Axon Guidance Molecules and Optic Nerve Disease

描述（由申请人提供）：视网膜神经节细胞（RGC）及其轴突的慢性和进行性损失是青光眼的标志。尽管其与眼内压（IOP）升高的联系已被充分认识，但导致RGC功能障碍和随后死亡的分子事件序列尚不清楚。虽然IOP的增加可能直接影响视网膜中的RGC细胞体，但大量证据表明原发性损伤的部位实际上可能在视神经乳头（ONH）。据认为，ONH的内在组织特性使其特别容易受到机械损伤，导致局部细胞和分子的变化，影响视神经轴突的生理和生存。青光眼视神经轴突功能障碍的直接分子触发因素的确定将显着提高我们对疾病发病机制的理解，也可能提供新的重要的治疗途径。轴突导向分子作为关键的发育蛋白，在视神经形成过程中共同对RGC轴突产生重要影响。轴突导向分子可以直接激活发育中的RGC轴突的细胞内信号通路，以触发细胞骨架解体和消除不适当的轴突分支。最近的工作已经报道，轴突导向分子也存在于成人神经系统中，特别是在神经元损伤和病理学的环境中，其中它们可能对神经元和轴突具有先前未被认识到的损伤功能。在我们自己的工作中，我们发现特定的引导分子在视神经创伤后重新出现，并控制受损的成人RGC轴突再生的能力。轴突导向分子在更慢性和进行性形式的视神经损伤（如青光眼）中引起轴突损伤的可能功能作用尚未被探索。在本申请中，我们提出了一组研究，以测试的概念，即轴突导向分子的表达上调，在acumcomatous成人ONH地区，这些轴突导向分子能够引起显着的生理反应，在成人RGC轴突。这些研究形成了一个更广泛的假设的初步测试，即ONH的轴突导向分子触发RGC轴突功能障碍，并参与了神经胶质瘤损伤的发展或严重程度。我们的初步证据表明，特异性轴突导向分子的表达确实在DBA/2 J胶质瘤小鼠的ONH中在轴突损伤开始时上调。此外，这些分子能够在生理上激活成人RGC轴突，这与我们的特定假设一致，即引导分子可能在介导青光眼中的轴突损伤中起主要作用。

DESCRIPTION (provided by applicant): The chronic and progressive loss of Retinal Ganglion Cells (RGC) and their axons is a hallmark of Glaucoma. Despite its well-appreciated link with elevated intraocular pressure (IOP), the sequence of molecular events that lead to RGC dysfunction and subsequent death is not clearly understood. Although increases in IOP may directly impact RGC cell bodies in the retina, a substantial body of evidence suggests that the site of primary damage may in fact be at the optic nerve head (ONH). It is thought that intrinsic tissue properties in the ONH makes it especially susceptible to mechanical damage, resulting in localized cellular and molecular changes that affect optic nerve axon physiology and survival. The identification of the direct molecular triggers of optic nerve axon dysfunction in glaucoma will significantly enhance our understanding of disease pathogenesis and may also potentially provide new important therapeutic avenues. Axon guidance molecules serve as key developmental proteins that collectively exert major effects on RGC axons during formation of the optic nerve. Axon guidance molecules can directly activate intracellular signaling pathways in developing RGC axons to trigger cytoskeletal disassembly and the elimination of inappropriate axon branches. Recent work has reported that axon guidance molecules are also present in the adult nervous system particularly in settings of neuronal injury and pathology, where they may have previously unappreciated injurious functions on both neurons and axons. In our own work, we have found that specific guidance molecules reappear after optic nerve trauma and govern the ability of damaged adult RGC axons to regenerate. A possible functional role for axon guidance molecules in causing axon damage in more chronic and progressive forms of optic nerve injury, such as glaucoma, has not been explored. In this application, we propose a set of studies to test the notion that axon guidance molecule expression is up-regulated at the glaucomatous adult ONH region and that these axon guidance molecules are capable of eliciting significant physiological responses in adult RGC axons. These studies form the initial tests of a broader hypothesis that axon guidance molecules at the ONH trigger RGC axon dysfunction and are involved in the development or severity of glaucomatous damage. Our preliminary evidence shows that expression of specific axon guidance molecules are indeed up-regulated at the ONH of DB A/2J glaucomatous mice around the time of onset of axon damage. Furthermore, these molecules are capable of physiologically activating adult RGC axons, consistent with our specific hypothesis that guidance molecules may have a primary role in mediating axon damage in glaucoma.