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Regulation of RNA expression in nephron progenitor cells

Clugston, Andrew S. (2021) Regulation of RNA expression in nephron progenitor cells. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

To function, the mammalian kidney is dependent on its endowment of nephrons: the cellular structures within which filtration of waste as well as reabsorption of water, proteins, and important solutes take place. In mammals, these nephrons originate entirely during development and are never replaced, making an individual’s nephron endowment at birth of critical importance for a long and healthy life. A low nephron endowment increases risk of hypertension, cardiovascular disease, and chronic kidney disease. Genetic abnormalities that affect the kidney are among the most common developmental defects observed, and hypoplastic kidneys (those with an abnormally low nephron endowment) are estimated to occur in 2% of all births. The causes of these conditions are varied as kidney development is a complex process that hinges on dynamic feedback mechanisms between over 20 cell types, but key among the cell types influencing nephron endowment are the nephron progenitor cells. Nephron progenitors are multipotent cells that differentiate into nephrons, but they also self-renew to maintain their population long enough to build a full complement of nephrons They also propagate feedback mechanisms which shape the kidney, and they respond dynamically to the continually changing structure of the kidney by modulating their rates of self-renewal and differentiation to meet its needs based on signals from one another and from their surrounding cells. Over the course of nephrogenesis, nephron progenitors become increasingly likely to differentiate, which gradually decreases their rate of renewal until their population is ultimately depleted in a wave of differentiation, brought on in part by expression of miRNA in the let-7 family. Understanding the genetics of nephron endowment requires understanding the dynamics of the progenitor population, which we sought to do by identifying miRNA expressed in nephron progenitors, then measuring how their expression changes over time. In parallel, we also measured changes in chromatin accessibility that implicated regulatory features that may drive some of these changes. Finally, we measured heterogeneous gene expression of the progenitor population using single-cell RNA-seq, and observed parallels between the changes that define progenitors of different ages and progenitors of different predilections for self-renewal versus differentiation.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Clugston, Andrew S.anc174@pitt.eduanc1740000-0002-8521-9452
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairHukriede, Neilhukriede@pitt.eduHUKRIEDE0000-0002-9655-9030
Committee MemberChikina, MariaMCHIKINA@pitt.eduMCHIKINA0000-0003-2550-5403
Committee MemberButterworth, Michaelmichael7@pitt.eduMICHAEL70000-0002-2173-8333
Committee MemberBenos, Takisbenos@pitt.edu0000-0003-3172-3132
Thesis AdvisorHo, Jacquelinejacqueline.ho2@chp.edu0000-0002-7944-416X
Thesis AdvisorKostka, Denniskostka@pitt.edu0000-0002-1460-5487
Date: 31 January 2021
Date Type: Publication
Defense Date: 25 September 2020
Approval Date: 31 January 2021
Submission Date: 29 October 2020
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 190
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Integrative Systems Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Chromatin accessibility, nephrogenesis, microRNA, Enhancer, Development,
Date Deposited: 31 Jan 2021 20:55
Last Modified: 31 Jan 2021 20:55
URI: http://d-scholarship.pitt.edu/id/eprint/39825

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