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Functional Collaboration Between Igf-1 Receptor And Growth Hormone Signaling Pathway, Yujun Gan Jan 2012

Functional Collaboration Between Igf-1 Receptor And Growth Hormone Signaling Pathway, Yujun Gan

All ETDs from UAB

GH receptor (GHR) binds GH in its extracellular domain (ECD) to activate the GHR-associated cytoplasmic tyrosine kinase, JAK2. IGF-1 binds IGF-1R, a disulfide-linked heterotetramer with tyrosine kinase activity in its intracellular domain (ICD). Classically, IGF-1 is a GH effector in a “linear” GH→GHR→IGF-1→IGF-1R pathway. Our recent studies suggest IGF-1R also subserves GH signaling in several novel ways: 1) GH induces a GHR-JAK2-IGF-1R complex, whose formation is independent of tyrosine phosphorylation of any of the partners; 2) Cotreatment with IGF-1 augments acute GH signaling; 3) deletion of IGF-1R in primary osteoblasts or human prostate cancer cells blunts acute GH signaling. In …

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Regulation Of Neuronal Cell Death By Bh3-Only Proteins, Arindam P. Ghosh Jan 2012

Regulation Of Neuronal Cell Death By Bh3-Only Proteins, Arindam P. Ghosh

All ETDs from UAB

Apoptosis in metazoan organisms plays critical roles in normal development, tissue homeostasis and immunity, and its disturbed regulation leads to many pathological states, including cancer, autoimmunity, infection and degenerative disorders. Apoptosis can be triggered by the engagement of `death receptors' of the tumor necrosis factor receptor family on the cell surface or by diverse intracellular signals that act upon the BCL2 (B-cell CLL/lymphoma 2) protein family, which controls the integrity of the mitochondrial outer membrane through the complex interactions of family members. Both the pathways lead to cellular demolition by dedicated proteases termed caspases. Different BH3-only proteins (or combinations of …

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Scaffold-Mediated Size Determination Of Bacteriophage Capsids By Mobile Genetic Elements, Altaira Davida Dearborn Jan 2012

Scaffold-Mediated Size Determination Of Bacteriophage Capsids By Mobile Genetic Elements, Altaira Davida Dearborn

All ETDs from UAB

Bacteriophage can mediate the transfer of unrelated mobile genetic elements (MGE) from a carrier bacterial cell to the susceptible population around it. This transfer results in the spread of virulence or other accessory genes encoded on the MGE. During viral particle assembly, the MGE can discourage the formation of viable bacteriophage progeny by limiting the size of the particles to those large enough to encapsidate the MGE, but too small to fit the complete bacteriophage genome which is three times larger. Here, I present models for size determination by an external scaffolding protein which is independent of and dominant over …

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The Role Of St6gal-I Sialylation In Fas (Cd95) Death Receptor Function And Tumorigenesis, Amanda F. Swindall Jan 2012

The Role Of St6gal-I Sialylation In Fas (Cd95) Death Receptor Function And Tumorigenesis, Amanda F. Swindall

All ETDs from UAB

The golgi glycosyltransferase, ST6Gal-I, adds a negatively-charged sialic acid in an alpha-2-6 linkage to N-linked glycans. ST6Gal-I is upregulated in many cancers, and is associated with increased metastasis and poor patient prognosis. ST6Gal-I expression has been shown to be driven by oncogenic-ras signaling. However, mechanistic details of the role ST6Gal-I plays in tumor initiation and progression are not well defined. Historically, studies have focused on contributions of ST6Gal-I to the malignant cell phenotypes of migration and invasion. Emerging evidence including studies contained in this dissertation have begun to elucidate a role for ST6Gal-I as a regulator of apoptotic signaling by …

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Regulatory T Cells In The Fvb.Mdr1a-/- Model Of Colitis, Scott Tanner Jan 2012

Regulatory T Cells In The Fvb.Mdr1a-/- Model Of Colitis, Scott Tanner

All ETDs from UAB

Regulatory T cells (Treg) are necessary for the maintenance of immune homeostasis, and have been implicated in several autoimmune diseases, including inflammatory bowel disease (IBD). Most murine studies focusing on the function of Tregs have been done on the C57BL/6 or BALB/c background, creating a bias towards these two strains. In addition, it has been shown that C57BL/6 and BALB/c Tregs function in different manners. To further investigate potential strain differences in Treg phenotype and function, we chose to analyze FVB/N Tregs. Several differences were observed, including de-creased FVB/N Treg suppression in a non-cell contact dependent manner, decreased FVB/N and …

