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Full-Text Articles in Medical Sciences
The Sodium-Potassium-Chloride Cotransporter In Glioma Biology, Brian R. Haas
The Sodium-Potassium-Chloride Cotransporter In Glioma Biology, Brian R. Haas
All ETDs from UAB
The most common malignant primary brain tumor, gliomas usually derive from glial cells including oligodendrocytes and astrocytes. These tumors are characterized by high rates of proliferation and aberrant migration which make them notoriously difficult to treat using standard treatment paradigms such as chemotherapy and radiation. In order for glioma cells to migrate into the surrounding brain tissue, they must undergo rapid and dynamic volume changes. Previous work published by the Sontheimer laboratory and others indicates glioma utilize the flux of ions across the cell membrane to aid in volume changes associate with cell migration. In this dissertation, I show the …
Assessment Of Mitochondrial Stressors On Cellular Bioenergetics, Blake Reid Zelickson
Assessment Of Mitochondrial Stressors On Cellular Bioenergetics, Blake Reid Zelickson
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The mitochondrion plays a central role in the maintenance of bioenergetic function through the production of ATP and essential metabolites. The development of mitochondrial bioenergetic defects is a hallmark of important pathologies such as cardiovascular and liver diseases. It is well established that a decrease in mitochondrial function, typically of 20-40%, is associated with the progression of these pathologies. Causal relationships have been more difficult to establish because of the challenge of assessing mitochondrial function in a cellular setting. Specifically, it is known that mitochondria function at less than their maximal respiratory capacity and the remainder, known as reserve or …
The Role Of Tgf-Ss Receptors In The Induction Of Mucosal Tolerance, Rebekah Sims Gilbert
The Role Of Tgf-Ss Receptors In The Induction Of Mucosal Tolerance, Rebekah Sims Gilbert
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Oral tolerance, defined as the immunologic state of systemic and mucosal unresponsiveness to an antigen, is an essential function of the mucosal immune system. Although antigen presentation has been found to play an important role in oral tolerance, T cells are known to be the effector immune cells that perpetrate this state. Recent studies found that antigen-specific T regulatory (Treg) cells are important in the induction and maintenance of oral tolerance. The extrathymic development of these Tregs depends on the presence of TGF-ß1 during the differentiation process. However, it has also been shown that oral tolerance could be induced in …
Oxidative Stress And Xanthine Oxidase In Acute And Chronic Cardiac Volume Overload In Rats, James Douglas Gladden
Oxidative Stress And Xanthine Oxidase In Acute And Chronic Cardiac Volume Overload In Rats, James Douglas Gladden
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Mechanisms of left ventricular dysfunction in cardiac volume overload (VO) are not well understood and there is no medical therapy. Cardiac VO is marked by eccentric remodeling and contractile dysfunction ultimately resulting in cardiac failure. Oxidative stress is implicated in the pathophysiology of heart failure and recent evidence suggests xanthine oxidase (XO) plays a role in VO. To study VO, we used a rat model of aortocaval fistula (ACF). ACF results in early diastolic stress on the left ventricle (LV) and recapitulates the progressive nature of heart failure with contractile function being initially maintained and then depressed by 6 weeks. …
The Effects Of Simvastatin On Learning And Memory Mechanisms In Mice, Robert Mans
The Effects Of Simvastatin On Learning And Memory Mechanisms In Mice, Robert Mans
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Statins, a widely prescribed class of cholesterol-lowering drug, inhibit HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway. Due to the identification of cholesterol as a risk factor for developing Alzheimer's disease (AD), a number of studies have examined whether statins are neuroprotective against developing AD or dementia. While some epidemiological studies do indicate a lower prevalence of AD in people taking statins, other reports are contradictory. A consensus has therefore not been reached regarding the neuroprotective effects of statin treatment. Aside from the well-characterized reduction in circulating cholesterol resulting from statin therapy, numerous cholesterol-independent, pleiotropic effects have been …
Bone Morphogenetic Protein Signaling Pathways During Mouse Heart Development: Roles For Chd7 And Mycn, Cristina Harmelink
