國立虎尾科技大學 |

Aging, Aniridia, and Injury : = Transcriptomic Perspectives on the Molecular Pathology of the Ocular Lens.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	Aging, Aniridia, and Injury :/
Reminder of title:	Transcriptomic Perspectives on the Molecular Pathology of the Ocular Lens.
Author:	Faranda, Adam P.
Description:	1 online resource (440 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 85-03, Section: B.
Contained By:	Dissertations Abstracts International85-03B.
Subject:	Bioinformatics. -
Online resource:	click for full text (PQDT)
ISBN:	9798380376525

Aging, Aniridia, and Injury : = Transcriptomic Perspectives on the Molecular Pathology of the Ocular Lens.
Faranda, Adam P.

Aging, Aniridia, and Injury :Transcriptomic Perspectives on the Molecular Pathology of the Ocular Lens. - 1 online resource (440 pages)

Source: Dissertations Abstracts International, Volume: 85-03, Section: B.

Thesis (Ph.D.)--University of Delaware, 2023.

Includes bibliographical references

By helping to focus incoming light, the lens of the eye has an essential role in the vertebrate visual system. Consisting of two basic cell types, the lens has a simple yet sophisticated internal architecture and biochemistry. The growth of the mammalian lens continues indefinitely over a lifetime as new cell layers accumulate over older ones in a precise pattern of cell packing, via a differentiation process that culminates with near-total elimination of cellular organelles. Without the ability to construct new cellular components, cellular integrity in deeper layers can become compromised over time if cumulative insults exceed the capacity of the protective mechanisms maintained by the outermost metabolically active cells. Disruption of lens cell differentiation or failure of these protective mechanisms can lead to protein insolubility, damage to cell membranes, morphological defects or disorganization of cellular packing that produces opacities or refractive aberrations. The accumulation of opacified lens tissue results in a cataract, a partial or complete opacification of the lens. While genetic factors and exposure to various environmental hazards can directly induce lens opacities or increase one's risk, one of the most important risk factors for cataract is aging.Aging is a complex biological process associated with physiological deterioration that involves transcriptome-wide changes in gene expression. RNA Sequencing (RNA-Seq) is an established technology for profiling transcriptomic shifts related to aging and other drivers of cataract formation. In Chapter 3, I address the impact of unique lens cell characteristics, such as the small size of the lens epithelial cell population, and the presence of partially degraded RNA in lens fiber cells, on RNA-Sequencing data generation and analysis. Chapter 3 explores an approach for incorporating various bioinformatic tools into a cohesive pipeline, evaluates the performance of these tools on several lens data sets, and shows how variation in RNA integrity may introduce certain unavoidable biases. The pipeline described in this chapter was subsequently used to investigate the consequences of aging on the mouse lens, and the impact of aging on the response of lens cells to cataract surgery.The micro-surgical restoration of vision in cataract patients is nothing short of a medical miracle, however a small but significant fraction of patients develop posterior capsular opacification (PCO), a vision compromising sequelae of cataract surgery requiring surgical follow up. Inflammatory signaling and fibrotic cell-transformation have a central role in driving the development of PCO in cataract patients. These pathways are attractive therapeutic targets for PCO prevention and can themselves lead to cataract formation. The mouse lens-aging study documented in Chapter 4 was originally motivated by a comment from a fellow lens biologist that young mice are prone to inflammation, and the inflammatory lens-injury response we observe in mice less than 5 months old may not occur in older mice or older humans for that matter. Not only did this study categorically demonstrate that the lens in geriatric mice is equally susceptible to injury dependent inflammation, it also revealed age-dependent increases in basal expression of certain inflammatory markers. These and other transcriptomic shifts observed in the aging mouse lens affecting oxidative stress response genes, and key regulators of fiber cell differentiation, may have important roles in age related cataract.The intent of Chapter 5 was to advance our knowledge of the aging biology of the lens from mice to humans. While there are acknowledged limitations of this study's design, it was possible to identify age dependent changes in human-lens gene expression affecting genes that are likely relevant to cataract formation, for example we observe upregulation of the transcription factor KLF4 in aging humans, and its murine homolog Klf4 in aging mice. Klf4 regulates lens maturation in mice, and single nucleotide polymorphism (SNP) mutations at the KLF4 locus are associated with age-related cataract in humans.While most people maintain lens clarity beyond their 50's, genetic abnormalities can dramatically accelerate the process, one example being PAX6 haploinsufficiency. A keystone in the process of embryonic eye and lens development, the transcription factor PAX6 continues to have a vital role in the lifelong maintenance of lens homeostasis. With only a single functional copy of PAX6, haploinsufficient individuals develop a pan-ocular syndrome known as aniridia. Juvenile cataract is one of several of the sequelae of aniridia that compromise vision, and frequently occurs at ages as young as 1 to 3 years old. To address a significant knowledge gap in the molecular etiology of aniridic cataract, Chapter 6 examines the impact of Pax6 haploinsufficiency on the mouse lens transcriptome. This analysis identified profound changes in gene expression that imply a radical disruption of the normal fiber cell differentiation process, which may be responsible for the visible lens defects we observe, and lead to the activation of inflammatory and fibrotic markers. My analysis shows that PAX6 haploinsufficiency leads to transcriptomic changes in the lens that normally characterize the response of wildtype lens cells to injury. These findings, which include an inflammatory response, support the hypothesis that PAX6 haploinsufficient lenses persist in a chronically wounded state. Throughout this work, inflammation appears to be a common thread that unifies the lens pathology associated with aging, injury and aniridia.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798380376525Subjects--Topical Terms:

583857
Bioinformatics.
Subjects--Index Terms:

InflammationIndex Terms--Genre/Form:

554714
Electronic books.

Aging, Aniridia, and Injury : = Transcriptomic Perspectives on the Molecular Pathology of the Ocular Lens.
LDR:07083ntm a22003977 4500 001 1147653
005 20240916065428.5
006 m o d
007 cr bn ---uuuuu
008 250605s2023 xx obm 000 0 eng d
020 $a 9798380376525
035 $a (MiAaPQ)AAI30571851
035 $a AAI30571851
040 $a MiAaPQ $b eng $c MiAaPQ $d NTU
100 1 $a Faranda, Adam P. $3 1473420
245 1 0 $a Aging, Aniridia, and Injury : $b Transcriptomic Perspectives on the Molecular Pathology of the Ocular Lens.
264 0 $c 2023
300 $a 1 online resource (440 pages)
336 $a text $b txt $2 rdacontent
337 $a computer $b c $2 rdamedia
338 $a online resource $b cr $2 rdacarrier
500 $a Source: Dissertations Abstracts International, Volume: 85-03, Section: B.
500 $a Advisor: Duncan, Melinda K.
502 $a Thesis (Ph.D.)--University of Delaware, 2023.
504 $a Includes bibliographical references
520 $a By helping to focus incoming light, the lens of the eye has an essential role in the vertebrate visual system. Consisting of two basic cell types, the lens has a simple yet sophisticated internal architecture and biochemistry. The growth of the mammalian lens continues indefinitely over a lifetime as new cell layers accumulate over older ones in a precise pattern of cell packing, via a differentiation process that culminates with near-total elimination of cellular organelles. Without the ability to construct new cellular components, cellular integrity in deeper layers can become compromised over time if cumulative insults exceed the capacity of the protective mechanisms maintained by the outermost metabolically active cells. Disruption of lens cell differentiation or failure of these protective mechanisms can lead to protein insolubility, damage to cell membranes, morphological defects or disorganization of cellular packing that produces opacities or refractive aberrations. The accumulation of opacified lens tissue results in a cataract, a partial or complete opacification of the lens. While genetic factors and exposure to various environmental hazards can directly induce lens opacities or increase one's risk, one of the most important risk factors for cataract is aging.Aging is a complex biological process associated with physiological deterioration that involves transcriptome-wide changes in gene expression. RNA Sequencing (RNA-Seq) is an established technology for profiling transcriptomic shifts related to aging and other drivers of cataract formation. In Chapter 3, I address the impact of unique lens cell characteristics, such as the small size of the lens epithelial cell population, and the presence of partially degraded RNA in lens fiber cells, on RNA-Sequencing data generation and analysis. Chapter 3 explores an approach for incorporating various bioinformatic tools into a cohesive pipeline, evaluates the performance of these tools on several lens data sets, and shows how variation in RNA integrity may introduce certain unavoidable biases. The pipeline described in this chapter was subsequently used to investigate the consequences of aging on the mouse lens, and the impact of aging on the response of lens cells to cataract surgery.The micro-surgical restoration of vision in cataract patients is nothing short of a medical miracle, however a small but significant fraction of patients develop posterior capsular opacification (PCO), a vision compromising sequelae of cataract surgery requiring surgical follow up. Inflammatory signaling and fibrotic cell-transformation have a central role in driving the development of PCO in cataract patients. These