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Mechanisms Of Lrrk2 Regulation, Philip J. Webber Jan 2012

Mechanisms Of Lrrk2 Regulation, Philip J. Webber

All ETDs from UAB

Non-synonymous mutations in LRRK2 are the most common known cause of familial and sporadic Parkinson's disease (PD). The dominant inheritance of these mutations in familial PD suggests a gain-of-function mechanism. Increased kinase activity observed in the most common PD associated LRRK2 mutation G2019S suggests that kinase activity is central to disease. However, not all mutations associated with disease are reported to alter kinase activity and controversy exists in the literature about the effects of mutations appearing in the GTPase domain on kinase activity. The studies conducted as a part of this work aim to characterize the mechanisms that regulate LRRK2 …

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Siderophore-Mediated Iron Acquisition In Mycobacterium Tuberculosis, Ryan Wells Jan 2012

Siderophore-Mediated Iron Acquisition In Mycobacterium Tuberculosis, Ryan Wells

All ETDs from UAB

Mycobacterium tuberculosis is a dangerous human pathogen that has the capacity to adapt to and survive within the harsh phagosomal environment of macrophages. One obstacle that must be overcome by pathogens is to acquire iron, an essential component and cofactor of proteins required for vital cellular processes. M. tuberculosis meets its iron demands in the face of an array of sequestration strategies of the host by synthesizing and secreting two siderophores called mycobactin and carboxymycobactin. Siderophores are low molecular weight high affinity iron binding compounds that steal iron away from host stores and have been shown to be important for …

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C-C-Motif Chemokine Receptor/Ligand Gene Variants And Their Associations With Hiv-1 Transmission And Pathogenesis, Liangyuan Hu Jan 2012

C-C-Motif Chemokine Receptor/Ligand Gene Variants And Their Associations With Hiv-1 Transmission And Pathogenesis, Liangyuan Hu

All ETDs from UAB

Host factors including genes and their variants are important to HIV-1 acquisition, transmission and disease progression. In particular, chemokine (C-C motif) receptors 2 and 5 genes (CCR2 and CCR5) have multiple variants of interest. We first investigated the impact of CCR2-CCR5 haplotypes on several outcomes among 567 HIV-1 discordant Zambian couples. HHF*2 homozygosity was associated with significantly lower VL in seroconverters (mean beta=-0.58 log10 P=0.027) and the HHD/HHE diplotype was associated with significantly higher VL in the seroconverters (mean beta=0.54, log10 P=0.014) adjusted for age and gender in multivariable model. HHD/HHE was associated with more rapid acquisition of infection by …

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Retinoids And Abnormal Alveolar Development, Masheika L. James Jan 2012

Retinoids And Abnormal Alveolar Development, Masheika L. James

All ETDs from UAB

Extremely preterm infants are at high risk for a form of chronic lung disease called bronchopulmonary dysplasia (BPD), which is characterized by impaired alveolar development. Exposure to hyperoxia and deficiency of vitamin A (VA) contribute to the development of BPD in preterm infants. Randomized controlled trials indicate VA supplementation decreases BPD and/or death. However, 25% of preterm infants continue to remain VA deficient despite supplementation, probably due to impairment in VA transport, VA is stored in the liver as retinyl esters which are transported to the lung and irreversibly metabolized into all-trans-retinoic acid (ATRA), the active metabolite. A combination of …

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The Role Of Endoplasmic Reticulum Stress Response In Glioma Cell Death, Guyla G. Johnson Jan 2012

The Role Of Endoplasmic Reticulum Stress Response In Glioma Cell Death, Guyla G. Johnson

All ETDs from UAB

Malignant gliomas, including glioblastomas, are the main primary adult brain tumor. Even with current therapies, the median survival time for patients diagnosed with glioblastomas is only about 12 months. Therefore, it is imperative to identify pathways that can induce glioma cell death. This dissertation provides evidence defining how Endoplasmic Reticulum Stress Response (ERSR) induction promotes cell death selectively in malignant glioma cells (MGCs). I present data showing a correlation between ER Ca2+ storage abnormalities, ER ribosome-translocon expression and activity, ERSR intensity and cell death in MGCs. These data show ERSR induction with thapsigargin (THAP) results in a larger loss of …

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The Role Of C-Reactive Protein In Arthritic Disease, Nicholas Ryan Jones Jan 2012

