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Role Of Jip1-Jnk Signaling In Beta-Cell Function And Autophagy, Seda Barutcu Jan 2018

Role Of Jip1-Jnk Signaling In Beta-Cell Function And Autophagy, Seda Barutcu

GSBS Dissertations and Theses

Proper functioning of endocrine cells is crucial for organismal homeostasis. The underlying mechanisms that fine-tune the amount, and the timing of hormone secretion are not clear. JIP1 / MAPK8IP1 (JNK interacting protein 1) is a scaffold protein that mediates cellular stress response, and is highly expressed in endocrine cells, including insulin secreting b-cells in pancreas islets. However, the role of JIP1 in b-cells is unclear. This study demonstrates that b-cell specific Jip1 ablation results in decreased glucose-induced insulin secretion, without a change in Insulin1 and Insulin2 gene expression. Inhibition of both JIP1-kinesin interaction, and JIP1-JNK interaction by genetic mutations also resulted ...


Intergenerational Effects Of Nicotine In An Animal Model Of Paternal Nicotine Exposure, Markus Parzival Vallaster Aug 2017

Intergenerational Effects Of Nicotine In An Animal Model Of Paternal Nicotine Exposure, Markus Parzival Vallaster

GSBS Dissertations and Theses

Environmental conditions imposed onto organisms during certain phases of their life cycles such as embryogenesis or puberty can not only impact the organisms’ own health, but also affect subsequent generations. The underlying mechanisms causing intergenerational phenotypes are not encoded in the genome, but the result of reversible epigenetic modifications. This work investigates in a mouse model the impact of paternal nicotine exposure on the next generation regarding addictive behavior modulation, metabolic changes, and molecular mechanisms. It provides evidence that male offspring from nicotine-exposed fathers (NIC offspring) is more resistant to lethal doses of nicotine. This phenotype is gender-specific and depends ...


Complement-Related Regulates Autophagy In Neighboring Cells, Lin Lin Jun 2017

Complement-Related Regulates Autophagy In Neighboring Cells, Lin Lin

GSBS Dissertations and Theses

Autophagy is a conserved process that cells use to degrade their own cytoplasmic components by delivery to lysosomes. Autophagy ensures intracellular quality control and is associated with diseases such as cancer and immune disorders. The process of autophagy is controlled by core autophagy (Atg) genes that are conserved from yeast to mammal. Most Atg proteins and their regulators were identified through pioneering studies of the single cell yeast Saccharomyces cerevisiae, and little is known about factors that systematically coordinate autophagy within the tissues of multicellular animals. The goal of this thesis is to identify new autophagy regulators and provide a ...


Role Of Energy Metabolism In The Thermogenic Gene Program, Minwoo Nam Jan 2017

Role Of Energy Metabolism In The Thermogenic Gene Program, Minwoo Nam

GSBS Dissertations and Theses

In murine and human brown adipose tissue (BAT), mitochondria are powerful generators of heat. Emerging evidence has suggested that the actions of mitochondria extend beyond this conventional biochemical role. In mouse BAT and cultured brown adipocytes, impaired mitochondrial respiratory capacity is accompanied by attenuated expression of Ucp1, a key thermogenic gene, implying a mitochondrial retrograde signaling. However, few have investigated this association in the context of mitochondria-nucleus communication.

Using mice with adipose-specific ablation of LRPPRC, a regulator of respiratory capacity, we show that respiration-dependent retrograde signaling from mitochondria to nucleus contributes to transcriptional and metabolic reprogramming of BAT. Impaired respiratory ...


The Effects Of Interleukin-10 On Skeletal Muscle Insulin Resistance And Myogenesis, Sezin Dagdeviren Dec 2016

The Effects Of Interleukin-10 On Skeletal Muscle Insulin Resistance And Myogenesis, Sezin Dagdeviren

GSBS Dissertations and Theses

Skeletal muscle insulin resistance is a major characteristic of obesity and type 2 diabetes. Although obesity-mediated inflammation is causally associated with insulin resistance, the underlying mechanism is unclear. Our lab and others have shown that a chronic low-grade inflammation takes place in skeletal muscles during diet-induced obesity, as evidenced by increased macrophage markers and pro-inflammatory cytokine levels. Interleukin (IL)-10 is a Th2-type cytokine that inhibits the synthesis and activity of pro-inflammatory cytokines and counteracts the Toll-like receptor-mediated inflammation. Our lab has previously demonstrated the preventive role of IL-10 against insulin resistance. Here, I have analyzed the effects ...