Bone Morphogenetic Protein Signaling Pathways During Mouse Heart Development: Roles For Chd7 And Mycn, Cristina Harmelink
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Bone Morphogenetic Protein (BMP) signaling pathways are imperative for proper heart development. BMP ligands bind serine threonine kinase receptors, which activate intracellular receptor-regulated SMAD proteins. SMAD1, SMAD5, and SMAD8 transduce BMP signals from the cytoplasm to the nucleus, where they regulate transcription. We have investigated two aspects of BMP signaling during mouse cardiogenesis: identifying SMAD1-interacting proteins and exploring the roles of a known BMP target, Mycn, in the developing myocardium. Chromodomain helicase DNA binding protein 7 (CHD7) is a highly conserved transcription factor that promotes protein synthesis, proliferation, and differentiation. Haploinsufficiency for CHD7 causes CHARGE syndrome, a developmental disorder characterized …
Low And High Let Irradiation Of Human Aortic Endothelial Cells Induces Dose And Time Dependent Adhesion Of Monocytes Which Is Mediated By Chemokines Expressed By The Irradiated Endothelium., Saman Fatima Khaled
Low And High Let Irradiation Of Human Aortic Endothelial Cells Induces Dose And Time Dependent Adhesion Of Monocytes Which Is Mediated By Chemokines Expressed By The Irradiated Endothelium., Saman Fatima Khaled
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Exposure to radiation from a variety of sources is associated with increased risk of heart disease and stroke. Since radiation also induces inflammation, a possible mechanism is a change in the adhesiveness of vascular endothelial cells, triggering pro-atherogenic accumulation of leukocytes. To investigate this mechanism at the cellular level, the effect of xrays, iron (Fe56) ions, and protons on adhesiveness of cultured human aortic endothelial cells (HAECs) was determined. HAECs were grown as monolayers and exposed to 0 to 30 Gy X-rays, 0, 2, and 5 Gy Fe56 ions, and 0, 0.5, and 2 Gy protons followed by measurement of …
Broad And Potent Neutralizing Antibody Responses Elicited In Natural Hiv-2 Infection, Rui Kong
Broad And Potent Neutralizing Antibody Responses Elicited In Natural Hiv-2 Infection, Rui Kong
All ETDs from UAB
Little is known about the potency, breadth and epitope specificities of neutralizing antibody (Nab) responses elicited in natural HIV-2 infection. Analysis of plasma specimens from 64 HIV-2 chronically-infected subjects in a single round infectivity assay (JC53bl-13/TZM-bl) revealed median reciprocal IC50 Nab titers of 1.7x105, 2.8x104 and 3.3x104 against three primary virus strains, HIV-27312A, HIV-2ST and HIV-2UC1, respectively. A subset of 5 plasma samples was tested on 17 additional HIV-2 strains, and similarly high Nab titers were observed against all but four viruses. These Nab titers were higher, by orders of magnitude, than HIV-1 Nab titers in plasma from chronically infected …
Regulation Of Neuronal Death By The Autophagy Lysosomal Pathway: Implications For Parkinson Disease, Violetta N. Pivtoraiko
Regulation Of Neuronal Death By The Autophagy Lysosomal Pathway: Implications For Parkinson Disease, Violetta N. Pivtoraiko
All ETDs from UAB
Parkinson Disease (PD) is the second most common age-related neurodegenerative disorder and is characterized pathologically by the loss of dopaminergic (DA) neurons in the stubstantia nigra pars compacta (SNpc). Mitochondrial dysfunction, increased oxidative stress, and accumulation of aggregated α-synuclein (α-syn), an intracellular protein involved in synaptic function, are all pathological hallmarks of PD have been implicated in PD pathogenesis. However, it is debated whether α-syn aggregates themselves are responsible for neurodegeneration in PD, cellular pathways involved in degradation of α-syn aggregates are believed to promote neuron survival. The autophagy lysosomal pathway (ALP), a physiological mechanism for recycling of intracellular components, …
Gabaergic Signaling To Adult-Generated Neurons In Hippocampus, Sean Markwardt
Gabaergic Signaling To Adult-Generated Neurons In Hippocampus, Sean Markwardt
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In the central nervous system of adult mammals, new neurons are produced throughout life in at least two regions, the subventricular zone and dentate gyrus of the hippocampus. New neurons in the SVZ migrate via the rostral migratory stream and eventually participate in adaptive olfactory processes. In the dentate gyrus, a variety of physiological functions for continued addition of neurons have been proposed, but its role in normal or pathological conditions remains largely unclear. Neurogenesis in the dentate gyrus consists of the stepwise process of generating fully functional granule cells (GCs) from adult neural stem cells. Regulation of neurogenesis can …
