Alevriadou, Rita

My areas of expertise are in vascular biology/bioengineering, endothelial cell mechano­transduc­tion (signal trans­duction due to mechanical forces, especially shear stress), oxidative stress, mole­cular mechanisms of blood cell adhesion, throm­bosis and inflamma­tion. My research focus has been on: (a) The role of hemodynamic forces and oxidative stress in vascular endothelial cell signal trans­duction, gene expression and protein synthe­sis, with empha­sis on the mitochondrial endothelial cell dysfunc­tion fol­lowing ischemia/reperfusion. (b) The role of hemodynamic forces, cell receptors and plasma proteins in thrombosis (platelet ad­hesion/ag­grega­tion) and inflammation (leukocyte-endothelial cell adhesion). 

Alfonzo, Juan

Two major research efforts are underway in my laboratory: 1) tRNA editing and modification in trypanosomes and 2) the mechanism of tRNA import into mitochondria. On the tRNA editing front, our research focuses on how anticodon editing is specified. tRNA undergoes a number of posttranscriptional modifications (including editing) that are essential for cell viability.  We believe that editing and modification are interrelated processes that lead to an exquisite level of substrate specificity. Although in our view modifications provide a changing structural landscape that leads to editing specificity, these ever changing structures will be in fact meaningless unless they lead to specific recognition by protein factors involved in both editing and modification. We therefore concentrate in defining structure/function relationships that maintain the overall fidelity of these processes. On the import front, we are interested in using a number of biochemical and biophysical approaches to define how tRNA import into mitochondria is specified, which will undoubtedly involve both specific protein receptors on the mitochondrial membrane as well as cis-acting determinants on the imported tRNAs. Therefore the central theme of our research rests on the principle that a variety of protein-nucleic acid interactions are key to defining the proper recognition of tRNA. In the case of tRNA editing this recognition is unique in that it does not occur in humans. As an essential step in tRNA maturation in trypanosomatids (Leishmania and Trypanosoma) it thus provides a very attractive target for therapeutic intervention against parasites of very major medical importance. In the case of tRNA import, many studies link mitochondrial tRNA mutations with metabolic disorders in humans leading to the development of a number of mitochondrial diseases. Defining the key protein-nucleic acid interactions involved in import specificity will lead to a possible exploitation of import mechanisms to introduce mutant tRNAs into mitochondria. This will not only help clarify the specific roles that tRNA mutations play in mitochondrial malfunction but could even serve in the long term as a form of gene therapy. 

Broekemeier, Kimberly

My research focuses on mitochondrial lipid metabolism and its relationship to the mitochondrial permeability transition.  I recently established that rat liver mitochondria contain a Ca2+-independent phospholipase A2 whose activity is up-regulated when mitochondria are de-energized.  Efforts are directed at clarification of the mechanism by which PLA2 activity is linked to mitochondrial de-energization and to determine the physiological/pathological conditions that might function to up-regulate PLA2 activity in vivo.  Since it is established that free fatty acids facilitate opening of the permeability transition pore, it is also of interest to determine whether the products of this PLA2 activity play a role in opening the permeability pore and in processes affected by pore opening such as apoptosis and mitochondrial autophagy.  In conjunction with a role in PLA2 in mitochondria autophagy, I am also investigating whether those mitochondria who have sustained a greater amount of peroxidative or other damage are more likely to undergo the permeability transition and subsequent degradation.  An additional area of investigation is whether there is a lysophospholipase activity in mitochondria that is either associated with the putative PLA2 or free standing that could participate in mitochondrial degradation. .

Chen, Yeong-Renn

My research activities are focused on bioenergetics and free radical metabolism in postischemic heart. The long-term goal of my research is to elucidate the molecular mechanism of how mitochondria-derived oxygen free radical(s) and its related post-translational redox modifications are related to the pathogenesis of myocardial injury.  Specifically, we have used the model systems of isolated enzyme, in vitro and in vivo postischemic myocardium to test our hypothesis.  Our specific research interests encompass two areas: (a) Fundamental mechanism of oxygen free radical(s) generation in mitochondria and its derived post-translational modification(s). (b) Oxidative injury and redox modification of mitochondrial electron transport chain in postischemic heart.

