{"id":{"repo_id":"buffalo","oai_identifier":"oai:ubir.buffalo.edu:10477/86676"},"canonical_url":"https://search.dev.ndltd.org/etd/buffalo/oai:ubir.buffalo.edu:10477/86676","repository":{"repo_id":"buffalo","name":"Buffalo","base_url":"https://ubir.buffalo.edu/oai/request"},"display":{"title":"ST6GAL1 from the Blood to the Gut: Influence on Myelopoiesis and Gastrointestinal Radiation Sensitivity","abstract":"Ph.D.","abstract_html":"Ph.D.","abstract_has_math":false,"creators":["Punch, Patrick; 0000-0002-2662-6285"],"institution":"State University of New York at Buffalo","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Lau, Joseph","Roswell Park"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-02-21T21:36:20Z","date_published":"2025-02-21T21:36:20Z","updated_at":"2026-07-27T19:05:34Z","subjects":["biology","immunology"],"languages":["eng"],"rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/10477/86676","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Lau, Joseph","Roswell Park"]},{"key":"dc:creator","label":"Author","values":["Punch, Patrick; 0000-0002-2662-6285"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2025-02-21T21:36:20Z","2020"]},{"key":"dc:publisher","label":"Institution","values":["State University of New York at Buffalo"]},{"key":"dc:type","label":"Dc Type","values":["Text","Dissertation"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["biology","immunology"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/10477/86676"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Ph.D.","The importance of protein glycosylation is becoming difficult to ignore, especially when studying how immune cells interact with their environment. An especially important glycan, built primarily by the sialyltransferase ST6GAL1, is α2,6-linked sialic acid occurring on N-linked glycan chains of cell surface and secreted proteins. α2,6-linked sialic acids have been shown to mediate numerous cellular events, from controlling hematopoiesis and inflammatory cell interactions, to influencing a cell's response to apoptotic signaling. Here we report novel roles for α2,6 sialylation: In mitigating death of gastrointestinal epithelial cells in response to high-dose total body irradiation and in preventing the maturation of monocytes into macrophages. Chapter 1 builds upon previous observations that, in vitro, several colon cancer cell lines exhibit increased radiation-induced apoptosis when ST6GAL1 is underexpressed, and that ST6GAL1 overexpression decreases radiation-induced apoptosis. Using an St6gal1-KO mouse model, we show that a lack of functional ST6GAL1 in vivo drastically increases the mouse's sensitivity to total body ionizing radiation, resulting in death that cannot be mitigated by bone marrow transplantation as it can in wild-type counterparts. Using various gross and histological observation methods, we observe that these St6gal1-KO mice experience severe damage to the gastrointestinal epithelium upon radiation exposure, resulting in a near-complete lack of functional GI crypt stem cells which are necessary to rebuild the epithelium after injury. Attempted rescue through inhibition of various cell death pathways, or the addition of recombinant ST6GAL1 back into St6gal1 KO animals was unable to rescue these mice. Finally, we speculate how future work could elucidate the exact mechanism at play in this phenotype, and how ST6GAL1 could be developed into a potential medical counter measure given directly after acute radiation exposure. In chapter 2 we identify a role for extrinsic sialylation of monocytes by ST6GAL1 in inhibiting their maturation into macrophages. We review the previously known roles of α2,6 linked sialylation, and glycosylation in general, in dictating myeloid cell development and function. We identify the MCSF receptor (CD115) as a target of sialylation by extracellular ST6GAL1 and show that sialylation diminishes MCSF signaling in the murine monocyte/macrophage cell line RAW 264.7. We show that extrinsic sialylation of primary monocytes inhibits their maturation into macrophages ex vivo, and that this results in diminished overall ability to respond to the inflammatory stimulant LPS. Furthermore, we show that sialylation of mature bone marrow derived macrophages does not influence the response to LPS. In chapter 3 we summarize the findings relating to the immune response in this thesis, and attempt to fit this into the overall view of ST6GAL1 and immunity. We discuss the influence of ST6GAL1 on myelopoiesis, the production and survival of B cells, and how this may impact the overall health of an organism. We review the sources of ST6GAL1 and sialic acids needed to facilitate the enzymatic addition of α2,6 linked sialic acids. We also provide evidence of ST6GAL1 involvement in disease states, especially cancer. Finally, we offer overall future directions and outstanding questions that may lead to the development of recombinant ST6GAL1, or the blocking of ST6GAL1 activity as potential therapies for disease states.","**To request an accessible version of the file(s) associated with this item, contact library@buffalo.edu. