Date of Award

1-1-2014

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Nanoscale Science and Engineering

Program

Nanoscale Sciences

Content Description

1 online resource (xii, 124 pages) : illustrations (some color)

Dissertation/Thesis Chair

Juan A. Melendez

Committee Members

David Jourd'heuil, Thomas Begley, Nathaniel Cady, Yubing Xie

Keywords

Aging, Calpain, Inflammation, Interleukin, Senescence, Cells, Interleukin-1, Oxidizing agents, Carcinogenesis, Ultrastructure (Biology), Calcium, Oxidation-reduction reaction

Subject Categories

Biochemistry | Cell Biology | Molecular Biology

Abstract

The accumulation of senescent cells during the process of aging has been implicated as causal in numerous age-related pathologies. Senescent cells adopt a secretory phenotype consisting of many factors including matrix remodeling enzymes, growth factors, cytokines, and chemokines. Their secretory nature is the primary reason that they are associated with disease, but it remains unclear why they become so inflammatory. Using primary human fibroblasts cultured to senescence, we mechanistically determined why senescent cells are such potent inducers of inflammation. Our findings indicate that the early production of the cytokine Interleukin 1-α (IL-1α) is central to this transition. We found that alterations in redox-state and Ca2+ homeostasis synergistically modulate IL-1α function through enhanced expression and subsequent activation. The coupling of these processes promotes downstream IL-1α signaling that converges on the enhanced expression of other secreted factors associated with age-associated disease. Connecting how these molecular events in senescent cells impacted neighboring cancer cell behavior demonstrated the physiological relevance of these findings. The factors secreted by senescent cells caused a transition to the more mobile, mesenchymal phenotype increasing their ability to metastasize. Overall, due to the high-level expression, processing, and function of the cytokine IL-1α, senescent cells secrete several inflammatory mediators that create an environment that promotes the invasive properties of epithelial cancer cells. Finally, using carefully designed particles for drug delivery, we exploit the unique secretory phenotype of senescent cells in order to selectively target their microenvironment. Our data demonstrate the feasibility of this approach, showing that senescent cells cause the selective breakdown of our drug delivery vehicle, and causing payload release locally. In summary, these findings provide molecular insight into the critical signaling events in senescent cells that underscore their ability to induce metastasis in neighboring pre-malignant cells. We used this information for the rational design of particles capable of sensing the senescent microenvironment as a potential method to enhance local drug delivery for the treatment of age-associated disease.

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