Analysis Of Nphp Complex Genetic Interactions Associated With Human Cilia Disorders, Svetlana Viktorovna Masyukova
Analysis Of Nphp Complex Genetic Interactions Associated With Human Cilia Disorders, Svetlana Viktorovna Masyukova
All ETDs from UAB
Primary cilia are antenna-like organelles that extend from the surface of almost all mammalian cell types. They regulate many signaling pathways and sense physical and chemical changes in the extracellular environment. Defects in primary cilia cause several human disorders of different severity collectively called ciliopathies, including nephronophthisis (NPHP), Joubert syndrome (JBTS), and Meckel-Gruber syndrome (MKS). Numerous MKS, JBTS and NPHP genes have been identified but in most cases of these ciliopathies the genetic defect is unknown. Despite the fact that NPHP, JBTS and MKS patients present with distinct clinical features, they have mutations in identical genes. This can be explained …
The Role Of Protein Folding And Protein Trafficking In Human Disease, Cristy Davette Tower-Gilchrist
The Role Of Protein Folding And Protein Trafficking In Human Disease, Cristy Davette Tower-Gilchrist
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This dissertation documents my findings in two unrelated projects. Project 1: Expansion of CAG repeats encoding glutamine in huntingtin and ataxin 3 causes the neurodegenerative diseases Huntington's disease (HD) and spinocerebellar ataxia 3 (SCA3), respectively. Both poly-glutamine (polyQ) expanded proteins misfold and ag-gregate within the cell. Preventing aggregation of polyQ proteins through molecular or pharmacological approaches provide therapeutic advantage in animal models of HD and SCA3. I hypothesized that the UL97 kinase encoded by the human cytomegalovirus (HCMV) may be able to prevent the aggregation of polyQ proteins. Initially, I showed that the UL97 kinase prevents the deposition of aggregates …
Expanding Genetic Analysis Of Patients With A Neurofibromatosis Type 1-Like Phenotype, Emily Spencer
Expanding Genetic Analysis Of Patients With A Neurofibromatosis Type 1-Like Phenotype, Emily Spencer
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Neurofibromatosis Type 1, a common autosomal dominant disorder with neuro-cardio- facio-cutaneous presentation, is caused by mutations in the NF1 gene, a negative regulator of RAS-MAPK signaling. The presentation of NF1 is overlapping, yet clinically distinct from other diseases of RAS-MAPK signaling. An RNA-based comprehensive approach for mutation detection identifies an NF1 alteration in over 95% of non-founder NF1 patients with a classical NF1 presentation. However, no NF1 mutation was identified in 54.2% of the 2432 patients referred for molecular diagnostics due to the presence one or more NF1 related sign between August 2003 and July 2007. In order to clarify …
Molecular Piracy In The Mobilization Of Staphylococcus Aureus Pathogenicity Island 1, Michael Spilman
Molecular Piracy In The Mobilization Of Staphylococcus Aureus Pathogenicity Island 1, Michael Spilman
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Staphylococcus aureus bacteriophage 80α is a temperate, double-stranded DNA phage that serves as a "helper" phage for the mobilization of several S. aureus pathogenicity islands (SaPIs), including SaPI1. When mobilized by 80α, SaPI1 genomes are packaged into smaller phage-like transducing particles composed of 80α capsid (gp47), scaffolding (gp46) and portal (gp42) proteins. In this dissertation, I utilize electron microscopy and biochemistry to tease apart the structural and genetic controls and consequences of SaPI1 as a molecular pirate. More specifically, I show that two SaPI1 proteins shift assembly from 63-nm, T = 7 icosahedral capsids to 47-nm, T = 4 capsids, …
Myosin Ii In Hippocampal Synapses: Regulation Of Synaptic Plasticity, Strength And Actin Dynamics By Two Distinct Isoforms, Maria Dolores Rubio
Myosin Ii In Hippocampal Synapses: Regulation Of Synaptic Plasticity, Strength And Actin Dynamics By Two Distinct Isoforms, Maria Dolores Rubio
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Cytoskeletal actin filaments underlie dendritic spine plasticity, critical for several forms of learning and memory. Therefore, understanding the mechanisms that regulate actin dynamics is essential to elucidate memory formation pathways. Myosins, a superfamily of actin binding proteins, have emerged as candidates for regulation of actin dynamics in the brain. Several myosin class II isoforms have been identified in brain, but their individual contribution to synaptic activity is still unknown. Based on the finding that myosin IIB regulates actin polymerization in the growth cone of developing neurons and that it is necessary for maintenance of dendritic spine structure, I hypothesized that …