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.**"]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["ST6GAL1 from the Blood to the Gut: Influence on Myelopoiesis and Gastrointestinal Radiation Sensitivity"]}]}],"canonical_facts":{"dc:contributor":["Lau, Joseph","Roswell Park"],"dc:creator":["Punch, Patrick; 0000-0002-2662-6285"],"dc:date":["2025-02-21T21:36:20Z","2020"],"dc:description":["Ph.D.","The importance of protein glycosylation is becoming difficult to ignore, especially when studying how immune cells interact with their environment. An especially important glycan, built primarily by the sialyltransferase ST6GAL1, is α2,6-linked sialic acid occurring on N-linked glycan chains of cell surface and secreted proteins. α2,6-linked sialic acids have been shown to mediate numerous cellular events, from controlling hematopoiesis and inflammatory cell interactions, to influencing a cell's response to apoptotic signaling. Here we report novel roles for α2,6 sialylation: In mitigating death of gastrointestinal epithelial cells in response to high-dose total body irradiation and in preventing the maturation of monocytes into macrophages. Chapter 1 builds upon previous observations that, in vitro, several colon cancer cell lines exhibit increased radiation-induced apoptosis when ST6GAL1 is underexpressed, and that ST6GAL1 overexpression decreases radiation-induced apoptosis. Using an St6gal1-KO mouse model, we show that a lack of functional ST6GAL1 in vivo drastically increases the mouse's sensitivity to total body ionizing radiation, resulting in death that cannot be mitigated by bone marrow transplantation as it can in wild-type counterparts. Using various gross and histological observation methods, we observe that these St6gal1-KO mice experience severe damage to the gastrointestinal epithelium upon radiation exposure, resulting in a near-complete lack of functional GI crypt stem cells which are necessary to rebuild the epithelium after injury. Attempted rescue through inhibition of various cell death pathways, or the addition of recombinant ST6GAL1 back into St6gal1 KO animals was unable to rescue these mice. Finally, we speculate how future work could elucidate the exact mechanism at play in this phenotype, and how ST6GAL1 could be developed into a potential medical counter measure given directly after acute radiation exposure. In chapter 2 we identify a role for extrinsic sialylation of monocytes by ST6GAL1 in inhibiting their maturation into macrophages. We review the previously known roles of α2,6 linked sialylation, and glycosylation in general, in dictating myeloid cell development and function. We identify the MCSF receptor (CD115) as a target of sialylation by extracellular ST6GAL1 and show that sialylation diminishes MCSF signaling in the murine monocyte/macrophage cell line RAW 264.7. We show that extrinsic sialylation of primary monocytes inhibits their maturation into macrophages ex vivo, and that this results in diminished overall ability to respond to the inflammatory stimulant LPS. Furthermore, we show that sialylation of mature bone marrow derived macrophages does not influence the response to LPS. In chapter 3 we summarize the findings relating to the immune response in this thesis, and attempt to fit this into the overall view of ST6GAL1 and immunity. We discuss the influence of ST6GAL1 on myelopoiesis, the production and survival of B cells, and how this may impact the overall health of an organism. We review the sources of ST6GAL1 and sialic acids needed to facilitate the enzymatic addition of α2,6 linked sialic acids. We also provide evidence of ST6GAL1 involvement in disease states, especially cancer. Finally, we offer overall future directions and outstanding questions that may lead to the development of recombinant ST6GAL1, or the blocking of ST6GAL1 activity as potential therapies for disease states.","**To request an accessible version of the file(s) associated with this item, contact library@buffalo.edu. Please include the item's persistent URL [http://hdl.handle.net/. . .] in your request.**"],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/10477/86676"],"dc:language":["eng"],"dc:publisher":["State University of New York at Buffalo"],"dc:rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"dc:subject":["biology","immunology"],"dc:title":["ST6GAL1 from the Blood to the Gut: Influence on Myelopoiesis and Gastrointestinal Radiation Sensitivity"],"dc:type":["Text","Dissertation"]},"updated_at":"2026-07-27T19:05:34Z"}