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Sweet Dissertation v4.pdf (113.54 MB)

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Kruppel-Like Factor 2 Regulation of Aging and Healthspan: A Link Between the 3D Nucleome and Disease

Sweet, David Ryan
http://rave.ohiolink.edu/etdc/view?acc_num=case1619459260412975

Abstract Details

2021, Doctor of Philosophy, Case Western Reserve University, Pathology.
As modern medicine expands its reach, the downstream effects of successful medical intervention become realized. As many populations are beginning to experience an extension of healthy aging due to these interventions, there is increasingly greater understanding of diseases that preferentially impact aging individuals. At the heart all of these conditions are sustained or repetitive inflammation. While the cellular players in aging have been identified, molecular mechanisms regulating progression to disease remain to be discovered. Here, I describe insights into transcriptional regulators of inflammation that are implicated in aging and age-associated disease (AAD). Specifically, I explore the interplay between members of the Kruppel-like factor (KLF) family of transcription factors in the hemovascular system (i.e. endothelial and myeloid cells). First, I describe how two of these factors, KLF2 and KLF4, have evolved together in order to protect higher order organisms from aberrant activation of hemovascular cells. I then expand on the downstream consequences of this co-evolution in endothelial cells (ECs) by identifying novel mechanisms of long-range gene regulatory networks. Next, I make the case that inflammation resulting from KLF deletion is not all created equal. I demonstrate that although loss of KLF2 expression in myeloid cells worsens thrombotic disease, its downregulation may be critical for the vascular remodeling that occurs as a result. Long-term loss of KLF2 expression is nearly always detrimental as is discussed in chapters exploring the role of KLF2 in regulating metabolic disease and AADs. Outside of specific disease, KLF2 loss can also drive intrinsic aging processes which I describe in the context of a novel model for immunometabolic regulation of aging. Finally, I attempt to make the case that the diverse and robust phenotypes that occur due to loss of myeloid KLF2 are, in part, due to previously unappreciated genome-wide regulatory mechanisms. In particular, KLF2 maintains chromatin architecture critical for maintaining macrophage quiescence. Broadly, this work explores the fascinating world of inflammatory biology through the lens of KLF-driven transcriptional networks and how finding the delicate balance of immune and vascular cell activation may prove to be a viable option for targeting aging and AADs.
Parameswaran Ramakrishnan, PhD (Committee Chair)
Mukesh Jain, MD (Advisor)
George Dubyak, PhD (Committee Member)
Aaron Proweller, MD, PhD (Committee Member)
Andrew Pieper, MD, PhD (Committee Member)
Clive Hamlin, PhD (Committee Member)
340 p.
Biomedical Research; Cellular Biology; Genetics; Health Sciences; Immunology; Medicine; Molecular Biology; Pathology; Physiology
aging; macrophage; transcription; inflammation; genome; metabolism; obesity; endothelial; myeloid

Recommended Citations

Citations

  • Sweet, D. R. (2021). Kruppel-Like Factor 2 Regulation of Aging and Healthspan: A Link Between the 3D Nucleome and Disease [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1619459260412975

    APA Style (7th edition)

  • Sweet, David. Kruppel-Like Factor 2 Regulation of Aging and Healthspan: A Link Between the 3D Nucleome and Disease. 2021. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1619459260412975.

    MLA Style (8th edition)

  • Sweet, David. "Kruppel-Like Factor 2 Regulation of Aging and Healthspan: A Link Between the 3D Nucleome and Disease." Doctoral dissertation, Case Western Reserve University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1619459260412975

    Chicago Manual of Style (17th edition)

case1619459260412975
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© 2021, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.