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Full-Text Articles in Molecular Biology

Investigating The Dysregulation And Therapeutic Potential Of Neuroprotective Stress Response Proteins In Huntington’S Disease, Julianne M. Rieders Jan 2019

Investigating The Dysregulation And Therapeutic Potential Of Neuroprotective Stress Response Proteins In Huntington’S Disease, Julianne M. Rieders

Publicly Accessible Penn Dissertations

Huntington’s disease (HD) is a fatal, genetic neurodegenerative disease that shares many features with other common neurological disorders, including early synapse loss. In both human HD brain and murine models, apoptotic pathways are dysregulated and mammalian target of rapamycin complex 1 (mTORC1) activity is reduced. These pathways are of particular interest because they regulate cell survival and metabolism, and enhancing mTORC1 is protective in HD models. RNA binding motif protein 3 (RBM3) is a stress response protein that promotes synaptic plasticity and cell survival, and is dysregulated in Alzheimer, prion and HD models. Hippocampal overexpression of RBM3 in Alzheimer ...


The Role Of Molecular Motors In Peripheral Nerve Regeneration, Melissa D. Priest Jan 2018

The Role Of Molecular Motors In Peripheral Nerve Regeneration, Melissa D. Priest

Publicly Accessible Penn Dissertations

Following injury, axons of the peripheral nervous system have retained the capacity for regeneration. While it is well established that injury signals require molecular motors for their transport from the injury site to the nucleus, whether kinesin and dynein motors play additional roles in peripheral nerve regeneration is not well understood. Here we use genetic mutants of motor proteins in a zebrafish peripheral nerve regeneration model to visualize and define in vivo roles for kinesin and dynein. We find that both kinesin-1 and dynein are required for zebrafish peripheral nerve regeneration. While loss of kinesin-1 reduced the overall robustness of ...


Investigating Molecular Mechanisms Underlying Mild Phenotype In Friedreich Ataxia Patients With G130v Missense Mutation, Elisia Clark Jan 2018

Investigating Molecular Mechanisms Underlying Mild Phenotype In Friedreich Ataxia Patients With G130v Missense Mutation, Elisia Clark

Publicly Accessible Penn Dissertations

Friedreich’s Ataxia (FRDA) is an incurable neurodegenerative disease caused by mutations in the frataxin (FXN) gene, resulting in decreased expression of the mitochondrial protein FXN. 2-3% of FRDA patients carry a GAA expansion on one FXN allele, and a missense mutation on the other. The mechanism behind the disease‐causing features remains elusive. The phenotype associated with patients carrying point mutations cannot be predicted with certainty; these patients can have a mild or severe clinical outcome, creating a unique platform to understand clinical heterogeneity. FXN is important for proper mitochondrial function, and is involved in Fe-S cluster biogenesis, metabolism ...


Epigenetic Mechanisms Governing Behavioral Reprogramming In The Ant Camponotus Floridanus, Riley John Graham Jan 2018

Epigenetic Mechanisms Governing Behavioral Reprogramming In The Ant Camponotus Floridanus, Riley John Graham

Publicly Accessible Penn Dissertations

Eusocial insect colonies divide behaviors among specialist groups called castes. In some species, caste identity is determined by the interaction of endogenous (e.g. genomic) and exogenous (e.g. juvenile hormone from nurses) signals during larval development, suggesting epigenetic mechanisms underlie plastic traits tied to caste identity. Previous work demonstrated a link between patterns of histone H3 lysine 27 acetylation (H3K27ac) and caste-specific gene expression in Major and Minor workers of the ant Camponotus floridanus, and we hypothesized caste-specific behaviors such as foraging may be similarly regulated by histone acetylation. To test this hypothesis, we fed mature (~30d old) Majors ...


