The OAKTrust Digital Repository
The OAKTrust digital repository at Texas A&M is a digital service that collects, preserves, and distributes the scholarly output of the University. The repository facilitates open access scholarly communication while preserving the scholarly legacy of the Texas A&M community.
Recent Submissions
mRNA-Encoded Anti-VapA Monoclonal IgG1 for Passive Immunization of Foals Against Rhodococcus equi
(2024-12) Legere, Rebecca Maria 1985-; Cohen, Noah; Berghman, Luc; Cannon, Carolyn; Criscitiello, Michael; Bordin, Angela
Pneumonia caused by Rhodococcus equi is an important cause of disease and death in newborn foals. Neonatal foals are most susceptible to infection because their naïve, immature immune responses fail to protect against inhaled R. equi, which is ubiquitous in their environment. Virulent R. equi strains express the virulence-associated protein A (VapA) that is necessary to cause disease in foals. Passive immunization with transfusion of hyperimmune plasma (REHIP) protects foals against R. equi pneumonia; potency is assessed by anti-VapA titers. REHIP transfusion, however, is expensive and risky for foals; REHIP products also vary markedly in anti-VapA activity. Monoclonal antibodies (mAbs) provide superior specificity and consistency, but costs and complexity limit feasibility. In vitro transcribed (IVT) mRNA encoding mAbs (mRNA-mAbs) enables safe, ondemand mAb production within the patient, including in the lungs following nebulized delivery of mRNA-mAbs. Thus, our objective was to generate IVT mRNA encoding an equine mAb of the IgG1 sub-isotype against VapA for intrapulmonary passive immunization of neonatal foals. The first chapter provides a literature review summarizing current knowledge of mRNA-mAb for passive immunization and its promise against rhodococcal pneumonia. The following chapters describe studies conducted to demonstrate proof-of-principle for aerosolized IVT mRNA expression in foals. First, we conducted a pilot study demonstrating safe expression of aerosolized IVT mRNA encoding a reporter protein in the guttural pouches and lungs of foals. Next, we investigated intrapulmonary expression of a functional mRNA-mAb. VapA-specific memory Bcells were isolated from a hyperimmunized adult horse and single-cell sequenced to identify an IgG1 mAb sequence. Expression of IVT mRNA encoding the mAb in equine lung cultures produced a mAb specific for virulent R. equi. A mRNA-mAb was then formulated in a polymer-based carrier and nebulized to 12 neonatal foals, resulting in safe, consistent mAb expression for up to 12 days. Expressed mAb within the lungs specifically recognized both VapA and virulent R. equi. This project represents the first mRNA-mAb developed for equine passive immunization and the first mRNA-mAb delivered to neonatal lungs in any species. This platform holds great translational potential for veterinary and human medical applications, especially for delivering near-immediate protection to neonatal airways via neutralizing antibodies.
The BAZ Family of Chromatin Remodelers in Colorectal Cancer: Insights into Oncogenesis, Alternative Splicing and Chemosensitization
(2024-05) Mohan, Nivedhitha; Dashwood, Roderick; Rajendran, Praveen; Reiner, David; Cheng, Chonghui
Colorectal cancer (CRC) poses a significant healthcare challenge worldwide, necessitating a deeper understanding of the molecular mechanisms underlying its pathogenesis for improved therapeutic interventions. This thesis investigates the BAZ (Bromodomain Adjacent to Zinc finger) family of chromatin remodelers and their intricate involvement in CRC. The BAZ family members, including BAZ1A, BAZ1B, BAZ2A, and BAZ2B, exert critical regulatory functions in chromatin architecture and transcription, impacting various cellular processes from development to disease.
In colorectal cancer, BAZ1A is overexpressed, and its depletion resulted in diminished cell viability, increased apoptosis, augmented DNA damage, and cellular senescence, concomitant with the downregulation of components within the Wnt/β-catenin signaling pathway. In vivo studies corroborated these findings, revealing that knockdown of BAZ1A leads to diminished tumor growth and alterations in chromatin regulation. Interestingly, BAZ1A undergoes alternative splicing, which is promoted by treatment with histone deacetylase inhibitors, thereby highlighting its therapeutic potential. Remarkably, the full-length form of BAZ1A is implicated in DNA repair mechanisms, while its alternatively spliced counterpart is susceptible to increased DNA damage and sensitivity to DNA-damaging agents. These observations underscored the oncogenic role of BAZ1A in colorectal cancer and the importance of considering an oncogene’s alternative splicing patterns.
