SINGH, SHUBHNITA
(2024)
Title Page
Exploring the Influence of Progranulin on Vascular Contractility and Mitochondrial Homeostasis.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Cardiovascular diseases (CVDs) encompass a spectrum of conditions impacting the heart and blood vessels, attributing to around 19.1 million global deaths in 2020. These diseases can be congenital, acquired, or have a hereditary basis. Vascular smooth muscle cells (VSMCs) are crucial in maintaining vessel structure, diameter regulation, and vascular calcification—central processes in CVDs. Progranulin (PGRN), a glycoprotein, plays diverse roles in various tissues and cell types, involving embryogenesis, inflammation, wound healing, neurodegeneration, and lysosomal function. Mutations in the granulin (GRN) gene causing PGRN protein insufficiency lead to neurodegeneration. Our research reveals the significance of PGRN in protecting against CVDs.
Analyzing aorta from PGRN-deficient mice, we discovered reduced aortic contractility, unveiling a new facet of PGRN’s function. RNA sequencing showed suppressed oxidative phosphorylation (OXPHOS) in aortae from PGRN knockout mice, notably downregulating genes related to complex I activity in the electron transport chain pathways.
PGRN's functions span cell growth, embryogenesis, anti-inflammatory responses, and wound healing. We propose studying the molecular mechanisms behind mutant PGRN, potentially driving cardiovascular defects. Primary VSMCs from PGRN knockout mice exhibited perturbed contraction, reduced oxygen consumption rate (OCR), and impaired mitophagy, paralleled by lower ATP levels and increased mitochondrial oxidative stress due to PGRN deficiency.
Increasing PGRN expression through a viral vector significantly improved vascular contractility, OCR, mitochondrial complex I activity, and reduced oxidative stress. PGRN deficiency disrupted lysosomal function within VSMCs, affecting mitophagy. In a model with chronic Angiotensin II treatment, PGRN-deficient mice displayed unresponsiveness in hypercontractility and increased collagen deposition.
Our research underscores PGRN's crucial role in maintaining vascular contractility by regulating mitochondrial function. With the need for novel CVD therapies, these findings are significant. PGRN's influence on mitochondrial complex I quality, mitochondria recycling, and redox signaling pathways suggest its potential as a therapeutic target for CVDs, positioning PGRN as a promising alternative in treatment strategies.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
2 January 2024 |
| Date Type: |
Publication |
| Defense Date: |
9 November 2023 |
| Approval Date: |
2 January 2024 |
| Submission Date: |
2 December 2023 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
104 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Human Genetics |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
human genetics, progranulin, vascular contraction, mitochondria |
| Date Deposited: |
02 Jan 2024 22:10 |
| Last Modified: |
02 Jan 2024 22:10 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/45594 |
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