pathways are attractive therapeutic targets for PCO prevention and can themselves lead to cataract formation. The mouse lens-aging study documented in Chapter 4 was originally motivated by a comment from a fellow lens biologist that young mice are prone to inflammation, and the inflammatory lens-injury response we observe in mice less than 5 months old may not occur in older mice or older humans for that matter. Not only did this study categorically demonstrate that the lens in geriatric mice is equally susceptible to injury dependent inflammation, it also revealed age-dependent increases in basal expression of certain inflammatory markers. These and other transcriptomic shifts observed in the aging mouse lens affecting oxidative stress response genes, and key regulators of fiber cell differentiation, may have important roles in age related cataract.The intent of Chapter 5 was to advance our knowledge of the aging biology of the lens from mice to humans. While there are acknowledged limitations of this study's design, it was possible to identify age dependent changes in human-lens gene expression affecting genes that are likely relevant to cataract formation, for example we observe upregulation of the transcription factor KLF4 in aging humans, and its murine homolog Klf4 in aging mice. Klf4 regulates lens maturation in mice, and single nucleotide polymorphism (SNP) mutations at the KLF4 locus are associated with age-related cataract in humans.While most people maintain lens clarity beyond their 50's, genetic abnormalities can dramatically accelerate the process, one example being PAX6 haploinsufficiency. A keystone in the process of embryonic eye and lens development, the transcription factor PAX6 continues to have a vital role in the lifelong maintenance of lens homeostasis. With only a single functional copy of PAX6, haploinsufficient individuals develop a pan-ocular syndrome known as aniridia. Juvenile cataract is one of several of the sequelae of aniridia that compromise vision, and frequently occurs at ages as young as 1 to 3 years old. To address a significant knowledge gap in the molecular etiology of aniridic cataract, Chapter 6 examines the impact of Pax6 haploinsufficiency on the mouse lens transcriptome. This analysis identified profound changes in gene expression that imply a radical disruption of the normal fiber cell differentiation process, which may be responsible for the visible lens defects we observe, and lead to the activation of inflammatory and fibrotic markers. My analysis shows that PAX6 haploinsufficiency leads to transcriptomic changes in the lens that normally characterize the response of wildtype lens cells to injury. These findings, which include an inflammatory response, support the hypothesis that PAX6 haploinsufficient lenses persist in a chronically wounded state. Throughout this work, inflammation appears to be a common thread that unifies the lens pathology associated with aging, injury and aniridia.
533 $a Electronic reproduction. $b Ann Arbor, Mich. : $c ProQuest, $d 2024
538 $a Mode of access: World Wide Web
650 4 $a Bioinformatics. $3 583857
650 4 $a Biology. $3 599573
650 4 $a Aging. $3 559847
653 $a Inflammation
653 $a Lens
653 $a Transcriptomics
653 $a Fibrotic markers
653 $a Genetic abnormalities
655 7 $a Electronic books. $2 local $3 554714
690 $a 0715
690 $a 0306
690 $a 0493
710 2 $a ProQuest Information and Learning Co. $3 1178819
710 2 $a University of Delaware. $b Bioinformatics and Systems Biology. $3 1437838
773 0 $t Dissertations Abstracts International $g 85-03B.
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30571851 $z click for full text (PQDT)