Similar to BAZ1A, BAZ2A is also upregulated in CRC and associated with reduced patient survival. Functional studies demonstrated their roles in inhibiting cell viability, colony formation, and modulating Wnt/β-catenin signaling. Inhibition of BAZ2A led to reduced tumor growth rates in mouse models, where it also affected histone modification patterns, favoring a less repressive chromatin state, and influencing major histocompatibility complex (MHC) regulation.
In contrast to BAZ1A and BAZ2A, BAZ1B knockdown enhanced cell viability, colony formation, and altered cell cycle progression, suggesting a tumor-suppressive role in metastatic CRC. BAZ1B impacted c-MYC expression independently of the Wnt/β-catenin pathway, and influenced p53 and p21 levels, implicating its involvement in tumor suppressive pathways.
Overall, the study underscores the potential of BAZ family members as therapeutic targets in CRC. Future research should focus on elucidating their molecular mechanisms, translating findings into clinical applications, and exploring combination therapies to improve treatment outcomes for CRC patients, thus advancing more personalized therapeutic approaches for CRC.
The BAZ Family of Chromatin Remodelers in Colorectal Cancer: Insights into Oncogenesis, Alternative Splicing and Chemosensitization
(2024-05) Mohan, Nivedhitha; Dashwood, Roderick; Rajendran, Praveen; Reiner, David; Cheng, Chonghui
Colorectal cancer (CRC) poses a significant healthcare challenge worldwide, necessitating a deeper understanding of the molecular mechanisms underlying its pathogenesis for improved therapeutic interventions. This thesis investigates the BAZ (Bromodomain Adjacent to Zinc finger) family of chromatin remodelers and their intricate involvement in CRC. The BAZ family members, including BAZ1A, BAZ1B, BAZ2A, and BAZ2B, exert critical regulatory functions in chromatin architecture and transcription, impacting various cellular processes from development to disease.
In colorectal cancer, BAZ1A is overexpressed, and its depletion resulted in diminished cell viability, increased apoptosis, augmented DNA damage, and cellular senescence, concomitant with the downregulation of components within the Wnt/β-catenin signaling pathway. In vivo studies corroborated these findings, revealing that knockdown of BAZ1A leads to diminished tumor growth and alterations in chromatin regulation. Interestingly, BAZ1A undergoes alternative splicing, which is promoted by treatment with histone deacetylase inhibitors, thereby highlighting its therapeutic potential. Remarkably, the full-length form of BAZ1A is implicated in DNA repair mechanisms, while its alternatively spliced counterpart is susceptible to increased DNA damage and sensitivity to DNA-damaging agents. These observations underscored the oncogenic role of BAZ1A in colorectal cancer and the importance of considering an oncogene’s alternative splicing patterns.
Similar to BAZ1A, BAZ2A is also upregulated in CRC and associated with reduced patient survival. Functional studies demonstrated their roles in inhibiting cell viability, colony formation, and modulating Wnt/β-catenin signaling. Inhibition of BAZ2A led to reduced tumor growth rates in mouse models, where it also affected histone modification patterns, favoring a less repressive chromatin state, and influencing major histocompatibility complex (MHC) regulation.
In contrast to BAZ1A and BAZ2A, BAZ1B knockdown enhanced cell viability, colony formation, and altered cell cycle progression, suggesting a tumor-suppressive role in metastatic CRC. BAZ1B impacted c-MYC expression independently of the Wnt/β-catenin pathway, and influenced p53 and p21 levels, implicating its involvement in tumor suppressive pathways.
Overall, the study underscores the potential of BAZ family members as therapeutic targets in CRC. Future research should focus on elucidating their molecular mechanisms, translating findings into clinical applications, and exploring combination therapies to improve treatment outcomes for CRC patients, thus advancing more personalized therapeutic approaches for CRC.
The BAZ Family of Chromatin Remodelers in Colorectal Cancer: Insights into Oncogenesis, Alternative Splicing and Chemosensitization
(2024-05) Mohan, Nivedhitha; Dashwood, Roderick; Rajendran, Praveen; Reiner, David; Cheng, Chonghui
Colorectal cancer (CRC) poses a significant healthcare challenge worldwide, necessitating a deeper understanding of the molecular mechanisms underlying its pathogenesis for improved therapeutic interventions. This thesis investigates the BAZ (Bromodomain Adjacent to Zinc finger) family of chromatin remodelers and their intricate involvement in CRC. The BAZ family members, including BAZ1A, BAZ1B, BAZ2A, and BAZ2B, exert critical regulatory functions in chromatin architecture and transcription, impacting various cellular processes from development to disease.