The Role Of C-Reactive Protein In Arthritic Disease, Nicholas Ryan Jones

All ETDs from UAB

C-reactive protein (CRP) is an acute phase protein that is commonly used to evaluate systemic inflammation level. Blood CRP level also correlates very well with rheumatoid arthritis (RA) disease severity. However, CRP has many biological actions that lead one to suspect that it may be playing a role in the development or pathology of the disease. We have directly addressed whether this is the case by the use of novel mouse models (CRP deficiency or transgenic overexpression). We have shown that CRP positively affects collagen-induced arthritis development and progression. In order to thoroughly address the question, we have also reported …

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Mycobacterial Iron Acquisition Systems, Christopher M. Jones Jan 2012

Mycobacterial Iron Acquisition Systems, Christopher M. Jones

All ETDs from UAB

Iron is an essential nutrient for the vast majority of organisms; yet, the availability of iron is limited to microorganisms due to the insolubility of ferric hydroxides and to pathogens by iron withholding strategies of their hosts. Many bacteria produce small, high-affinity iron chelators called siderophores to scavenge iron from the environment. In addition, many bacterial pathogens have evolved mechanisms to steal host iron contained in heme, hemoglobin, or transferrin. Mycobacteria are unique genera of bacteria represented by the notorious pathogens Mycobacterium tuberculosis and Mycobacterium leprae, the causative agents of tuberculosis (TB) and leprosy, respectively. Tuberculosis remains a global health …

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A Study Of The Genetic Mechanisms Used To Regulate The Third Complementarity Determining Region Of The Immunoglobulin H Chain, Mohamed Khass Jan 2012

A Study Of The Genetic Mechanisms Used To Regulate The Third Complementarity Determining Region Of The Immunoglobulin H Chain, Mohamed Khass

All ETDs from UAB

Developing B cells exhibit sequential changes in the representation of immunoglobulin (Ig) heavy (H) chain sequences with excess hydrophobic or charged amino acids in complementarity determining region 3 (CDR-H3). To begin to elucidate the mechanisms by which this process occurs, we used Bromodeoxy Uridine (BrdU) incorporation and Annexin V binding to quantify B cell turnover and cell cycle progression in developing B cell subsets in the bone marrow, spleen and peritoneal cavity of wild-type BALB/c mice. To magnify the effects of hydrophobicity and charge, we included in this analysis mice limited to the use of an IgH allele with a …

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Is P53 A Target Of Hpv-18 E6 In The Viral Life Cycle?, Eun-Young Kho Jan 2012

Is P53 A Target Of Hpv-18 E6 In The Viral Life Cycle?, Eun-Young Kho

All ETDs from UAB

The large family of human papillomaviruses (HPVs) infects the cutaneous or mucosal epithelia causing benign hyper proliferative diseases. Infections by the high-risk (HR) HPV genotypes in the anogenital tracts can progress to high grade lesions and cancers in men and women. Because the viral productive program requires squamous differentiation of epithelia, HPV encodes oncoproteins that recondition the differentiated cells that have withdrawn from the cell cycle to support viral DNA amplification. The HR HPV E6 and E7 oncogenes are selectively expressed in cervical carcinomas and are necessary to maintain the malignant state. In vitro, constitutive expression of the HR HPV …

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Regulation Of Cell Death By Autophagy In Glial Neoplasms, Latika R. Kohli Jan 2012

Regulation Of Cell Death By Autophagy In Glial Neoplasms, Latika R. Kohli

All ETDs from UAB

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive malignancies of the peripheral nervous system. The majority of MPNSTs arise in patients of the autosomal dominant genetic disorder neurofibromatosis type I (NF1) although they also arise sporadically. In the absence of any effective chemotherapeutic options and with surgery constituting the mainstay of treatment, MPNST patients face an extremely poor prognosis. This underscores the need to develop novel therapeutic strategies against this tumor type. It is well accepted that the crosstalk between autophagy and apoptosis can be exploited to derive maximal therapeutic benefit, especially through combinatorial therapies. However, this interaction is extremely …

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Mechanism Of Nfi-C Functionin During Tooth Root Formation, Ejvis Lamani Jan 2012

Mechanism Of Nfi-C Functionin During Tooth Root Formation, Ejvis Lamani

All ETDs from UAB

Currently, very little is known regarding tissue-specific gene regulation during the later stages of tooth development, especially those associated with root formation. Re-cent studies have identified nuclear factor I-C (NFI-C) as a critical factor for root for-mation in mammals. NFI-C functions as a cellular transcription factor and adenovirus DNA replication factor. Its role in root formation first became evident when Nfi-c null mice were shown to lack molar roots. A similar phenotype of incomplete or absent root formation is observed in patients with the autosomal dominant disease Radicular Dentin Dysplasia (RDD; MIM125400) also known as Rootless Teeth or Dentin Dysplasia …

