Targeting the Anterior Segment with Homing Peptides from Phage Display

描述（由申请人提供）：这是R21的新申请。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，这些肽可用作控制和降低眼内压的治疗递送剂。青光眼导致视网膜神经节细胞的不可逆损失，影响全球约6700万人。它们通常与眼内压（IOP）水平升高相关，这是由于从TM流出的房水减少。尽管通过TM的房水引流减少占导致青光眼的异常的至少90%，但很少有药物可以特异性靶向TM以增加房水流出。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中的归巢肽。然后，这些归巢肽用于在体内产生组织特异性递送系统并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产生体内组织特异性归巢肽的Cx7C噬菌体文库。我们还计划产生一个噬菌体展示文库，该文库偏向于α 4 β 1整联蛋白序列基序PRARI。我们实验室发表的研究表明，这种PRARI肽可用于靶向TM。在过去的研究中，这种肽引起培养的前节流出设施的增加。我们的目标是生产具有更高亲和力的更特异性的PRARI肽。TM的归巢肽的鉴定将具有治疗青光眼的多种用途。除了靶向药物递送和组织特异性病毒载体的产生之外，这些肽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.