Axon Guidance Molecules and Optic Nerve Disease

描述（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丧失是青光眼的标志。尽管它与眼压升高（IOP）有密切联系，但导致RGC功能障碍和随后死亡的分子事件的顺序尚不清楚。虽然IOP升高可能直接影响视网膜上的RGC细胞体，但大量证据表明，主要损伤的位置实际上可能在视神经头（ONH）。人们认为，ONH的内在组织特性使其特别容易受到机械损伤，从而导致局部细胞和分子变化，影响视神经轴突的生理和存活。确定青光眼视神经轴突功能障碍的直接分子触发因素将大大提高我们对该病发病机制的理解，并可能提供新的重要治疗途径。轴突引导分子作为关键的发育蛋白，在视神经形成过程中共同对RGC轴突发挥重要作用。轴突引导分子可以直接激活RGC轴突发育过程中的细胞内信号通路，触发细胞骨架解体和不适当轴突分支的消除。最近的研究报道，轴突引导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的情况下，它们可能对神经元和轴突都具有以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损伤后重新出现，并控制受损的成年RGC轴突的再生能力。轴突引导分子在慢性和进行性视神经损伤（如青光眼）中引起轴突损伤的可能功能作用尚未探讨。在本应用中，我们提出了一系列研究来验证青光眼成人ONH区轴突引导分子表达上调的概念，并且这些轴突引导分子能够在成人RGC轴突中引发显着的生理反应。这些研究形成了一个更广泛的假设的初步测试，即ONH轴突引导分子触发RGC轴突功能障碍，并参与青光眼损伤的发展或严重程度。我们的初步证据表明，在DB A/2J青光眼小鼠的ONH中，特定轴突引导分子的表达确实在轴突损伤发生前后上调。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，即引导分子可能在青光眼中介导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.