Targeting the Anterior Segment with Homing Peptides from Phage Display

描述（由申请人提供）：这是一份新的R21申请。这项资助的长期目标是利用噬菌体展示文库来鉴定小梁网（TM）的组织特异性归巢肽，这些肽可以用作治疗递送剂来控制和降低眼压。青光眼导致视网膜神经节细胞不可逆转的丧失，全世界约有6700万人患有青光眼。它们通常与眼内压（IOP）水平升高有关，这是由于从TM流出的房水减少所致。虽然房水通过TM的引流减少至少占导致青光眼异常的90%，但很少有药物可以专门针对TM以增加房水流出为目标。靶向药物递送的一种方法是使用附着在化合物上或克隆到病毒外壳上的归巢肽。然后使用这些归巢肽在体内产生组织特异性递送系统，减少不需要的组织相互作用的靶向。为了鉴定TM的归巢肽，我们计划使用先前显示的Cx7C噬菌体文库来产生体内组织特异性归巢肽。我们还计划生成一个噬菌体展示文库，该文库偏向于a4b1整合素序列基序PRARI。我们实验室发表的研究表明，这种PRARI肽可以用于靶向TM。在过去的研究中，这种肽引起培养前节段流出设施的增加。我们的目标是生产一种具有更高亲和力、更特异的PRARI肽。TM归巢肽的鉴定将对青光眼的治疗有多种用途。除了靶向药物递送和组织特异性病毒载体的产生外，这些肽还可以用作细胞干细胞递送的生物标志物和青光眼手术的成像工具。

DESCRIPTION (provided by applicant): This is a new application for a R21. The long-term objective of this grant is to use phage display libraries to identify tissue specific homing peptids for the trabecular meshwork (TM) that can be used as therapeutic delivery agents to control and lower intraocular pressure. The glaucomas, which lead to irreversible loss of retinal ganglion cells, affect approximately 67 million people worldwide. They are commonly associated with elevated levels of intraocular pressure (IOP) due to a reduction in aqueous humor outflow from the TM. Although reduced drainage of aqueous humor through the TM accounts for at least 90% of abnormalities resulting in glaucoma, there are very few drugs that can specifically target the TM with the goal of increasing aqueous humor outflow. One way to target drug deliver is to use homing peptides attached to the compound or cloned into the viral coat. These homing peptides are then used to generate tissue specific delivery systems in vivo and reduce targeting of unwanted tissue interactions. To identify homing peptides for the TM, we plan to use the Cx7C phage library previously shown to produce in vivo tissue specific homing peptides. We also plan to generate a phage display library that is biased towards the a4b1 integrin sequence motif, PRARI. Published studies from our laboratory have shown that this PRARI peptide can be used to target the TM. In past studies, this peptide caused an increase in outflow facility in cultured anterior segments. It is our goal to produce a more specific PRARI peptide with a higher affinity. The identification of homing peptides for the TM would have multiple uses for the treatment for glaucoma. In addition to targeted drug delivery and generation of tissue specific viral vectors, these peptides could be used as biomarkers for cell stem delivery and as imaging tools for glaucoma surgery.