellular Assay; Cellular Membrane; Cellular biology; Chronic; Complex; Data; Development; Dimerization; Disease; Dopamine D1 Receptor; Event; Eye; Eyedrops; Funding; Future; Health; Kinetics; Knowledge; Label; Laboratories; Lead; Long-Term Effects; Maps; Membrane; Molecular; Molecular Conformation; Mutagenesis; NMR Spectroscopy; Nature; Neuropilin-1; Neuropilins; Patients; Peptides; Pharmaceutical Preparations; Pilot Projects; Play; Property; Proteins; Receptor Signaling; Regulation; Reporting; Resistance; Retina; Signal Pathway; Signal Transduction; Signaling Molecule; Solutions; Structure; Swelling; System; Tertiary Protein Structure; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Thermodynamics; Time; Transmembrane Domain; United States; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Vision; Visual Fields; Work; angiogenesis; antiangiogenesis therapy; bevacizumab; biophysical properties; blood vessel development; cell motility; design; dimer; extracellular; inhibitor/antagonist; insight; macula; molecular dynamics; mutant; plexin; pre-clinical; ranibizumab; receptor; receptor function; rho GTP-Binding Proteins; targeted treatment; therapeutic angiogenesis; therapeutic development

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is responsible for approx. 9% of the world's blindness, affecting 2 million people in the United States. Pathological neovasculation is one of the main causes of degeneration of the central vision region of the retina. VEGF and its receptors, VEGFR and co-receptor Neuropilin (Nrp) together with plexins, direct this formation of blood vessels, but the receptors also regulate cell survival and proliferation. Over the last decade, anti-VEGF therapy has become a principal mode of treatment for AMD. Several antibodies against VEGF-A, Ranibizumab and off-label use of Bevacizumab, are effective in slowing visual loss in 90% of patients. However, their long term effects on angiogenesis are not yet known and resistance against VEGFR blockade-like treatments has already become a problem. Thus a deeper understanding of Neuropilin/VEGFR/Plexin signaling is needed at the molecular level for the design of more specific agents. Furthermore, both drugs need to be injected directly into the eye every month, making the development of therapeutics that can be administered at least intravenously, if not orally, highly desirable. The proposed project focuses on Neuropilin signaling at the molecular and mechanistic level. As yet there is no detailed structural information for the transmembrane (TM) segment, for the well conserved 46 residues just outside the cell, or for the 44 residue intracellular region of Nrp1. We hypothesize that the relationship between the TM and membrane proximal regions constitutes key parts of the mechanism for transmembrane signaling; specifically the regions are likely to participate in regulatory events in a hierarchica manner. Peptides corresponding to the Nrp1 TM region can inhibit receptor function and angiogenesis. However, insights are needed at the molecular level in order to understand this mechanism and to optimize the peptide inhibitors, utilizing the context of the membrane surrounding regions, for anti- angiogenesis therapy. Our structural studies will synergize with functional studies of Nrp1 that are ongoing in several laboratories. The R21 project has two exploratory aims: Aim 1 will take steps towards the determination of the neuropilin- 1 (Nrp1) transmembrane (TM) dimer structure by solution NMR spectroscopy and characterization of TM inhibitory peptide interactions, also the context of the intracellular and a portion of the extracellular region. Aim 2 examines the intracellular 44 residue region and its newly discovered interaction with the Nrp1 co- receptor plexin-D1.

描述(由申请人提供)：老年性黄斑变性(AMD)约为全世界有9%的人失明，美国有200万人受到影响。病理性新生血管是视网膜中央视区变性的主要原因之一。血管内皮生长因子及其受体、血管内皮生长因子受体和共同受体神经粘连蛋白(NRP)与神经丛蛋白一起引导血管的形成，但这些受体也调节细胞 生存和繁殖。在过去的十年中，抗血管内皮生长因子治疗已经成为AMD的主要治疗模式。几种抗血管内皮生长因子-A的抗体，雷尼比珠单抗和贝伐单抗的非标签使用，在减缓90%的患者视力损失方面是有效的。然而，它们对血管生成的长期影响尚不清楚，对VEGFR阻滞剂类治疗的耐药性已经成为一个问题。因此，需要在分子水平上对Neuropilin/VEGFR/Plexin信号有更深入的了解，以便设计更具体的药物。此外，这两种药物都需要每月直接注射到眼睛里，这使得开发至少可以静脉注射(如果不是口服)的治疗方法是非常必要的。拟议的项目集中在分子和机制水平上的Neuropilin信号转导。到目前为止，还没有关于跨膜(TM)片段、细胞外保守的46个残基或Nrp1的44个残基的详细结构信息。我们假设TM和膜近端区域之间的关系构成了跨膜信号机制的关键部分；具体地说，这些区域可能以分级的方式参与调控事件。Nrp1TM区对应的多肽可以抑制受体功能和血管生成。然而，需要在分子水平上的洞察才能理解这一机制，并利用膜周围区域的背景优化多肽抑制剂，用于抗血管生成治疗。我们的结构研究将与Nrp1的功能研究相配合，这些研究正在几个实验室进行。R21项目有两个探索性目标：目标1将通过溶液核磁共振光谱和TM抑制肽相互作用的表征，以及细胞内和部分细胞外区域的上下文，逐步确定神经粘连蛋白-1(Nrp1)跨膜(TM)二聚体的结构。目的2研究细胞内44个残基及其与Nrp1共受体Plexin-D1的相互作用。