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Development Of An Adenoviral Vector Platform For Selective Gene Delivery To Neurons, Travis Benjamin Lewis Jan 2012

Development Of An Adenoviral Vector Platform For Selective Gene Delivery To Neurons, Travis Benjamin Lewis

All ETDs from UAB

Parkinson disease (PD) is a devastating movement disorder affecting between 500,000 and 1,000,000 individuals in the United States alone, and for which there is currently no cure. Therapies such as dopamine replacement help initially, but with disease progression these lose efficacy and do not alter the underlying degenerative process. Gene therapy is the delivery of exogenous genetic material to correct an underlying disorder. A major advantage of this approach is the ability to distribute potent therapies to specific targets over an extended duration, properties necessary for the treatment of progressive degenerative diseases such as PD. A number of clinical trials …

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Regulation Of P27kip1 By Trip6 And Its Implications In Cancer Progression, Victor T G Lin Jan 2012

Regulation Of P27kip1 By Trip6 And Its Implications In Cancer Progression, Victor T G Lin

All ETDs from UAB

TRIP6 is a focal adhesion molecule that functions as an adaptor protein to mediate diverse cellular functions, including motility and antiapoptotic signaling, through a wide variety of protein-protein interactions. We were able to characterize a novel interaction between TRIP6 and p27KIP1, a CDK inhibitor which can both suppress and promote tumorigenesis, depending on its regulation. TRIP6 expression specifically promotes the AKT-mediated phosphorylation of p27KIP1 at T157, which leads to its cytosolic retention, and accelerates the protein turnover rate of p27KIP1. We also found that phosphorylation of T157 by itself promotes cell motility and can be linked to the formation of …

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Regulation Of Membrane Traffic By The Big2 Member Of Guanine Nucleotide Exchange Factors, Jason Lowery Jan 2012

Regulation Of Membrane Traffic By The Big2 Member Of Guanine Nucleotide Exchange Factors, Jason Lowery

All ETDs from UAB

Vesicular transport is an essential cellular process that facilitates the movement of molecules within a cell. The importance of vesicular transport is highlighted by numerous human diseases that result from mutations affecting protein trafficking. The Brefeldin A-inhibited guanine nucleotide exchange factor 2 (BIG2) has emerged as a key regulator of protein trafficking within the late secretory pathway, between the trans-Golgi Network (TGN) and endosomal compartments and within the recycling endosomal pathway. Mutations in BIG2 lead to Autosomal Recessive Periventricular Heterotopia with Microcephly (ARPHM), a disorder characterized by severe brain malformations. BIG2 stimulates nucleotide exchange of GDP for GTP on ADP-ribosylation …

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Using Mouse Models To Investigate Ciliopathies, Raymond Carl Pasek Jan 2012

Using Mouse Models To Investigate Ciliopathies, Raymond Carl Pasek

All ETDs from UAB

Cilia and flagella are microtubule based organelles found on nearly every cell type in the mammalian body. Flagella have an essential role in sperm locomotion and reproduction, while motile cilia have a known role in fluid movement in the brain, lungs, and portions of the female reproductive tract. While the role of most primary cilia remained unknown for decades, they are now recognized as being essential to mammalian development, renal homeostasis, and satiety, just to name a few. Because of their widespread presence and importance, dysfunction of cilia and flagella can lead to a variety of human diseases, collectively referred …

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Targeting Mitochondrial Function In Diabetic Nephropathy, Colin Reily Jan 2012

Targeting Mitochondrial Function In Diabetic Nephropathy, Colin Reily

All ETDs from UAB

TARGETING MITOCHONDRIAL FUNCTION IN DIABETIC NEPHROPATHY The incidence of diabetes has increased to epidemic proportions over the last 50 years, due to a complex interaction of lifestyle and dietary factors. Changes in physical activity, caloric intake, and the composition of foods consumed over the last century are thought to interact with metabolic syndrome prone subpopulations leading ultimately to diabetes. It is widely accepted that chronic hyperglycemia in the blood characterizes the diabetic condition. Since the discovery of insulin therapy in the first half of the 20th century, diabetics have extended their lifespan considerably, but at the cost of increased morbitity …