Identification Of Essential Metabolic And Genetic Adaptations To The Quiescent State In Mycobacterium Tuberculosis: A Dissertation, Emily S. C. Rittershaus Dec 2016

Identification Of Essential Metabolic And Genetic Adaptations To The Quiescent State In Mycobacterium Tuberculosis: A Dissertation, Emily S. C. Rittershaus

GSBS Dissertations and Theses

Mycobacterium tuberculosis stably adapts to respiratory limited environments by entering into a nongrowing but metabolically active state termed quiescence. This state is inherently tolerant to antibiotics due to a reduction in growth and activity of associated biosynthetic pathways. Understanding the physiology of the quiescent state, therefore, may be useful in developing new strategies to improve drug efficiency. Here, we used an established in vitro model of respiratory stress, hypoxia, to induce quiescence. We utilized metabolomic and genetic approaches to identify essential and active pathways associated with nongrowth. Our metabolomic profile of hypoxic M. tuberculosis revealed an increase in several free ...


Targeting Drug Resistance In Chronic Myeloid Leukemia: A Dissertation, Leyuan Ma Nov 2016

Targeting Drug Resistance In Chronic Myeloid Leukemia: A Dissertation, Leyuan Ma

GSBS Dissertations and Theses

Inhibiting BCR-ABL kinase activity with tyrosine kinase inhibitors (TKIs) has been the frontline therapy for CML. Resistance to TKIs frequently occurs, but the mechanisms remain elusive.

First, to uncover survival pathways involved in TKI resistance in CML, I conducted a genome-wide RNAi screen in human CML cells to identify genes governing cellular sensitivity to the first generation TKI called IM (Gleevec). I identified genes converging on and activating the MEK/ERK pathway through transcriptional up-regulation of PRKCH. Combining IM with a MEK inhibitor synergistically kills TKI-resistant CML cells and CML stem cells.

Next, I performed single cell RNA-seq to compare ...


Macrophages Are Regulators Of Whole Body Metabolism: A Dissertation, Joseph C. Yawe Oct 2016

Macrophages Are Regulators Of Whole Body Metabolism: A Dissertation, Joseph C. Yawe

GSBS Dissertations and Theses

Obesity is the top risk factor for the development of type 2 diabetes mellitus in humans. Obese adipose tissue, particularly visceral depots, exhibits an increase in macrophage accumulation and is described as being in a state of chronic low-grade inflammation. It is characterized by the increased expression and secretion of inflammatory cytokines produced by both macrophages and adipocytes, and is associated with the development of insulin resistance. Based on these observations, we investigated the potential role of macrophage infiltration on whole body metabolism, using genetic and diet-induced mouse models of obesity.

Using flow cytometry and immunofluorescence imaging we found that ...


Mtorc2 Promotes Lipid Storage And Suppresses Thermogenesis In Brown Adipose Tissue In Part Through Akt-Independent Regulation Of Foxo1: A Dissertation, Chien-Min Hung Oct 2016

Mtorc2 Promotes Lipid Storage And Suppresses Thermogenesis In Brown Adipose Tissue In Part Through Akt-Independent Regulation Of Foxo1: A Dissertation, Chien-Min Hung

GSBS Dissertations and Theses

Recent studies suggest adipose tissue plays a critical role in regulating whole body energy homeostasis in both animals and humans. In particular, activating brown adipose tissue (BAT) activity is now appreciated as a potential therapeutic strategy against obesity and metabolic disease. However, the signaling circuits that coordinate nutrient uptake and BAT function are poorly understood. Here, I investigated the role of the nutrient-sensing mTOR signaling pathway in BAT by conditionally deleting Rictor, which encodes an essential component of mTOR Complex 2 (mTORC2) either in brown adipocyte precursors or mature brown adipocytes. In general, inhibiting BAT mTORC2 reduces glucose uptake and ...


