Glorioso, Christin Ann
(2010)
Between destiny and disease: genetics and molecular pathways of CNS aging.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Human brain aging is associated with robust "normal" functional, structural, and molecular changes that underlie changes in cognition, memory, mood and motor function, amongst other processes. Normal aging is also a requirement for onset of many neurological diseases, ranging from later onset neurodegenerative diseases such as Alzheimer's(AD) and Parkinson's diseases(PD), to earlier onset psychiatric disorders such as bipolar disorder(BPD) and schizophrenia(SCHZ). Understanding the molecular mechanisms and genetic underpinnings of normal age-related brain changes would have profound consequences for prevention and treatment of age-related impairments and disease. Here I introduce current knowledge of these functional changes, their structural and molecular underpinnings, their genetic modulators, and the contribution of normal aging to age-related neurological disease. I then present my contribution to this field in the form of three papers on genetic modulation of mammalian brain molecular aging. These studies demonstrate and investigate mechanisms underlying the causal modulation of molecular brain aging rates by Brain Derived Neurotrophic Factor (BDNF) and Serotonin (5-HT) in knock-out (KO) mice, and associative modulation by the putative longevity gene, Sirtuin 5, in humans (novel low-expressing promoter polymorphism (Sirt5prom2)). In humans we additionally investigate the potential mechanism(s) underlying neurological disease gating by normal aging, providing supporting evidence for molecular aging being a genetically controlled "transcriptional program" that progressively promotes age-regulated neurological diseases. In the discussion, I place these studies in a broader context within the field, detailing their implications and future directions.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
20 April 2010 |
| Date Type: |
Completion |
| Defense Date: |
17 March 2010 |
| Approval Date: |
20 April 2010 |
| Submission Date: |
1 April 2010 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Neurobiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
bdnf; biosignature; brain aging; human; microarray; Parkinson's disease; serotonin; sirtuin |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-04012010-142303/, etd-04012010-142303 |
| Date Deposited: |
10 Nov 2011 19:33 |
| Last Modified: |
15 Nov 2016 13:38 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/6691 |
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