자료유형  

 학위논문

Control Number  

0017164566

International Standard Book Number  

9798384046073

Dewey Decimal Classification Number  

574

Main Entry-Personal Name  

Redmond, Catherine J.

Publication, Distribution, etc. (Imprint  

[S.l.] : University of Michigan., 2024

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Physical Description  

245 p.

General Note  

Source: Dissertations Abstracts International, Volume: 86-03, Section: B.

General Note  

Advisor: Shah, Yatrik M.

Dissertation Note  

Thesis (Ph.D.)--University of Michigan, 2024.

Summary, Etc.  

요약Complex epithelia are essential barrier-forming tissues across the body characterized by their expression of cytoskeletal proteins called keratins. Keratins are an expansive family of intermediate filament (IF) forming proteins exhibiting diverse biochemical properties in addition to their highly conserved intermediate filament-forming domains. Keratins are expressed in all vertebrates, epithelia, and developmental timepoints; the expression of specific keratins and their post-translational modifications are tightly regulated in response to developmental stage, differentiation, stress, and disease. Complex epithelial barrier function is maintained throughout life despite constant damaging insults (dehydration, UV radiation, pathogens, etc.) by carefully balancing the proliferation and differentiation of keratin-expressing keratinocytes, the predominant cell type within complex epithelia. The balance between stem-like progenitor keratinocyte identity and function, keratinocyte terminal differentiation and keratinocyte shedding at the tissue surface describes the incompletely understood process of epithelial homeostasis. This thesis describes novel functions for keratin expression and post-translational modifications in the regulation of epithelial homeostasis. In Chapter 1, I review recent impactful research into the diverse contributions of intermediate filaments towards differentiation in numerous cell types and contexts in the body. In Chapter 2, we analyze the transgenic Krt14C373A/C373A mouse to uncover a differentiation-dependent signaling role for a disulfide-bonded form of basally expressed keratin 14 (K14) through the cooperation of the scaffolding protein 14-3-3σ and the transcriptional co-activator YAP1. In Chapter 3, we utilize publicly available single cell RNA-seq (scRNA-seq) datasets to revisit long-established principles of keratin expression domains and transcriptional regulation. Finally, in Chapter 4, we contextualize our K14 discoveries from Chapter 2 into the broader keratin filament network to uncover, for the first time, a role for the additional basally expressed keratin 15 (K15) in the counteraction of the pro-differentiation role of K14 and the promotion of a stem-like progenitor cell identity. In the final Discussion, I put these discoveries into the context of the field of epithelial homeostasis and provide Future Directions to follow up on several key unanswered questions from this thesis. Keratin expression patterning has long been considered simply a consequence of the homeostatic differentiation program. This thesis expands our understanding of the direct contributions of keratin proteins towards the regulation of keratinocyte progenitor identity, terminal differentiation, and ultimately epithelial homeostasis. A greater understanding of epithelial homeostasis from the perspective of keratin proteins can help inform the pathophysiology of numerous diseases induced by a failure of homeostasis, including psoriasis, atopic dermatitis, and squamous cell carcinomas throughout the body.

Subject Added Entry-Topical Term  

Cellular biology.

Subject Added Entry-Topical Term  

Pathology.

Subject Added Entry-Topical Term  

Molecular biology.

Subject Added Entry-Topical Term  

Biochemistry.

Index Term-Uncontrolled  

Keratin

Index Term-Uncontrolled  

Differentiation

Index Term-Uncontrolled  

Epithelia

Index Term-Uncontrolled  

Transcriptional regulation

Index Term-Uncontrolled  

Pathophysiology

Added Entry-Corporate Name  

University of Michigan Cancer Biology

Host Item Entry  

Dissertations Abstracts International. 86-03B.

Electronic Location and Access  

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Control Number  

joongbu:656725