{"id":{"repo_id":"rochester","oai_identifier":"oai:urresearch.rochester.edu:395"},"canonical_url":"https://search.dev.ndltd.org/etd/rochester/oai:urresearch.rochester.edu:395","repository":{"repo_id":"rochester","name":"Rochester University","base_url":"http://urresearch.rochester.edu/oai2.action"},"display":{"title":"Identification and functional characterization of novel receptor ligands of CD40 and alpha(v) beta(3) integrin: implications for gene delivery","abstract":"Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Microbiology and Immunology, 2002.","abstract_html":"Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Microbiology and Immunology, 2002.","abstract_has_math":false,"creators":["Richards Gunzler, Julie","Dewhurst, Stephen"],"institution":"University of Rochester School of Medicine and Dentistry","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2004,"date_issued":"Mon, 2 Aug 2004 19:59:57","date_published":"Mon, 2 Aug 2004 19:59:57","updated_at":"2026-07-27T20:46:02Z","subjects":["CD40","alpha(v) beta(3) integrin"],"languages":["eng"],"rights":["This item is protected by copyright, with all rights reserved."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/1802/547","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Richards Gunzler, Julie","Dewhurst, Stephen"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["Mon, 2 Aug 2004 19:59:57","Year: 2002","Thu, 4 Dec 2025 16:11:36"]},{"key":"dc:publisher","label":"Institution","values":["University of Rochester School of Medicine and Dentistry"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["CD40","alpha(v) beta(3) integrin"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["This item is protected by copyright, with all rights reserved."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/1802/547"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Microbiology and Immunology, 2002.","Gene delivery to target tissues is often limited by the native tropism of the viral or non-viral vector used. Failure to infect the target cell of choice may limit the use of an otherwise advantageous vector; conversely, a vector with broad tropism may require a higher introduced dose which may increase immunogenicity or pathogenicity. Recent advances in technology have allowed for modification of gene delivery vectors with molecules ranging in size from short peptides to polypeptides such as single chain variable regions (scFvs). Since our lab has an interest in exploring gene delivery for tumor therapy and vaccination, we selected two model receptor systems for ligand selection: CD40 and alpha(V) beta(3) integrin. Both receptors are expressed on dendritic cells, tumor cells and endothelium. However, CD40 and alpha(V) beta(3) have different roles in antigen presentation, dendritic cell maturation, and tumor biology. Using phage display technology, we selected for linear CD40-binding peptides containing a novel FPGN consensus sequence that dramatically enhance infection of CD40-positive cells, including both murine and human dendritic cells. These peptides could be incorporated into a variety of viral capsid proteins and other gene delivery systems. Using a phage display scaffold based on the tenth fibronectin type III domain (FNfn10), we developed a modified domain, 3JCLI4-FNfn10, which acts as an antibody mimic when binding to avb3. 3JCLI4-FNfn10 binds to alpha(V) beta(3) with high affinity similarly to the disintegrin echistatin. Specifity of 3JCLI4-FNfn10 for alpha(V) beta(3) integrin binding over related integrins was demonstrated on plate-immobilized purified integrins, by flow cytometric analysis on K562 cell lines expressing a panel of different integrins. and by its ability to inhibit alpha(V) beta(3)-cell adhesion but not alpha(5) beta(1)-mediated adhesion to fibronectin and with minor cross-reactivity in inhibitng alpha(II) beta(3)- mediated adhesion to vitronectin. Because 3JCLI4-FNfn10 is only 15kDa in size and extremely stable, it may be used to modify viral vectors in existing systems utilizing scFv, as well having therapeutic potential for inhibiting alpha(V) beta(3) interactions in vivo. In conclusion, both the CD40-binding FPGN peptides and 3JCLI4-FNfn10 may be useful in retargeting gene delivery vectors for more efficient infection of CD40-positive or alpha(V) beta(3)-positive cells, including dendritic cells, solid tumors, and activated endothelial cells."]},{"key":"dc:title","label":"Title","values":["Identification and functional characterization of novel receptor ligands of CD40 and alpha(v) beta(3) integrin: implications for gene delivery"]}]}],"canonical_facts":{"dc:creator":["Richards Gunzler, Julie","Dewhurst, Stephen"],"dc:date":["Mon, 2 Aug 2004 19:59:57","Year: 2002","Thu, 4 Dec 2025 16:11:36"],"dc:description":["Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Microbiology and Immunology, 2002.","Gene delivery to target tissues is often limited by the native tropism of the viral or non-viral vector used. Failure to infect the target cell of choice may limit the use of an otherwise advantageous vector; conversely, a vector with broad tropism may require a higher introduced dose which may increase immunogenicity or pathogenicity. Recent advances in technology have allowed for modification of gene delivery vectors with molecules ranging in size from short peptides to polypeptides such as single chain variable regions (scFvs). Since our lab has an interest in exploring gene delivery for tumor therapy and vaccination, we selected two model receptor systems for ligand selection: CD40 and alpha(V) beta(3) integrin. Both receptors are expressed on dendritic cells, tumor cells and endothelium. However, CD40 and alpha(V) beta(3) have different roles in antigen presentation, dendritic cell maturation, and tumor biology. Using phage display technology, we selected for linear CD40-binding peptides containing a novel FPGN consensus sequence that dramatically enhance infection of CD40-positive cells, including both murine and human dendritic cells. These peptides could be incorporated into a variety of viral capsid proteins and other gene delivery systems. Using a phage display scaffold based on the tenth fibronectin type III domain (FNfn10), we developed a modified domain, 3JCLI4-FNfn10, which acts as an antibody mimic when binding to avb3. 3JCLI4-FNfn10 binds to alpha(V) beta(3) with high affinity similarly to the disintegrin echistatin. Specifity of 3JCLI4-FNfn10 for alpha(V) beta(3) integrin binding over related integrins was demonstrated on plate-immobilized purified integrins, by flow cytometric analysis on K562 cell lines expressing a panel of different integrins. and by its ability to inhibit alpha(V) beta(3)-cell adhesion but not alpha(5) beta(1)-mediated adhesion to fibronectin and with minor cross-reactivity in inhibitng alpha(II) beta(3)- mediated adhesion to vitronectin. Because 3JCLI4-FNfn10 is only 15kDa in size and extremely stable, it may be used to modify viral vectors in existing systems utilizing scFv, as well having therapeutic potential for inhibiting alpha(V) beta(3) interactions in vivo. In conclusion, both the CD40-binding FPGN peptides and 3JCLI4-FNfn10 may be useful in retargeting gene delivery vectors for more efficient infection of CD40-positive or alpha(V) beta(3)-positive cells, including dendritic cells, solid tumors, and activated endothelial cells."],"dc:identifier":["http://hdl.handle.net/1802/547"],"dc:language":["eng"],"dc:publisher":["University of Rochester School of Medicine and Dentistry"],"dc:rights":["This item is protected by copyright, with all rights reserved."],"dc:subject":["CD40","alpha(v) beta(3) integrin"],"dc:title":["Identification and functional characterization of novel receptor ligands of CD40 and alpha(v) beta(3) integrin: implications for gene delivery"],"dc:type":["Thesis"]},"updated_at":"2026-07-27T20:46:02Z"}