The Natural History Of Sivcpz Infection In Wild Living Chimpanzees, Rebecca Steele Rudicell
The Natural History Of Sivcpz Infection In Wild Living Chimpanzees, Rebecca Steele Rudicell
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Simian immunodeficiency virus of chimpanzees (SIVcpz) is the immediate precursor to human immunodeficiency virus type 1 (HIV-1), but even the most basic aspects of SIVcpz infection in its natural host are unknown. Here, we present the first comprehensive analysis of the natural history of SIVcpz infection in wild living chimpanzees. Using non-invasive (feces and urine based) methods, we studied two unique chimpanzee populations in Tanzania: the famous chimpanzees of Gombe National Park and the savanna chimpanzees of Ugalla, located about 135 km southeast of Gombe. Gombe chimpanzees are endemically infected with SIVcpz, and the park's established research infrastructure provides a …
Sensitization Of Glioma To Death Receptor 5-Mediated Apoptosis Through Genotoxic Stress And Cell Cycle Disruption: A Study Of Mechanism, Michael L. Belenky
Sensitization Of Glioma To Death Receptor 5-Mediated Apoptosis Through Genotoxic Stress And Cell Cycle Disruption: A Study Of Mechanism, Michael L. Belenky
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Our laboratory reported that a combination of ionizing radiation (IR) or temozolomide (Tmz), a DNA methylating agent clinically approved against glioblastoma multiforme (GBM), a type of human brain cancer, and TRA-8, an anti-DR5 monoclonal antibody produced synergistic cytotoxicity in GBM cells in culture and in mouse xenograft models through an yet unknown mechanism. I hypothesized that understanding of the synergy phenomenon can offer an insight into the nature of GBM vulnerability. The goals of this investigation were two-fold - to elucidate the mechanism of this enhancement in cytotoxicity, and to improve understanding of DR5 mediated apoptosis toward improvement of current …
Qualitative Analysis Of Hiv-1-Specific Cd8 T Cell Responses, Olusimidele Tolulope Akinsiku
Qualitative Analysis Of Hiv-1-Specific Cd8 T Cell Responses, Olusimidele Tolulope Akinsiku
All ETDs from UAB
In the absence of antiretroviral therapy (ART), the majority of individuals infected with human immunodeficiency virus-1 (HIV-1) will develop AIDS. HIV-1-infected controllers are exceptions to the rule; without the use of ART, these individuals spontaneously control virus replication. A better understanding of the immune mechanisms that mediate delayed disease progression, as seen in controllers, will provide valuable insight to the design and development of an effective HIV-1 vaccine. CD8 T cells are important mediators of the antiviral immune response. However, it is unclear which components of the response are critical for long-lasting protection during HIV-1 infection. We first review methods …
Limited Transplantation Of Antigen-Expressing Hematopoietic Stem Cells Induces Long-Lasting Cytotoxic T Cell Responses And Effect Of Altered Suppressive Myeloid Population On Hiv-Disease Progression, Warren L. Denning
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While each type of cancer and chronic viral infection has its own specific pathology, they share two common mechanisms of immune evasion. The first mechanism is the exhaustion or deletion of antigen-specific T cells. The second mechanism is the formation of an immunosuppressive environment responsible for the block of T cell function. Elicitation of antigen-specific T cells be accomplished by immunotherapy in place of conventional treatments such as HAART and chemotherapy. In addition, immunotherapy can alleviate the side-effects associated with long-term use of conventional therapies while reducing the total cost. The results presented here provide an alternative to conventional methods …
Significance And Regulation Of Cd68 Expression In The Osteoclast, Jason Waid Ashley
Significance And Regulation Of Cd68 Expression In The Osteoclast, Jason Waid Ashley
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The mucin-like Lysosome Associated Membrane Protein (LAMP) family member CD68 is a primarily myeloid lineage restricted transmembrane protein that is expressed in macrophages and osteoclasts. While the existence and expression pattern of human CD68 and mouse CD68 (sometimes called macrosialin) are well-known, and these molecules are routinely used as histological markers of tissue macrophages, the functional signific-ance of CD68 expression remains an unanswered question. Our overall goal is to deter-mine the significance and characterize the function of CD68 in osteoclasts and explore the effects of Receptor Activator of Nuclear Factor κB (RANK) signaling on CD68 post-translational modification. To achieve this …
