| dc.identifier.uri | http://hdl.handle.net/11401/78125 | |
| dc.description.sponsorship | This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree | en_US |
| dc.format | Monograph | |
| dc.format.medium | Electronic Resource | en_US |
| dc.language.iso | en_US | |
| dc.type | Dissertation | |
| dcterms.abstract | The lysosomal hydrolase acid ceramidase (AC) regulates the levels of bioactive sphingolipid metabolites ceramide and sphingosine. Bioactive sphingolipids have emerged as critical regulators of immune processes and their metabolism is often altered in inflammatory bowel disease (IBD). Ulcerative colitis (UC), one of the major forms of IBD, is characterized by chronic mucosal inflammation that affects the rectum and distal colon. Importantly, UC is associated with an increased risk for development of colorectal cancer, the second leading cause of cancer death in the United States. While UC is considered an idiopathic disorder, the current model suggest a multifactorial mechanism predisposed by genetics that involves damage to the intestinal epithelial barrier, elevated activation of mucosal immune cells, and alterations in the gut microbiome. The elevated incidence and prevalence of UC worldwide underscores the need to understand the mechanisms in play driving aberrant inflammatory pathways. Therefore, elucidating the sphingolipid enzymes and metabolic pathways involved in regulating inflammatory mechanisms in UC will provide critical insights into sphingolipid-mediated biology and their therapeutic potential. We demonstrate that in UC, the expression and activity of AC is elevated. We establish that pharmacological inhibition of AC in mice protects from dextran sulfate sodium (DSS)-induced colitis. Furthermore, using a myeloid tissue specific knock out (KO) mouse model, we define a novel role for AC in innate immunity and inflammation. We demonstrate that myeloid AC KO mice exhibit reduction of neutrophil infiltrate in the colon mucosa and decreased tissue injury and pathology associated with DSS-induced colitis. Mechanistically, we find that impairment of neutrophil recruitment results from reduced cytokine and chemokine production. Furthermore, KO of AC in myeloid cells prevents the expansion of tumor-associated myeloid derived suppressor cells (MDSC) and reduces the development of colitis-associated cancer. Collectively, this work demonstrates for the first time, a specific role for AC in regulating myeloid inflammation and provides evidence of novel mechanisms of neutrophil regulation with therapeutic potential in UC and colitis-associated cancer. | |
| dcterms.available | 2018-03-22T22:39:03Z | |
| dcterms.contributor | Obeid, Lina M. | en_US |
| dcterms.contributor | Bliska, James | en_US |
| dcterms.contributor | Del Poeta, Maurizio | en_US |
| dcterms.contributor | Sheridan, Brian | en_US |
| dcterms.contributor | Yang, Vincent, W. | en_US |
| dcterms.creator | Espaillat, Mel Pilar | |
| dcterms.dateAccepted | 2018-03-22T22:39:03Z | |
| dcterms.dateSubmitted | 2018-03-22T22:39:03Z | |
| dcterms.description | Department of Molecular Genetics and Microbiology. | en_US |
| dcterms.extent | 243 pg. | en_US |
| dcterms.format | Application/PDF | en_US |
| dcterms.format | Monograph | |
| dcterms.identifier | http://hdl.handle.net/11401/78125 | |
| dcterms.issued | 2017-08-01 | |
| dcterms.language | en_US | |
| dcterms.provenance | Made available in DSpace on 2018-03-22T22:39:03Z (GMT). No. of bitstreams: 1
Espaillat_grad.sunysb_0771E_11068.pdf: 154039448 bytes, checksum: 62e52e592d57b7ffeb2314f1ce28313a (MD5)
Previous issue date: 2017-08-01 | en |
| dcterms.subject | colorectal cancer | |
| dcterms.subject | Immunology -- Genetics. | |
| dcterms.subject | Immunity | |
| dcterms.subject | inflammation | |
| dcterms.subject | inflammatory bowel disease | |
| dcterms.subject | Neutrophils | |
| dcterms.subject | Sphingolipids | |
| dcterms.title | The Immunomodulatory Role of Acid Ceramidase in Ulcerative Colitis | |
| dcterms.type | Dissertation | |