Viral Proteases As Drug Targets And The Mechanisms Of Drug Resistance: A Dissertation, Kuan-Hung Lin Sep 2016

Viral Proteases As Drug Targets And The Mechanisms Of Drug Resistance: A Dissertation, Kuan-Hung Lin

GSBS Dissertations and Theses

Viral proteases have been shown to be effective targets of anti-viral therapies for human immunodeficiency virus (HIV) and hepatitis C virus (HCV). However, under the pressure of therapy including protease inhibitors, the virus evolves to select drug resistance mutations both in the protease and substrates. In my thesis study, I aimed to understand the mechanisms of how this protease−substrate co-evolution contributes to drug resistance. Currently, there are no approved drugs against dengue virus (DENV); I investigated substrate recognition by DENV protease and designed cyclic peptides as inhibitors targeting the prime site of dengue protease.

First, I used X-ray crystallography ...


Exploiting Dna Repair And Er Stress Response Pathways To Induce Apoptosis In Glioblastoma Multiforme: A Dissertation, Jessica L. Weatherbee Aug 2016

Exploiting Dna Repair And Er Stress Response Pathways To Induce Apoptosis In Glioblastoma Multiforme: A Dissertation, Jessica L. Weatherbee

GSBS Dissertations and Theses

Glioblastoma multiforme (GBM) is a deadly grade IV brain tumor characterized by a heterogeneous population of cells that are drug resistant, aggressive, and infiltrative. The current standard of care, which has not changed in over a decade, only provides GBM patients with 12-14 months survival post diagnosis. We asked if the addition of a novel endoplasmic reticulum (ER) stress inducing agent, JLK1486, to the standard chemotherapy, temozolomide (TMZ), which induces DNA double strand breaks (DSBs), would enhance TMZ’s efficacy. Because GBMs rely on the ER to mitigate their hypoxic environment and DNA repair to fix TMZ induced DSBs, we ...


Roles Of The Mother Centriole Appendage Protein Cenexin In Microtubule Organization During Cell Migration And Cell Division: A Dissertation, Hui-Fang Hung Aug 2016

Roles Of The Mother Centriole Appendage Protein Cenexin In Microtubule Organization During Cell Migration And Cell Division: A Dissertation, Hui-Fang Hung

GSBS Dissertations and Theses

Epithelial cells are necessary building blocks of the organs they line. Their apicalbasolateral polarity, characterized by an asymmetric distribution of cell components along their apical-basal axis, is a requirement for normal organ function. Although the centrosome, also known as the microtubule organizing center, is important in establishing cell polarity the mechanisms through which it achieves this remain unclear. It has been suggested that the centrosome influences cell polarity through microtubule cytoskeleton organization and endosome trafficking. In the first chapter of this thesis, I summarize the current understanding of the mechanisms regulating cell polarity and review evidence for the role of ...


A Role For Tnmd In Adipocyte Differentiation And Adipose Tissue Function: A Dissertation, Ozlem Senol-Cosar Jun 2016

A Role For Tnmd In Adipocyte Differentiation And Adipose Tissue Function: A Dissertation, Ozlem Senol-Cosar

GSBS Dissertations and Theses

Adipose tissue is one of the most dynamic tissues in the body and is vital for metabolic homeostasis. In the case of excess nutrient uptake, adipose tissue expands to store excess energy in the form of lipids, and in the case of reduced nutrient intake, adipose tissue can shrink and release this energy. Adipocytes are most functional when the balance between these two processes is intact. To understand the molecular mechanisms that drive insulin resistance or conversely preserve the metabolically healthy state in obese individuals, our laboratory performed a screen for differentially regulated adipocyte genes in insulin resistant versus insulin ...