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Cystine/Glutamate Transporters As Prognostic & Therapeutic Markers Of Primary Brain Tumors, Stephanie Marie Robert Jan 2012

Cystine/Glutamate Transporters As Prognostic & Therapeutic Markers Of Primary Brain Tumors, Stephanie Marie Robert

All ETDs from UAB

Glioblastoma multiforme (GBM) are the most prevalent and aggressive malignant brain tumors. Current treatment - a combination of radiation, chemotherapy and resection - has limited effectiveness and offers poor prognosis. In this study, we examined the roles of system xc- (SXC) and excitatory amino acid transporters (EAATs), which transport the amino acids cystine and glutamate, on tumor growth, neurotoxicity, and peritumoral seizure activity. Tissue micro-arrays from 45 patients were examined by immuno-histochemistry, comparing tumor-bearing tissue and adjacent normal brain. Using a novel flank tumor propagation technique, we chose 3 glioma samples with varying SXC and EAAT expression levels to study …

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Fcrl5 Exerts Binary And Compartment-Specific Influence On Innate-Like B Cell Receptor Signaling, Zilu Zhu Jan 2012

Fcrl5 Exerts Binary And Compartment-Specific Influence On Innate-Like B Cell Receptor Signaling, Zilu Zhu

All ETDs from UAB

Innate-like splenic marginal zone (MZ) and peritoneal cavity (PEC)-derived B1 B lymphocytes are the major contributors to primary humoral responses and play an important role in connecting innate and adaptive immunity, but are known to significantly differ in their B cell receptor (BCR) signaling characteristics. In mice, FCRL5 is discretely expressed by innate-like MZ and B1 B cells and is furthermore equipped with cytoplasmic ITAM-like and ITIM elements, suggesting diverse signaling potential for it. Our results showed that FCRL5 markedly inhibited BCR-mediated activation in MZ B cells, but not in PEC B1 B cells. To characterize its signaling function, a …

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Analysis Of Ergothioneine Production In Mycobacterium Tuberculosis, Loni Ann Guidry Jan 2012

Analysis Of Ergothioneine Production In Mycobacterium Tuberculosis, Loni Ann Guidry

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Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, currently infects more than two billion people worldwide. Mtb is a highly adaptable pathogen, capable of modifying its metabolism in response to its environment. We previously showed that Mtb WhiB3 is a redox-responsive regulator of core intermediary metabolism and lipid anabolism through which it maintains redox homeostasis. In this work, through the use of metabolomic analysis and a novel radioactive thin layer chromatography assay, we discovered that WhiB3 regulates the production of the intracellular thiol ergothioneine (ergo) when using immunomodulatory lipid precursors as the major carbon source. Our results suggest that this …

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The Role Of Histone Methylation In The Medial Temporal Lobe During Long-Term Memory Formation, Swati Gupta Jan 2012

The Role Of Histone Methylation In The Medial Temporal Lobe During Long-Term Memory Formation, Swati Gupta

All ETDs from UAB

Several studies have established the importance of epigenetic regulation of gene transcription in the brain during memory consolidation. Epigenetic mechanisms involve modifying the DNA or the associated histone proteins to determine the transcriptional outcome of a gene. The work encompassed in this dissertation serves as an initial investigation for the role of histone lysine methylation mechanisms in regulating gene activation and suppression in the medial temporal lobe that includes entorhinal cortex (EC), hippocampus, and amygdala during memory consolidation. To this end, we found that di-methylation of histone H3 at lysine 9 (H3K9me2) which promotes gene suppression was specific to associative …

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The Role Of Vpr-1 Msp Signaling In C. Elegans, Sung Min Han Jan 2012

The Role Of Vpr-1 Msp Signaling In C. Elegans, Sung Min Han

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In C. elegans, the major sperm protein (MSP) is the most abundant protein in sperm and functions as an intracellular cytoskeleton protein and a secreted extracellular signal that induces oocyte maturation and sheath contraction. Evolutionarily, MSP domain-containing proteins originate from the VAPs (VAMP/synaptobrevin-associated proteins), which comprise a highly conserved protein family with an MSP domain at the N-terminus and a transmembrane domain at the C-terminus. I have been studying the signaling role of VAP MSP domains using the C. elegans model system. In collaboration with Hugo Bellen's lab at Baylor College of Medicine, we have shown that C. elegans, Drosophila, …

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Innate Immune Mechanisms Against The Atypical Fungal Pathogen Pneumocystis Murina, Michael Paul Nelson Jan 2012

Innate Immune Mechanisms Against The Atypical Fungal Pathogen Pneumocystis Murina, Michael Paul Nelson

