Petty Howard R
Department of Ophthalmology and Visual Sciences, The University of Michigan Medical School, Ann Arbor, MI, United States.
Front Cell Dev Biol. 2018 Apr 6;6:32. doi: 10.3389/fcell.2018.00032. eCollection 2018.
Although many monogenic diseases are understood based upon structural changes of gene products, less progress has been made concerning polygenic disease mechanisms. This article presents a new interdisciplinary approach to understand complex diseases, especially their genetic polymorphisms. I focus upon primary open angle glaucoma (POAG). Although elevated intraocular pressure (IOP) and oxidative stress are glaucoma hallmarks, the linkages between these factors and cell death are obscure. Reactive oxygen species (ROS) promote the formation of oxidatively truncated phosphoglycerides (OTP), free fatty acids, lysophosphoglycerides, oxysterols, and other chemical species that promote membrane disruption and decrease membrane surface tension. Several POAG-linked gene polymorphisms identify proteins that manage damaged lipids and/or influence membrane surface tension. POAG-related genes expected to participate in these processes include: , and . POAG-related gene products are expected to influence membrane surface tension, strength, and repair. I propose that heightened IOP overcomes retinal ganglion cell (RGC) membrane compressive strength, weakened by damaged lipid accumulation, to form pores. The ensuing structural failure promotes apoptosis and blindness. The linkage between glaucoma genotype and phenotype is mediated by physical events. Force balancing between the IOP and compressive strength regulates pore nucleation; force balancing between pore line tension and membrane surface tension regulates pore growth. Similar events may contribute to traumatic brain injury, Alzheimer's disease, and macular degeneration.
尽管许多单基因疾病可基于基因产物的结构变化来理解，但在多基因疾病机制方面取得的进展较少。本文提出了一种新的跨学科方法来理解复杂疾病，尤其是它们的基因多态性。我将重点关注原发性开角型青光眼（POAG）。虽然眼压升高（IOP）和氧化应激是青光眼的标志，但这些因素与细胞死亡之间的联系尚不清楚。活性氧（ROS）促进氧化截短的磷酸甘油酯（OTP）、游离脂肪酸、溶血磷酸甘油酯、氧化甾醇和其他促进膜破坏并降低膜表面张力的化学物质的形成。几种与POAG相关的基因多态性可识别管理受损脂质和/或影响膜表面张力的蛋白质。预计参与这些过程的与POAG相关的基因包括： ，以及 。预计与POAG相关的基因产物会影响膜表面张力、强度和修复。我提出升高的眼压克服了因受损脂质积累而减弱的视网膜神经节细胞（RGC）膜抗压强度，从而形成孔隙。随之而来的结构破坏会促进细胞凋亡和失明。青光眼基因型与表型之间的联系是由物理事件介导的。眼压与抗压强度之间的力平衡调节孔隙成核；孔隙线张力与膜表面张力之间的力平衡调节孔隙生长。类似的事件可能导致创伤性脑损伤、阿尔茨海默病和黄斑变性。