Sex Differences In Μ-Opioid Regulation Of The Rat Locus Coeruleus, Herminio Manuel Guajardo Jan 2017

Sex Differences In Μ-Opioid Regulation Of The Rat Locus Coeruleus, Herminio Manuel Guajardo

Publicly Accessible Penn Dissertations

There are sex differences in disease susceptibility, time of onset of symptoms, and drug responses. Notably, sex differences are particularly prominent in pain and opioid analgesic responses, with females being less sensitive to opioid analgesia. A major site of action of opioids in the brain is the locus coeruleus (LC)-norepinephrine (NE) system. LC neurons express mu-opiate receptors (MOR), and MOR-agonists potently inhibit LC neuronal activity. Evidence suggests that endogenous opioids are released during stress, to restrain LC activation and to facilitate LC recovery when the stressor ends. On the basis of these observations, this dissertation tested the hypothesis that ...


Genetic Regulation Of Tmem106b In The Pathogenesis Of Frontotemporal Lobar Degeneration, Michael Gallagher Jan 2017

Genetic Regulation Of Tmem106b In The Pathogenesis Of Frontotemporal Lobar Degeneration, Michael Gallagher

Publicly Accessible Penn Dissertations

Neurodegenerative diseases are an emerging global health crisis, with the projected global cost of dementia alone expected to exceed $1 trillion, or >1% of world GDP, by 2018. However, there are no disease-modifying treatments for the major neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis. Therefore, there is an urgent need for a better understanding of the pathophysiology underlying these diseases. While genome-wide association studies (GWAS) have identified ~200 genetic variants that are associated with risk of developing neurodegenerative disease, the biological mechanisms underlying these associations are largely unknown. This ...


Shedding Light On General Anesthesia: Uncovering The Molecular Mechanisms For Propofol And Volatile Anesthetics, Kellie Ann Woll Jan 2017

Shedding Light On General Anesthesia: Uncovering The Molecular Mechanisms For Propofol And Volatile Anesthetics, Kellie Ann Woll

Publicly Accessible Penn Dissertations

General anesthetics have played a pivotal role in the history of medicine. Despite accounts of their use within the earliest of human records, our understanding of anesthetic mechanisms remains unclear. Understanding these molecular mechanisms would be a significant advance toward enhanced drug design and optimal the clinical use of these potentially hazardous agents. Recent advances in chemical and molecular biology, including photoaffinity labeling, have allowed enhanced appreciation of the complex interactions anesthetic’s have with their macromolecular substrates. This work is dedicated to further define the protein interactions of the frequently administered volatile anesthetics sevoflurane and isoflurane, as well as ...


Multiple Roles Of Ret Signaling In Mechanosensory Neuron Development, Michael Scott Fleming Jan 2016

Multiple Roles Of Ret Signaling In Mechanosensory Neuron Development, Michael Scott Fleming

Publicly Accessible Penn Dissertations

Somatosensation is critical for interaction with the surrounding environment. Somatosensory stimuli are detected by primary somatosensory neurons of the dorsal root ganglia and trigeminal ganglia, which detect distinct classes of stimuli, such as temperature, pain, and pressure. In Chapters 2 and 3 of this thesis, we focus on rapidly adapting low-threshold mechanoreceptors (RALTMRs), which mediate the detection of light touch. RALTMRs are molecularly defined by the early embryonic expression of the receptor tyrosine kinase Ret. Ret is required for the development of central axonal projections of RALTMRs into the dorsal spinal cord. RET responds to the glial cell line-derived family ...


Contextual Insights Into The Rett Syndrome Transcriptome, Brian Scott Roosevelt Johnson Jan 2016

Contextual Insights Into The Rett Syndrome Transcriptome, Brian Scott Roosevelt Johnson

Publicly Accessible Penn Dissertations

Mutations in MECP2 are responsible for Rett syndrome (RTT), a severe X-linked neurological disorder characterized by loss of developmental milestones, intellectual disability and motor impairments. However, molecular insight into how these mutations affect the neuronal transcriptiome, disrupt neuronal function and contribute to RTT is impeded by the cellular heterogeneity of the mammalian brain. A comparison between gene expression changes in the striatum, hypothalamus, and cerebellum of MeCP2-null mice revealed that gene expression changes are distinct between different brain regions, which suggests that MeCP2 function should be understood in a cell type-dependent context. To accomplish this task, I generated and phenotypically ...