Mechanisms Regulating Early Mesendodermal Differentiation Of Human Embryonic Stem Cells: A Dissertation, Jennifer J. Vanoudenhove Jun 2016

Mechanisms Regulating Early Mesendodermal Differentiation Of Human Embryonic Stem Cells: A Dissertation, Jennifer J. Vanoudenhove

GSBS Dissertations and Theses

Key regulatory events take place at very early stages of human embryonic stem cell (hESC) differentiation to accommodate their ability to differentiate into different lineages; this work examines two separate regulatory events.

To investigate precise mechanisms that link alterations in the cell cycle and early differentiation, we examined the initial stages of mesendodermal lineage commitment and observed a cell cycle pause that occurred concurrently with an increase in genes that regulate the G2/M transition, including WEE1. Inhibition of WEE1 prevented the G2 pause. Directed differentiation of hESCs revealed that cells paused during commitment to the endo- and mesodermal, but ...


Activation Of Mtorc1 Improves Cone Cell Metabolism And Extends Vision In Retinitis Pigmentosa Mice: A Dissertation, Aditya Venkatesh Apr 2016

Activation Of Mtorc1 Improves Cone Cell Metabolism And Extends Vision In Retinitis Pigmentosa Mice: A Dissertation, Aditya Venkatesh

GSBS Dissertations and Theses

Retinitis Pigmentosa (RP) is an inherited photoreceptor degenerative disease that leads to blindness and affects about 1 in 4000 people worldwide. The disease is predominantly caused by mutations in genes expressed exclusively in the night active rod photoreceptors; however, blindness results from the secondary loss of the day active cone photoreceptors, the mechanism of which remains elusive. Here, we show that the mammalian target of rapamycin complex 1 (mTORC1) is required to delay the progression of cone death during disease and that constitutive activation of mTORC1 is sufficient to maintain cone function and promote cone survival in RP. Activation of ...


Xist And Cot-1 Repeat Rnas Are Integral Components Of A Complex Nuclear Scaffold Required To Maintain Saf-A And Modify Chromosome Architecture: A Dissertation, Heather J. Kolpa Apr 2016

Xist And Cot-1 Repeat Rnas Are Integral Components Of A Complex Nuclear Scaffold Required To Maintain Saf-A And Modify Chromosome Architecture: A Dissertation, Heather J. Kolpa

GSBS Dissertations and Theses

XIST RNA established the precedent for a noncoding RNA that stably associates with and regulates chromatin, however it remains poorly understood how such RNAs structurally associate with the interphase chromosome territory. I demonstrate that transgenic XIST RNA localizes in cis to an autosome as it does to the inactive X chromosome, hence the RNA recognizes a structure common to all chromosomes. I reassess the prevalent thinking in the field that a single protein, Scaffold Attachment Factor-A (SAF-A/hnRNP U), provides a single molecule bridge required to directly tether the RNA to DNA. In an extensive series of experiments in multiple ...


The Mechanistic Role And Therapeutic Potential Of Microrna-122 In Alcoholic Liver Disease: A Dissertation, Abhishek Satishchandran Apr 2016

The Mechanistic Role And Therapeutic Potential Of Microrna-122 In Alcoholic Liver Disease: A Dissertation, Abhishek Satishchandran

GSBS Dissertations and Theses

Chronic alcohol use results in accelerated liver injury, leading to alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. However, due to the complex nature of this disease process, a central, druggable mechanism has remained elusive. microRNAs are potent post-transcriptional regulators of gene expression. A single miRNA has the ability to regulate hundreds of pathways simultaneously, defining cellular fate and function. microRNA-122 (miR-122), the most abundant miRNA in hepatocytes, has a demonstrated role as an tumor suppressor, regulator of hepatocyte metabolism, and hepatic differentiation.

In this dissertation I demonstrate the role of miR-122 on alcoholic liver disease (ALD) pathogenesis over four parts. In ...