Clanton, Thomas

Our laboratory’s research interests involve primarily the fields of skeletal and cardiac muscle function; the role of free radicals and inflammatory mediators on cell function; cellular stress responses to stimuli such as heat exposure, hypoxia and ischemia; and the interaction of reactive oxygen and reactive nitrogen species on metabolism, mitochondrial function and cell survival mechanisms.  We continue to develop new NMR and fluorescent technologies for free radical detection and imaging in vivo or in situ and are developing new areas of research related to the physiologic and genomic responses of cardiac and skeletal muscle to continuous and intermittent hypoxia.  

 Crestanello, Juan

The Crestanella Lab's research focuses on of ischemia- reperfusion injury in heart with an emphasis on mitochondrial function and the effects of ischemic preconditioning and post conditioning on mitochondrial properties. The role of mitochondrial KATP channels, the mitochondrial permeability transition pore, and oxygen free radicals are being investigated. in these regards.. 

Crouser, Elliott

The Crouser lab is primarily interested in the role of mitochondria in the pathogenesis of cell and organ dysfunction in the context of acute critical illness.  To this end, we are currently investigating specific biological markers of mitochondrial damage and examining the role of mitochondrial turnover, including biogenesis and destruction (autolysis, autophagy), in the context of acute organ failure, which is the leading cause of death in critically ill patients. 

Dalby, Ross

Our laboratory is studying how proteins assemble into biological membranes in bacteria.  Our main effort involves the role of YidC, a newly discovered protein, in membrane protein biogenesis.  YidC has homologs in eukaryotes called Oxa1 and Alb3 in mitochondria and chloroplasts, respectively.   Briefly, in the year 2000, YidC was shown to be an essential protein for bacterial growth.  YidC plays a direct role in the membrane insertion process and is absolutely essential for the membrane insertion of the Sec-independent M13 procoat and Pf3 coat protein.  Recent studies show that YidC plays an important role for the insertion of certain energy transduction proteins.  YidC can promote the insertion of the F0 sector subunits of the ATP synthase.  The ATP synthase inserts by the novel YidC pathway, while subunits a and b appear to insert by the Sec/YidC pathway.  In addition, YidC plays an important role for subunit II (cyoA) of the respiratory protein cytochrome bo oxidase, which is made with a cleavable signal peptide and spans the membrane twice with a short N-terminal domain and a large C-terminal domain.  These studies on the assembly of bacterial membrane proteins will help understand the role of Oxa1 in the membrane biogenesis in mitochondria. 

Doseff, Andrea

The main interest of my research is to understand the regulation of apoptosis, an essential process involved in normal development, innate immune response, cell differentiation and cancer.  Specifically we focus in studying the mechanisms that regulate the activation of caspases, cysteine proteases involved in apoptosis.  We combine molecular, biochemical, cellular biology and bioinformatic approaches to study the signaling pathways and the direct regulators that contribute to the activation and deactivation of caspases. Main interest is to understand the role of kinases, phosphatases, reactive oxygen species, and the mitochondria in the regulation of caspases. We have recently identified the direct role of PKCd and small heat shock proteins in the regulation of caspase-3 and the dissection of this interaction during normal and malignant differentiation are currently under investigation.  These findings are also being extended as a translational research using the apoptotic regulators as potential therapeutic targets and markers.  Furthermore, the conservation of this regulatory network in extended to other caspases.  In addition, we are investigating the mechanisms of flavonoids as anti-inflammatory and anti-neoplastic agents. These results should contribute to a better understanding of basic mechanisms during sepsis, cancer and the formation of the atherosclerotic plaque. 

Ghafourifar, Pedram

Pedram Ghafourifar’s areas of research include: Biology of mitochondrial nitric oxide synthase; Roles of nitrogen oxide species in regulating mitochondrial and cellular functions and homeostasis; Interactions of nitrogen oxide species with mitochondria; Functions of mitochondria for programmed cell death.  Dr. Ghafourifar’s laboratory is interested studying nitrogen oxide species particularly those generated by the mitochondria in physiologic and pathologic conditions in cardiovascular and central nervous systems.  His laboratory is studying mitochondria and nitrogen oxide species in cardiac ischemia/reperfusion and degenerative conditions of the nervous system. 