In colorectal cancer, BAZ1A is overexpressed, and its depletion resulted in diminished cell viability, increased apoptosis, augmented DNA damage, and cellular senescence, concomitant with the downregulation of components within the Wnt/β-catenin signaling pathway. In vivo studies corroborated these findings, revealing that knockdown of BAZ1A leads to diminished tumor growth and alterations in chromatin regulation. Interestingly, BAZ1A undergoes alternative splicing, which is promoted by treatment with histone deacetylase inhibitors, thereby highlighting its therapeutic potential. Remarkably, the full-length form of BAZ1A is implicated in DNA repair mechanisms, while its alternatively spliced counterpart is susceptible to increased DNA damage and sensitivity to DNA-damaging agents. These observations underscored the oncogenic role of BAZ1A in colorectal cancer and the importance of considering an oncogene’s alternative splicing patterns.
Similar to BAZ1A, BAZ2A is also upregulated in CRC and associated with reduced patient survival. Functional studies demonstrated their roles in inhibiting cell viability, colony formation, and modulating Wnt/β-catenin signaling. Inhibition of BAZ2A led to reduced tumor growth rates in mouse models, where it also affected histone modification patterns, favoring a less repressive chromatin state, and influencing major histocompatibility complex (MHC) regulation.
In contrast to BAZ1A and BAZ2A, BAZ1B knockdown enhanced cell viability, colony formation, and altered cell cycle progression, suggesting a tumor-suppressive role in metastatic CRC. BAZ1B impacted c-MYC expression independently of the Wnt/β-catenin pathway, and influenced p53 and p21 levels, implicating its involvement in tumor suppressive pathways.
Overall, the study underscores the potential of BAZ family members as therapeutic targets in CRC. Future research should focus on elucidating their molecular mechanisms, translating findings into clinical applications, and exploring combination therapies to improve treatment outcomes for CRC patients, thus advancing more personalized therapeutic approaches for CRC.
The BAZ Family of Chromatin Remodelers in Colorectal Cancer: Insights into Oncogenesis, Alternative Splicing and Chemosensitization
(2024-05) Mohan, Nivedhitha; Dashwood, Roderick; Rajendran, Praveen; Reiner, David; Cheng, Chonghui
Colorectal cancer (CRC) poses a significant healthcare challenge worldwide, necessitating a deeper understanding of the molecular mechanisms underlying its pathogenesis for improved therapeutic interventions. This thesis investigates the BAZ (Bromodomain Adjacent to Zinc finger) family of chromatin remodelers and their intricate involvement in CRC. The BAZ family members, including BAZ1A, BAZ1B, BAZ2A, and BAZ2B, exert critical regulatory functions in chromatin architecture and transcription, impacting various cellular processes from development to disease.
In colorectal cancer, BAZ1A is overexpressed, and its depletion resulted in diminished cell viability, increased apoptosis, augmented DNA damage, and cellular senescence, concomitant with the downregulation of components within the Wnt/β-catenin signaling pathway. In vivo studies corroborated these findings, revealing that knockdown of BAZ1A leads to diminished tumor growth and alterations in chromatin regulation. Interestingly, BAZ1A undergoes alternative splicing, which is promoted by treatment with histone deacetylase inhibitors, thereby highlighting its therapeutic potential. Remarkably, the full-length form of BAZ1A is implicated in DNA repair mechanisms, while its alternatively spliced counterpart is susceptible to increased DNA damage and sensitivity to DNA-damaging agents. These observations underscored the oncogenic role of BAZ1A in colorectal cancer and the importance of considering an oncogene’s alternative splicing patterns.
Similar to BAZ1A, BAZ2A is also upregulated in CRC and associated with reduced patient survival. Functional studies demonstrated their roles in inhibiting cell viability, colony formation, and modulating Wnt/β-catenin signaling. Inhibition of BAZ2A led to reduced tumor growth rates in mouse models, where it also affected histone modification patterns, favoring a less repressive chromatin state, and influencing major histocompatibility complex (MHC) regulation.
In contrast to BAZ1A and BAZ2A, BAZ1B knockdown enhanced cell viability, colony formation, and altered cell cycle progression, suggesting a tumor-suppressive role in metastatic CRC. BAZ1B impacted c-MYC expression independently of the Wnt/β-catenin pathway, and influenced p53 and p21 levels, implicating its involvement in tumor suppressive pathways.
Overall, the study underscores the potential of BAZ family members as therapeutic targets in CRC. Future research should focus on elucidating their molecular mechanisms, translating findings into clinical applications, and exploring combination therapies to improve treatment outcomes for CRC patients, thus advancing more personalized therapeutic approaches for CRC.