Understanding Drug Resistance And Antibody Neutralization Escape In Antivirals: A Dissertation, Kristina L. Prachanronarong Apr 2016

Understanding Drug Resistance And Antibody Neutralization Escape In Antivirals: A Dissertation, Kristina L. Prachanronarong

GSBS Dissertations and Theses

Antiviral drug resistance is a major problem in the treatment of viral infections, including influenza and hepatitis C virus (HCV). Influenza neuraminidase (NA) is a viral sialidase on the surface of the influenza virion and a primary antiviral target in influenza. Two subtypes of NA predominate in humans, N1 and N2, but different patterns of drug resistance have emerged in each subtype. To provide a framework for understanding the structural basis of subtype specific drug resistance mutations in NA, we used molecular dynamics simulations to define dynamic substrate envelopes for NA to determine how different patterns of drug resistance have ...


A Role For The Lipid Droplet Protein Hig2 In Promoting Lipid Deposition In Liver And Adipose Tissue: A Dissertation, Marina T. Distefano Mar 2016

A Role For The Lipid Droplet Protein Hig2 In Promoting Lipid Deposition In Liver And Adipose Tissue: A Dissertation, Marina T. Distefano

GSBS Dissertations and Theses

Chronic exposure of humans or rodents to high calorie diets leads to hypertriglyceridemia and ectopic lipid deposition throughout the body, resulting in metabolic disease. Cellular lipids are stored in organelles termed lipid droplets (LDs) that are regulated by tissue-specific LD proteins. These proteins are critical for lipid homeostasis, as humans with LD protein mutations manifest metabolic dysfunction. Identification of novel components of the LD machinery could shed light on human disease mechanisms and suggest potential therapeutics for Type 2 Diabetes.

Microarray analyses pinpointed the largely unstudied Hypoxia-Inducible Gene 2 (Hig2) as a gene that was highly expressed in obese human ...


Systematic Dissection Of Roles For Chromatin Regulators In Dynamics Of Transcriptional Response To Stress In Yeast: A Dissertation, Hsiuyi V. Chen Dec 2015

Systematic Dissection Of Roles For Chromatin Regulators In Dynamics Of Transcriptional Response To Stress In Yeast: A Dissertation, Hsiuyi V. Chen

GSBS Dissertations and Theses

The following work demonstrates that chromatin regulators play far more pronounced roles in dynamic gene expression than they do in steady-state. Histone modifications have been associated with transcription activity. However, previous analyses of gene expression in mutants affecting histone modifications show limited alteration. I systematically dissected the effects of 83 histone mutants and 119 gene deletion mutants on gene induction/repression in response to diamide stress in yeast. Importantly, I observed far more changes in gene induction/repression than changes in steady-state gene expression. The extensive dynamic gene expression profile of histone mutants and gene deletion mutants also allowed me ...


Roles Of Protein Arginine Methyltransferase 7 And Jumonji Domain-Containing Protein 6 In Adipocyte Differentiation: A Dissertation, Yu-Jie Hu Oct 2015

Roles Of Protein Arginine Methyltransferase 7 And Jumonji Domain-Containing Protein 6 In Adipocyte Differentiation: A Dissertation, Yu-Jie Hu

GSBS Dissertations and Theses

Regulation of gene expression comprises a wide range of mechanisms that control the abundance of gene products in response to environmental and developmental changes. These biological processes can be modulated by posttranslational modifications including arginine methylation. Among the enzymes that catalyze the methylation, protein arginine methyltransferase 7 (PRMT7) is known to modify histones to repress gene expression. Jumonji domain-containing protein 6 (JMJD6) is a putative arginine demethylase that potentially antagonize PRMT7. However, the biological significance of these enzymes is not well understood. This thesis summarizes the investigation of both PRMT7 and JMJD6 in cell culture models for adipocyte differentiation. The ...


Age-Related Changes In The Neuronal Architecture Of Caenorhabditis Elegans: A Dissertation, Anagha Khandekar Oct 2015

Age-Related Changes In The Neuronal Architecture Of Caenorhabditis Elegans: A Dissertation, Anagha Khandekar

GSBS Dissertations and Theses

Though symptoms such as loss of vision, decline in cognition and memory are evident during aging, the underlying processes that affect neuronal function during aging are not well understood. Unlike changes in other tissues and organs, age-related changes in the nervous system affect the overall physical, mental as well as social state of human beings. To start elucidating the molecular mechanisms underlying normal age-dependent brain decline, we have characterized structural neuronal changes occurring during Caenorhabditis elegans aging. Our analysis reveals distinct neuronal alterations that arise with age and that the types of changes and their age of onset are neuronal-type ...