Linking Acetyl-Coa Metabolism And Histone Acetylation To Dynamic Gene Regulation In Yeast And Mouse Hippocampus, Philipp Mews Jan 2016

Linking Acetyl-Coa Metabolism And Histone Acetylation To Dynamic Gene Regulation In Yeast And Mouse Hippocampus, Philipp Mews

Publicly Accessible Penn Dissertations

A compelling body of evidence suggests an intimate relationship between metabolic state and chromatin regulation. This link is manifested in key metabolites that participate in biochemical pathways as intermediates, and function as cofactors to regulate chromatin modifying enzymes. Of particular interest is the metabolite acetyl-CoA, given its central role as an intermediate of cellular energy metabolism and key determinant of all histone acetylation. How nuclear acetyl-CoA levels are regulated to, in turn, control histone acetylation is under intense investigation, and holds promise for increased understanding of the molecular mechanisms adapting gene expression to internal and external stimuli. We studied the ...


Identification Of Novel Molecular-Genetic Pathways Regulating The Development Of Subpallial Derivatives, David Tischfield Jan 2016

Identification Of Novel Molecular-Genetic Pathways Regulating The Development Of Subpallial Derivatives, David Tischfield

Publicly Accessible Penn Dissertations

The embryonic subpallium produces many different neuronal cell types present throughout the adult telencephalon, including striatal medium spiny neurons (MSN) and cortical interneurons. Dysfunction of either cell type leads to neurological and psychiatric disorders including schizophrenia, epilepsy, and Tourette’s syndrome. Thus, understanding the molecular pathways that regulate their development and function has important implications for understanding disease pathogenesis. This work describes novel methods and genetic factors that expand our ability to characterize the development and function of two major subpallial derivatives: cortical interneurons and striatal MSN. The first part of this thesis characterizes a novel enrichment method for producing ...


A Role For Lysosomal Ph Dysfunction In Alzheimer’S Disease And Strategies For Its Restoration, Erin Coffey Jan 2015

A Role For Lysosomal Ph Dysfunction In Alzheimer’S Disease And Strategies For Its Restoration, Erin Coffey

Publicly Accessible Penn Dissertations

Alzheimer’s disease (AD) is the most common form of dementia, leading to memory loss progressive cognitive decline over the course of what can be many years. Mutations in the catalytically active component of the γ-secretase complex, presenilin 1 (PS1), are the most common cause of familial Alzheimer’s disease (fAD), a less-prevalent but earlier-onset form of AD. PS1 mutation is associated with more severe lysosomal and autophagic pathologies than are found in sporadic AD; these pathologies may be a result of lysosomal pH dysregulation. The goal of this dissertation was to confirm a role for elevated lysosomal pH in ...


The Identification Of Novel Mechanisms In Neuronal Development And Degeneration, Angela Marie Jablonski Jan 2015

The Identification Of Novel Mechanisms In Neuronal Development And Degeneration, Angela Marie Jablonski

Publicly Accessible Penn Dissertations

The goal of this dissertation is to further understand two key, broad processes which occur over the course of a neuron's lifetime: its development and possible degeneration in disease. We identify novel components in both of these processes and attempt to understand the functional significance as well as the mechanism each component uses to exert its effects.

We begin with work done focusing on how the neuron's dendritic tree develops. The development of neurons has two phases: (1) a first phase relying on a genetic program and (2) a second phase that uses synaptic activity to guide the ...


A Role For Cell Cycle Protein E2f1 In Hiv-Induced Neurotoxicity, Jacob Zyskind Jan 2015

A Role For Cell Cycle Protein E2f1 In Hiv-Induced Neurotoxicity, Jacob Zyskind

Publicly Accessible Penn Dissertations

HIV-associated neurocognitive disorders (HAND) are a spectrum of HIV-related conditions affecting the central nervous system that range from mild memory impairments to severe dementia. HAND results from the release of inflammatory factors and excitotoxins by HIV-infected macrophages in the brain. These factors alter the extracellular environment and provoke a neuronal response, ultimately causing dendritic damage, synaptic loss, and neuronal death. Our previous data indicate that components of the cell cycle regulatory machinery are elevated in neurons from post-mortem brain tissue of HAND patients. One of these upregulated proteins, the transcription factor E2F1, is known to activate gene targets required for ...