The Effect Of Sulfasalazine On Functional Recovery And Neuropathic Pain Following Spinal Cord Injury, Kelly Dunham Atkins
The Effect Of Sulfasalazine On Functional Recovery And Neuropathic Pain Following Spinal Cord Injury, Kelly Dunham Atkins
All ETDs from UAB
Spinal cord injury (SCI) is a devastating condition resulting in loss of motor function as well as sensory abnormalities. Insight into the pathophysiology of SCI progression has been gained through use of pre-clinical animal models, however these have not been successful in yielding pharmacological interventions for clinical management of SCI. One proposed reason for this discrepancy may be the use of SCI models which are not fully clinically relevant and do not assess the contribution of gray matter pathology to SCI functional outcomes. Post-SCI inflammation is well-documented and may lead to downstream loss of motor function. Additionally, inflammation is thought …
Mechanisms And Consequences Of Thy-1 Shedding, John Edwin Bradley
Mechanisms And Consequences Of Thy-1 Shedding, John Edwin Bradley
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Idiopathic Pulmonary Fibrosis (IPF) is characterized by chronic fibrosis in the lung interstitium of unknown etiology, and causes death within 2 to 4 years after diagnosis. There are no clinical interventions save for lung transplantation that give any survival benefit. Aberrant collagen deposition and aggregates of proliferating fibroblasts and myofibroblasts called fibroblastic foci (FF) are the classic features of IPF. Therefore, the cell type most often implicated as pathogenic in IPF is the fibroblast, especially its differentiated phenotype, the myofibroblast. Fibroblasts are a remarkably heterogeneous cell type. Expression of the cell surface glycoprotein Thy-1 (Thymocyte differentiation antigen 1) delineates a …
Mitochondrial Genetics And Function In Cardiovascular Disease Susceptibility, Jessica L. Brenneman
Mitochondrial Genetics And Function In Cardiovascular Disease Susceptibility, Jessica L. Brenneman
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While progress has been made in understanding the development and progression of cardiovascular disease (CVD), the mechanisms of CVD risk and initiation are not completely understood. It is widely accepted that CVD is the result of a combination of genetic and environmental factors but it is not known why some populations with otherwise similar risk factors appear more susceptible to CVD than others. It is also known that different strains of laboratory mice have distinct susceptibilities to CVD development. For example, C3H mice are resistant to diet induced atherogenesis whereas C57 animals are susceptible. We have also found that the …
Role Of Ras Proteins In Malignant Peripheral Nerve Sheath Tumors, Nicole Marie Brossier
Role Of Ras Proteins In Malignant Peripheral Nerve Sheath Tumors, Nicole Marie Brossier
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Malignant peripheral nerve sheath tumors (MPNSTs) arising in patients with neurofibromatosis type I (NF1) are null for the tumor suppressor neurofibromin, a negative regulator of signaling from both classic Ras (H-Ras, N-Ras and K-Ras) and R-Ras (R-Ras, R-Ras2/TC21, M-Ras/R-Ras3) subfamily members. Treatment of these tumors with Ras-targeted agents such as farnesyltransferase inhibitors has proven unsuccessful, likely due to the inability of these agents to successfully target all of the Ras isoforms regulated by neurofibromin. Thus, determining which Ras isoforms are critical for MPNST pathogenesis would be of therapeutic value. In this dissertation, we first review the clinical manifestations of NF1 …
Identification And Characterization Of Novel Adenosine Cleavage Enzymes In Mycobacteria, Kajal Buckoreelall
Identification And Characterization Of Novel Adenosine Cleavage Enzymes In Mycobacteria, Kajal Buckoreelall
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Tuberculosis (TB) is one of the leading infectious diseases in the world. An estimated one third of the world's population is infected with Mycobacterium tuberculosis, the causative pathogen of TB. With the emergence of drug resistant strains of the mycobacterium, and the HIV-TB coinfection epidemic, TB remains a global health emergency. Purine metabolism is an essential cellular component to all living cells. Previous studies have shown that differences exist between mycobacterial and human purine metabolism. One of the differences was in the metabolism of adenosine (Ado), whose cleavage was observed in mycobacterial cells whereas Ado cleavage is inefficient in human …
Analysis Of The Structural And Kinetic Properties Of Sult2a1 Induced By The Binding Of 3'-Phosphoadenosine-5'-Phosphosulfate, Ian Thomas Cook