Regulation Of Metabolism By Hepatic Oxphos: A Dissertation, Thomas E. Akie Oct 2015

Regulation Of Metabolism By Hepatic Oxphos: A Dissertation, Thomas E. Akie

GSBS Dissertations and Theses

Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent issue in the modern world, predisposing patients to serious pathology such as cirrhosis and hepatocellular carcinoma. Mitochondrial dysfunction, and in particular, diminished hepatic oxidative phosphorylation (OXPHOS) capacity, have been observed in NAFLD livers, which may participate in NAFLD pathogenesis.

To examine the role of OXPHOS in NAFLD, we generated a model of enhanced hepatic OXPHOS using mice with liver-specific transgenic expression of LRPPRC, a protein which activates mitochondrial transcription and augments OXPHOS capacity. When challenged with high-fat feeding, mice with enhanced hepatic OXPHOS were protected from the development of liver steatosis ...


Diet-Responsive Gene Networks Rewire Metabolism In The Nematode Caenorhabditis Elegans To Provide Robustness Against Vitamin B12 Deficiency: A Dissertation, Emma Watson Sep 2015

Diet-Responsive Gene Networks Rewire Metabolism In The Nematode Caenorhabditis Elegans To Provide Robustness Against Vitamin B12 Deficiency: A Dissertation, Emma Watson

GSBS Dissertations and Theses

Maintaining cellular homeostasis is a complex task, which involves monitoring energy states and essential nutrients, regulating metabolic fluxes to accommodate energy and biomass needs, and preventing buildup of potentially toxic metabolic intermediates and byproducts. Measures aimed at maintaining a healthy cellular economy inherently depend on the composition of nutrients available to the organism through its diet. We sought to delineate links between dietary composition, metabolic gene regulation, and physiological responses in the model organism C. elegans.

As a soil-dwelling bacterivore, C. elegans encounters diverse bacterial diets. Compared to a diet of E. coli OP50, a diet of Comamonas aquatica accelerates ...


Exploring The Role Of Fus Mutants From Stress Granule Incorporation To Nucleopathy In Amyotrophic Lateral Sclerosis: A Dissertation, Hae Kyung Ko Sep 2015

Exploring The Role Of Fus Mutants From Stress Granule Incorporation To Nucleopathy In Amyotrophic Lateral Sclerosis: A Dissertation, Hae Kyung Ko

GSBS Dissertations and Theses

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by preferential motor neuron death in the brain and spinal cord. The rapid disease progression results in death due to respiratory failure, typically within 3-5 years after disease onset. While ~90% of cases occur sporadically, remaining 10% of ALS cases show familial inheritance, and the number of genes linked to ALS has increased dramatically over the past decade.

FUS/TLS (Fused in Sarcoma/ Translocated to liposarcoma) is a nucleic acid binding protein that may regulate several cellular functions, including RNA splicing, transcription, DNA damage repair and microRNA biogenesis. More than ...


Investigating The Effects Of Mutant Fus On Stress Response In Amyotrophic Lateral Sclerosis: A Thesis, Laura J. Kaushansky Aug 2015

Investigating The Effects Of Mutant Fus On Stress Response In Amyotrophic Lateral Sclerosis: A Thesis, Laura J. Kaushansky

GSBS Dissertations and Theses

During stress, eukaryotes regulate protein synthesis in part through formation of cytoplasmic, non-membrane-bound complexes called stress granules (SGs). SGs transiently store signaling proteins and stalled translational complexes in response to stress stimuli (e.g. oxidative insult, DNA damage, temperature shifts and ER dysfunction). The functional outcome of SGs is proper translational regulation and signaling, allowing cells to overcome stress.