Cellular Interactions During Motor Nerve Regeneration, Allison F. Rosenberg Jan 2014

Cellular Interactions During Motor Nerve Regeneration, Allison F. Rosenberg

Publicly Accessible Penn Dissertations

Vertebrate peripheral nerves can regenerate, enabling severed axons to reconnect with their original synaptic targets. The interactions between injured nerves with cells in their environment, as well as the functional significance of these interactions, have not been determined in vivo and in real time. Here we provide the first minute-by-minute account of cellular interactions between laser transected motor nerves, macrophages, and Schwann cells in live intact zebrafish using transgenic lines that label each cell type in vivo. We find that axon fragmentation triggers macrophage invasion into the nerve to engulf axonal debris, and that delaying nerve fragmentation in a Wlds ...


Degradation Of The Oncoprotein Mdmx In Neurodegenerative States: Evidence For A Pro-Survival Role Of Mdmx In Neurons, Daniel James Colacurcio Jan 2014

Degradation Of The Oncoprotein Mdmx In Neurodegenerative States: Evidence For A Pro-Survival Role Of Mdmx In Neurons, Daniel James Colacurcio

Publicly Accessible Penn Dissertations

Neurodegenerative diseases, such as Alzheimer Disease (AD) and HIV–associated neurocognitive disorder (HAND) represent a tremendous burden to healthcare and a devastating impact on society. A common feature of neurodegenerative diseases is progressive dysfunction and death of neurons in key regions of the brain. Observations of dysregulated cell cycle proteins in the brains of patients, along with research in animal models and cultured cells, suggest that aberrant functions of cell cycle proteins contribute to neuronal death and progression of neurodegenerative diseases.

The p53 tumor suppressor is a key component in cell cycle signaling and cell death. p53 maintains multiple functions ...


Regulation Of Sleep And Circadian Rhythms By Metabolic Neuropeptides, Renske Erion Jan 2014

Regulation Of Sleep And Circadian Rhythms By Metabolic Neuropeptides, Renske Erion

Publicly Accessible Penn Dissertations

The increasing prevalence of metabolic disease in modern society has accelerated our need to understand factors that may be contributing to its development. Both circadian disruption and sleep deprivation are associated with metabolic dysfunction. Thus, for my dissertation I sought to gain insight into this association by studying the genetic and neural basis of interactions between circadian rhythms, sleep and metabolism. The relative simplicity of fly neuroanatomy and physiology, vast array of available genetic tools, and conservation across many organisms, makes Drosophila melanogaster an ideal model to dissect complex interactions between physiological systems. Through our studies we identified a novel ...


The Regulation Of Gene Expression During Memory Consolidation In The Hippocampus, Shane Gary Poplawski Jan 2014

The Regulation Of Gene Expression During Memory Consolidation In The Hippocampus, Shane Gary Poplawski

Publicly Accessible Penn Dissertations

Memory consolidation is the process through which short-term memories are stabilized for long-term retention. New gene expression is required for this process to occur successfully. Although gene expression is a necessary component for memory consolidation, the targets and regulation of this gene expression are not well understood. The advent of next-generation sequencing technologies has provided a tremendous resource to probe important questions genome-wide in ways that were previously impossible. In this dissertation, I use next-generation sequencing to investigate the transcriptional targets of learning in the hippocampus. Chapter 1 reviews the previous research on the regulation of gene expression during memory ...


Molecular Mechanisms Of Sleep/Wake Regulation And Memory Formation In Young And Aged Mice, Mathieu E. Wimmer Jan 2012

Molecular Mechanisms Of Sleep/Wake Regulation And Memory Formation In Young And Aged Mice, Mathieu E. Wimmer

Publicly Accessible Penn Dissertations

Advancements in healthcare and medicine have greatly increased lifespan. Normal aging is accompanied by deterioration of key physiological processes, including sleep and cognition. Understanding the mechanisms by which these functions go awry with age is a critical step in identifying novel therapeutic strategies to improve quality of life for the elderly. One of the most prevalent complaints in the elderly is the deterioration of sleep/wake patterns, difficulties staying awake and reduced vigilance. Little is known about the molecular mechanisms controlling these states in the brain. Mouse models are ideally suited to address this question because they share many similarities ...