Gibbs, Lisle

Basal metabolic rate (BMR) is a fundamental physiological property of vertebrate organisms that sets the “pace of life” of individuals with consequent cascading effects on a wide range of important life history characteristics.  A colleague (Joe B. Williams, Dept. EEOB) and I are exploring the hypothesis that variation in BMR and peak metabolism (PMR) in wild birds and mammals can, at least in part, can be attributed to functional variation in the relatively few genes in the mitochondria, the organelles responsible for O2 consumption and heat production.  Specifically we propose that changes as a result of natural selection acting on mitochondrial genes in species from different environments influence the rate of electron (e-) flow in the electron transport system (ETS) and the proton leak across the inner mitochondrial membrane as well as its proton motive force, all modulated by polypeptides of mitochondrial complexes, and that these changes influence the rate of metabolism. We seek to test the proposed mechanism linking mitochondrial function and BMR using inbred stains of mice that vary substantially in BMR. The possible biomedical significance of this work is that Williams has recently demonstrated a link between BMR and resistance to infection in wild birds. If such a link also holds for mice then this may provide a system for studying previously unexplored links between mitochondrial function and infection resistance via metabolic processes. 

Hamel, Patrice

My research program focuses on the biogenesis of energy transducing membrane systems, in particular those evolved in organelles. Using Saccharomyces cerevisiae as a model system, we are investigating the assembly pathway of mitochondrial c-type cytochromes, a class of hemoproteins with a covalently bound cofactor. The discovery of an unrecognized flavoprotein involved in the maturation process and a candidate cytochrome c assembly complex in the mitochondrial inner membrane is a recent development of our work. The other aspect of my research deals with the biogenesis of mitochondrial complex I in the green alga Chlamydomonas reinhardtii. We are addressing this question through the isolation of nuclear mutants that are specifically impaired for the assembly of complex I and the molecular identification of novel assembly factor genes. A marker for biolistic transformation of the mitochondrial genome is being engineered in order to reconstruct pathogenic mutations in mitochondrial subunits and study their impact on the assembly/activity of complex I. 

Hoyt, Kari

We are interested in the molecular mechanisms underlying the loss of neurons in neurodegenerative diseases. Neuronal death or dysfunction is a consequence of acute events such as stroke or trauma, or more chronic degenerative processes that occur in Parkinson’s, Huntington’s, and Alzheimer’s diseases. While the proximate trigger of neuronal death in these acute and chronic neurodegenerative processes may be different, it is becoming clear that the actual processes leading to death may be similar. Our research is directed toward understanding the toxic cellular processes which lead to neuronal loss, with the ultimate goal of developing therapeutic interventions. Calcium dysregulation, oxidative stress and mitochondrial dysfunction are among the causes often implicated in neuronal death, and are currently under study in the lab.  

Hu, Keli

Ion channels are an important class of integral membrane proteins that allow cells to generate electrical signals. They are commonly involved in communication and regulation processes, and are the target for many drugs. While functional modulation of ion channels have been studied extensively, traffic regulation of ion channels is important but still poorly understood. Many heart diseases, such as congestive heart failure, hypertrophy, or atrial fibrillation, undergo electrical and ionic remodeling. Molecular mechanisms underlying ionic remodeling are not understood at traffic level. The long-term research interest in my laboratory is to study the function and regulation of metabolically-sensitive ion channels using cellular and molecular approaches, with a special emphasis on traffic regulation, molecular mechanisms and their physiological relevance, particularly as these processes relate to human diseases. One of our focuses is to define the role and regulation of ATP-sensitive K+ (KATP) channels during ischemia. The ultimate goal is to help developing preventive and therapeutic strategies for ischemic heart diseases.. 

Ibba, Micheal

Our work is focused on the biochemical and genetic analyses of the quality control mechanisms required for accurate protein synthesis. Accurate selection of amino acids is essential for faithful translation of the genetic code. Errors during amino acid selection are usually corrected by the editing activity of aminoacyl-tRNA synthetases, such as phenylalanyl-tRNA synthetases (PheRS), which edit misactivated tyrosine. Through comparison of cytosolic and mitochondrial PheRS from the yeast Saccharomyces cerevisiae we found that mitochondria lack the canonical editing activity. This difference between the mitochondria and the cytosol suggests that either organellar protein synthesis quality control is focused on another step or that translation in this compartment is inherently less accurate than in the cytosol.  Our current work is focused on examining the fidelity of mitochondrial protein synthesis, and how this relates to the disease phenotypes associated with mitochondrial myopathies resulting from mutations in transfer RNA genes. 