The fatal motor neuron disease Amyotrophic Lateral Sclerosis (ALS) develops in an age-related manner and is marked by progressive neuronal death, with cytoplasmic protein aggregation, excitotoxicity and increased oxidative stress as major hallmarks. Fused in Sarcoma/Translocated in Liposarcoma (FUS) is ...


The Influence Of The Insulin-Like Gene Family And Diet-Drug Interactions On Caenorhabditis Elegans Physiology: A Dissertation, Ashlyn D. Ritter Aug 2015

The Influence Of The Insulin-Like Gene Family And Diet-Drug Interactions On Caenorhabditis Elegans Physiology: A Dissertation, Ashlyn D. Ritter

GSBS Dissertations and Theses

Aging can be defined as the accumulation of changes affecting the maintenance of homeostatic processes over time, leading to functional decline and increased risk for disease and death. In its simplicity, aging is the systemwide deterioration of an organism. Genetic studies have identified many potential molecular mechanisms of aging including DNA damage, telomere shortening, mitochondrial dysfunction, increased oxidative stress, uncontrolled inflammation, and hormone dysregulation (reviewed in [1]). However, in reality, aging is likely to be a combination of some (or potentially all) of these mechanisms.

Interestingly, aging and metabolism are tightly coordinated. Aging is a major contributor to metabolic decline ...


Jun Kinases In Hematopoiesis, And Vascular Development And Function: A Dissertation, Kasmir Ramo Jul 2015

Jun Kinases In Hematopoiesis, And Vascular Development And Function: A Dissertation, Kasmir Ramo

GSBS Dissertations and Theses

Arterial occlusive diseases are major causes of morbidity and mortality in industrialized countries and represent a huge economic burden. The extent of the native collateral circulation is an important determinant of blood perfusion restoration and therefore the severity of tissue damage and functional impairment that ensues following arterial occlusion. Understanding the mechanisms responsible for collateral artery development may provide avenues for therapeutic intervention. Here, we identify a critical requirement for mixed lineage kinase (MLK) – cJun-NH2-terminal kinase (JNK) signaling in vascular morphogenesis and native collateral artery development. We demonstrate that Mlk2-/-Mlk3-/- mice or mice with compound JNK-deficiency in the vascular ...


Cell Size Control In The Fission Yeast Schizosaccharomyces Pombe: A Dissertation, Daniel L. Keifenheim Jun 2015

Cell Size Control In The Fission Yeast Schizosaccharomyces Pombe: A Dissertation, Daniel L. Keifenheim

GSBS Dissertations and Theses

The coordination between cell growth and division is a highly regulated process that is intimately linked to the cell cycle. Efforts to identify an independent mechanism that measures cell size have been unsuccessful. Instead, we propose that size control is an intrinsic function of the basic cell cycle machinery.

My work shows that in the fission yeast Schizosaccharomyces pombe Cdc25 accumulates in a size dependent manner. This accumulation of Cdc25 occurs over a large range of cell sizes. Additionally, experiments with short pulses of cycloheximide have shown that Cdc25 is an inherently unstable protein that quickly returns to a size ...


Cathosis: Cathepsins In Particle-Induced Inflammatory Cell Death: A Dissertation, Gregory M. Orlowski May 2015

Cathosis: Cathepsins In Particle-Induced Inflammatory Cell Death: A Dissertation, Gregory M. Orlowski

GSBS Dissertations and Theses

Sterile particles underlie the pathogenesis of numerous inflammatory diseases. These diseases can often become chronic and debilitating. Moreover, they are common, and include silicosis (silica), asbestosis (asbestos), gout (monosodium urate), atherosclerosis (cholesterol crystals), and Alzeihmer’s disease (amyloid Aβ). Central to the pathology of these diseases is a repeating cycle of particle-induced cell death and inflammation. Macrophages are the key cellular mediators thought to drive this process, as they are especially sensitive to particle-induced cell death and they are also the dominant producers of the cytokine responsible for much of this inflammation, IL-1β. In response to cytokines or microbial cues ...