자료유형  

 학위논문

Control Number  

0016932016

International Standard Book Number  

9798379712839

Dewey Decimal Classification Number  

575

Main Entry-Personal Name  

Villanueva, Jonathan William.

Publication, Distribution, etc. (Imprint  

[S.l.] : Cornell University., 2023

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2023

Physical Description  

1 online resource(198 p.)

General Note  

Source: Dissertations Abstracts International, Volume: 84-12, Section: B.

General Note  

Advisor: Sethupathy, Praveen.

Dissertation Note  

Thesis (Ph.D.)--Cornell University, 2023.

Restrictions on Access Note  

This item must not be sold to any third party vendors.

Summary, Etc.  

요약Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related death worldwide. Somatic mutations promote molecular variation across patients, or inter-tumor heterogeneity, that drives variable patient outcomes. Combinations of mutations can produce novel phenotypes and variability in the efficacy of different therapeutics. However, little is known about how different combinations of mutations affect gene regulatory mechanisms. In this dissertation, I leverage genetically modified organoid models of CRC to investigate how different combinations of CRC driver mutations affect miRNA profiles and transcriptional networks. In Chapter 2, I define mutation-specific patterns of miRNA expression across genetically modified mouse enteroid models. I show that miR-24-3p is aberrantly elevated in mouse enteroid and human colon tumor samples regardless of mutational context. Furthermore, I reveal that genes downregulated in various mutated mouse enteroids, and primary colon tumors are enriched for predicted miR-24-3p target genes. I demonstrate that inhibition of miR-24-3p decreases cell survival in HCT116 and WT mouse enteroids by increasing apoptosis. Predicted targets upregulated in response to miR-24-3p reduction are enriched for regulators of apoptosis. I highlight two post-transcriptionally regulated targets of miR-24-3p (HMOX1, PRSS8), the downregulation of which may contribute to the oncogenic function of miR-24-3p. Chapter 3 expands on my previous work by characterizing genotype-specific miRNA profiles and transcriptional regulatory element (TRE) activity in genetically modified human colonoid models. I highlight a group of miRNAs that are uniquely downregulated in APC/KRAS/TP53 mutant (AKP-mutant) colonoids. MiR-10a-5p and miR-34a-5p are two notable tumor suppressor miRNAs that are affiliated with this group. I demonstrate that most changes in AKP-mutant miRNA expression profiles are concordant with alterations in miRNA transcription. MiR-10a-5p is a notable exception to this trend, suggesting that it is primarily post-transcriptionally regulated in the AKP-mutant context. Additionally, I show that TREs upregulated in AKP-mutant colonoids are enriched for multiple oncogenic transcription factor (TFs) binding sites (HIF-2α, LRF, SP2). Interestingly, these TFs harbor predicted miRNA binding sites for miR-10a-5p and/or miR-34a-5p. Together, my dissertation provides novel insight into how combinations of somatic mutations may promote inter-tumor heterogeneity. Furthermore, I highlight candidate therapeutic targets for the advancement of precision medicine.

Subject Added Entry-Topical Term  

Genetics.

Subject Added Entry-Topical Term  

Bioinformatics.

Subject Added Entry-Topical Term  

Molecular biology.

Index Term-Uncontrolled  

Colorectal cancer

Index Term-Uncontrolled  

Gene regulation

Index Term-Uncontrolled  

MicroRNA

Index Term-Uncontrolled  

Mutation

Index Term-Uncontrolled  

Organoid

Index Term-Uncontrolled  

Transcription

Added Entry-Corporate Name  

Cornell University Biomedical and Biological Sciences

Host Item Entry  

Dissertations Abstracts International. 84-12B.

Host Item Entry  

Dissertation Abstract International

Electronic Location and Access  

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Control Number  

joongbu:643448