Identification and Function of Receptors and Ligands

描述(由申请人提供)：本申请的广泛长期目标是确定细胞表面受体的新配体，并表征脊椎动物发育，特别是神经连接发育的功能。目的1重点是寻找新的配体。AIM 1的第一部分涉及哺乳动物LAR家族的受体样蛋白酪氨酸磷酸酶。以前的遗传学研究表明，这些分子在神经发育中具有功能，但它们的作用和可能的配体仍然不太清楚。在初步研究中，一个新的由三个配体组成的家族已经被分子鉴定，并将进一步表征。AIM 1的第二部分涉及淀粉样前体蛋白(APP)，该蛋白被切割形成与阿尔茨海默病有关的β-淀粉样多肽。尽管APP与病理相关，但其自然功能尚未被很好地理解。长期以来，人们一直认为APP可能是一种配体或受体，在初步研究中，我们已经显示了一种新的与发育中的轴突结合的模式。建议进行进一步的研究来确定和表征负责这种结合的配体(S)。目的2建议继续研究Eparin的发育功能，Ephins是在项目早期周期中确定的一类配体。重点放在实验上，以阐明eaffin功能的新原理，例如在协调皮质细胞迁移方面的作用，以及在突触中的作用。目标3是开发新的小分子方法来研究轴突的生长和引导。提出了一种“化学遗传”筛查，以确定调节肾上腺素抑制作用的化合物，以及在发育和再生过程中抑制轴突生长的其他分子线索。虽然这项工作主要集中在基础生物学上，但识别、表征和调节新的细胞-细胞信号分子的研究可能最终导致用于维持、修复或再生神经连接的治疗剂。此外，我们对APP配体的研究可能会导致调节蛋白质分解过程的新策略，这可能会对阿尔茨海默病产生潜在的影响。目标3涉及筛选可以促进轴突生长和再生的化合物，重点是基础细胞生物学，但可以产生化合物或先导化合物，用于进一步开发治疗神经损伤的治疗方法。

DESCRIPTION (provided by applicant): The broad long-term goal of this application is to identify novel ligands for cell surface receptors, and to characterize functions in vertebrate development, particularly development of neural connections. Aim 1 focuses on identification of novel ligands. The first part of aim 1 deals with receptor-like protein tyrosine phosphatases of the mammalian LAR family. Previous genetic studies show functions for these molecules in neural development, but their actions and putative ligands are still not well understood. In preliminary studies, a novel family of three ligands has been molecularly identified, and will be characterized further. The second part of aim 1 deals with the Amyloid Precursor Protein (APP), which is cleaved to form the beta-amyloid peptide implicated in Alzheimer's disease. Despite its pathological relevance, the natural function of APP is not well understood. It has long been suggested that APP may function as a ligand or receptor, and in preliminary studies we have shown a novel-binding pattern to developing axons. Further studies are proposed to identify and characterize the ligand(s) responsible for this binding. Aim 2 proposes continued studies on developmental functions of the ephrins, a family of ligands identified during earlier cycles of the project. The focus is on experiments to elucidate novel principles of ephrin function, such as roles in coordinating cortical cell migration, and roles at the synapse. Aim 3 is to develop new small-molecule approaches to study axon outgrowth and guidance. A "chemical genetic" screen is proposed, to identify chemical compounds that modulate the inhibitory effect of ephrins, as well as other molecular cues that inhibit axon growth during development and regeneration. While this work focuses on basic biology, studies to identify, characterize, and modulate novel cell-cell signaling molecules may ultimately lead to therapeutic agents for maintenance, repair or regeneration of neural connections. Also, our studies on APP ligands may lead to new strategies to regulate proteolytic processing, with potential implications for Alzheimer's disease. Aim 3, involving a screen for chemical compounds that can promote axon growth and regeneration, focuses on basic cell biology but could produce compounds or lead-compounds for further therapeutic development for treatment of nerve injury.