All ETDs from UAB

Pneumonia caused by the fungal pathogen Pneumocystis continues to be the leading cause of morbidity and mortality in AIDS patients. In addition, there are a number of other non-HIV-associated diseases that render an individual susceptible to Pneumocystis infection, including chronic obstructive pulmonary disease. Innate immune mechanisms are important for controlling Pneumocystis lung infection. As alveolar macrophages serve the front lines of lung host defense, our goal was to elucidate their responses during lung Pneumocystis infection. Here, we established a role for Src family kinases in the lung immune response to Pneumocystis, which uncovered a role for alternatively activated alveolar macrophages. …

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Thomas Jefferson University, Department Of Pathology, Anatomy And Cell Biology, Oral Administration Of Apigenin Inhibits Metastasis Through Akt/P70s6k1/Mmp-9 Pathway In Orthotopic Ovarian Tumor Model., Jun He, Qing Xu, Min Wang, Chongyong Li, Xu Qian, Zhumei Shi, Ling-Zhi Liu, Bing-Hua Jiang Jan 2012

Thomas Jefferson University, Department Of Pathology, Anatomy And Cell Biology, Oral Administration Of Apigenin Inhibits Metastasis Through Akt/P70s6k1/Mmp-9 Pathway In Orthotopic Ovarian Tumor Model., Jun He, Qing Xu, Min Wang, Chongyong Li, Xu Qian, Zhumei Shi, Ling-Zhi Liu, Bing-Hua Jiang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Apigenin, a flavonoid commonly present in the daily diet, is known for its potential anti-tumor properties. However, the effect of apigenin via oral administration on tumor growth and metastasis remains unknown. In this study we developed an orthotopic ovarian tumor model in nude mice to test the effect of apigenin oral administration, and showed that apigenin inhibited the micrometastasis of cancer cells in the animal tumor model. To understand the mechanism of apigenin in inhibiting metastasis, we found that apigenin greatly inhibited MMP-9 expression and p-AKT and p-p70S6K1 levels in the tumor tissues compared to the control group. We further …

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Loss Of Axonal Mitochondria Promotes Tau-Mediated Neurodegeneration And Alzheimer's Disease-Related Tau Phosphorylation Via Par-1., Kanae Iijima-Ando, Michiko Sekiya, Akiko Maruko-Otake, Yosuke Ohtake, Emiko Suzuki, Bingwei Lu, Koichi M Iijima Jan 2012

Loss Of Axonal Mitochondria Promotes Tau-Mediated Neurodegeneration And Alzheimer's Disease-Related Tau Phosphorylation Via Par-1., Kanae Iijima-Ando, Michiko Sekiya, Akiko Maruko-Otake, Yosuke Ohtake, Emiko Suzuki, Bingwei Lu, Koichi M Iijima

Farber Institute for Neuroscience Faculty Papers

Abnormal phosphorylation and toxicity of a microtubule-associated protein tau are involved in the pathogenesis of Alzheimer's disease (AD); however, what pathological conditions trigger tau abnormality in AD is not fully understood. A reduction in the number of mitochondria in the axon has been implicated in AD. In this study, we investigated whether and how loss of axonal mitochondria promotes tau phosphorylation and toxicity in vivo. Using transgenic Drosophila expressing human tau, we found that RNAi-mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD-related site Ser262 …

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Testosterone Treatment Fails To Accelerate Disease In A Transgenic Mouse Model Of Spinal And Bulbar Muscular Atrophy., Erica S Chevalier-Larsen, Diane E Merry Jan 2012

Testosterone Treatment Fails To Accelerate Disease In A Transgenic Mouse Model Of Spinal And Bulbar Muscular Atrophy., Erica S Chevalier-Larsen, Diane E Merry

Department of Biochemistry and Molecular Biology Faculty Papers

Evidence from multiple animal models demonstrates that testosterone plays a crucial role in the progression of symptoms in spinal and bulbar muscular atrophy (SBMA), a condition that results in neurodegeneration and muscle atrophy in affected men. Mice bearing a transgene encoding a human androgen receptor (AR) that contains a stretch of 112 glutamines (expanded polyglutamine tract; AR112Q mice) reproduce several aspects of the human disease. We treated transgenic male AR112Q mice with testosterone for 6 months. Surprisingly, testosterone treatment of AR112Q males did not exacerbate the disease. Although transgenic AR112Q males exhibited functional deficits when compared with non-transgenics, long-term testosterone …

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