Analysis Of The Structural And Kinetic Properties Of Sult2a1 Induced By The Binding Of 3'-Phosphoadenosine-5'-Phosphosulfate, Ian Thomas Cook
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Sulfation is an important Phase II drug metabolism reaction catalyzed by the cytosolic sulfotransferases (SULTs). SULT2A1 is a major SULT in liver and adrenal cortex that has been reported to sulfate a wide variety of substrates including bile acids, steroids, and drugs. The crystal structures of SULT2A1 suggest that PAPS binding causes a structural change. This study examines the kinetic changes in SULT2A1 caused by PAPS binding using computer modeling, enzyme kinetics, binding studies, and mammalian cells expressing SULT2A1. The data presented clearly demonstrate that the binding of PAPS changes the affinity of some substrates to SULT2A1 resulting in different …
Understanding Molecular Mechanisms Of Breast Cancer Metastasis Using Genetically-Engineered Mice, Leah M. Cook
Understanding Molecular Mechanisms Of Breast Cancer Metastasis Using Genetically-Engineered Mice, Leah M. Cook
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Morbidity and mortality of breast cancer patients are drastically increased when primary tumor cells metastasize to distant organ sites. Effective treatment of metastatic disease has been limited; therefore, an increased molecular understanding to identify biomarkers and therapeutic targets is needed. Breast cancer metastasis suppressor 1 (BRMS1) suppresses development of metastases when expressed in a variety of cancer types, including metastatic mammary carcinoma. Little is known of Brms1 function throughout the initiation and progression of mammary carcinoma. Thus Brms1 transgenic mice (derived on C57BL/6 background) were generated by utilizing MMTV promoter expression (for mammary-selective overexpression) or the beta-actin promoter (for ubiquitous …
Structural And Mechanistic Studies On Er Upr Sensor Perk And Mitochondrial Translocon Element Tim44, Wenjun Cui
Structural And Mechanistic Studies On Er Upr Sensor Perk And Mitochondrial Translocon Element Tim44, Wenjun Cui
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The unfolded protein response is one mechanism utilized by endoplasmic reticulum (ER) to maintain the homeostasis between ER protein folding machinery and ER proteins. UPR is induced by three ER transmembrane sensors: IRE1, ATF6 and PERK. PKR-like ER kinase (PERK) can sense the ER stress signal through its luminal domain to activate its cytoplasmic kinase domain catalytic activity. PERK kinase domain belongs to the eIF2α family. Members in this family are activated after being autophosphorylated at their activation loops and then specifically phosphorylate eIF2α at its Ser51 position. Phosphorylation of eIF2α can shutdown the cytosol protein translation from the initiation …
Characterization Of Tbx20 Isoforms And Protein Interactions In Heart Development, Paige Debenedittis
Characterization Of Tbx20 Isoforms And Protein Interactions In Heart Development, Paige Debenedittis
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Proper cardiogenesis is critical for the development of vertebrates. Abnormalities in cardiogenesis can lead to congenital heart defects (CHDs), which occur in approximately 1% of live births. The cardiac transcription factor network contains different transcription factor families which direct the expression of critical cardiac genes. Determining how the cardiac transcription factors are regulated will provide insight in the mechanisms of cardiogenesis and CHDs. The T-box (TBX) transcription factor family is an ancient gene family important for development. Several TBX genes are expressed within the developing heart and play critical roles in differentiation, proliferation, and morphogenesis. One important TBX protein is …
Role Of The Cardiomyocyte Circadian Clock In Modulating Myocardial Physiology And Pathophysiology, David Joseph Durgan
Role Of The Cardiomyocyte Circadian Clock In Modulating Myocardial Physiology And Pathophysiology, David Joseph Durgan
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It is well established that multiple parameters of cardiovascular physiology and pathophysiology exhibit diurnal variations. For example, human heart rate and blood pressure peak during the morning and trough in the evening. Similarly, there is a morning prevalence for the onset of multiple adverse cardiovascular events, including myocardial ischemia, arrhythmias, and sudden cardiac death. Traditionally these rhythms have been attributed to rhythms in neurohumoral stimulation. However recent identification of the circadian clock mechanism in cardiovascular relevant cell types, including the cardiomyocyte, has prompted investigation into its role in modulating myocardial physiology and pathophysiology over the course of the day. Preliminary …