Jurkowitz, Marianne

Our work focuses on the function and metabolism of plasmalogens and lysoplasmalogens in health and in diseases (e.g. energy metabolism compromise). Plasmalogens are major glycerophospholipid components of cell membranes, and are different from diacyl glycerophospholipids by presence of a vinyl ether bond at carbon 1 of glycerol backbone rather than an ester bond. Lysoplasmalogens are major products of the iPLA2 (calcium-independent phospholipase A2) catalyzed hydrolysis reaction in which plasmalogens are hydrolyzed at sn-2, and lysoplasmalogen and a free fatty acid (arachidonic acid or other PUFA) are formed. This reaction is documented in many cell types (myocytes, coronary artery endothelium, platelets, kidney cells, lung cells), and occurs during cell activation and also in cell injury (e.g. hypoxia/ischemia).

      Lysoplasmalogens are the intermediates in phospholipid remodeling reactions. Lysoplasmalogen reacts with 1-alkyl-2-acyl-glycerophosphocholine in a transacylation reaction forming plasmalogen and 1-alkyl-2-lyso-glycerophosphocholine, the critical precursor for platelet activating factor (PAF). Lysoplasmalogens also alter membrane fluidity, and at high levels can lyse cell membranes causing death. We are studying the biological effects of lysoplasmalogen on isolated neurons and glia, on hepatoma cell line, and on isolated mitochondria from rat liver, heart and brain.

      We are also studying the properties of, and purifying the enzyme, lysoplasmalogenase (EC 3.3.2.2, EC 3.3.2.5) (LPNase). This integral membrane protein of the endoplasmic reticulum catalyzes hydrolytic cleavage of the vinyl ether bond of lysoplasmalogen forming nontoxic glycerophosphoethanolamine and fatty aldehyde. The activity of the enzyme is cell specific and is high in hepatocyte, kupfer cell, intestinal mucosal cell, HL60 cells converted to phagocytic lineage, lower in brain microsomes, and undetectable in heart. We have solubilized, purified, and characterized lysoplasmalogenase 600- fold from rat liver microsomes. Knowledge of the amino acid sequence of LPNase will lead to the molecular tools necessary to elucidate the biological role for this enzyme in health and disease states. We propose that the enzyme is of critical importance in determining the levels of lysoplasmalogen in the cell, and in this role may function to “turn on” or “turn off” these critical effects of lysoplasmalogen. The enzyme may therefore be a candidate for pharmaceutical intervention in disease states.

Ma, Jiyan

Many neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and Prion disease, are characterized with late age onset and accumulation of protein aggregates (amyloid). The molecular mechanism behind neurotoxicity in these disorders remains elusive. Notably, many of the proteins involved in the pathogenesis of these neurodegenerative disorders shared a common characteristic, that is, they all interact with lipid membrane. It has been proposed that membrane disruption could be a common neurotoxic mechanism for these neurodegenerative disorders.

Our investigation focuses on the pathogenesis of prion disease, which differs from other neurodegenerative disorders in its infectious nature. The prion protein, PrP, is normally a cell surface localized, GPI-anchored protein. In addition to its cell surface localization, PrP has been found in the cytoplasm, resulted from either retro-translocation from the ER to the cytoplasm or impaired import into the lumen of ER. We found that cytoplasmically localized PrP causes neurodegeneration in transgenic mice. Moreover, the neurotoxicity correlates with PrP’s interaction with the hydrocarbon core of lipid membrane. We hypothesize that PrP-lipid interaction disrupts lipid membrane, causes intracellular ion concentration change, and leads to neurodegeneration. This model explains the pathological changes in the degenerating neurons, such as mitochondria permeability change the increased immunoreactivity of calcium dependent phospholipase A2. We are currently investigating PrP-lipid interaction, the consequence of this interaction, and its role in prion disease. 

Marsh, Clay

My laboratory focuses on the role of the growth factor macrophage colony-stimulating factor (M-CSF) and mononuclear phagocytes in health and disease. We are interested in understanding the native signaling pathways and proteins responsible for mononuclear phagocyte survival and differentiation and apply this information to understand how this is dysregulated in diseases. We are also interested in the mechanisms of repair and remodeling related to mononuclear phagocytes in the lung and in wound repair. Translationally, we are interested in lung fibrosis and lung injury. In addition, because of the important role of these cells in inflammation, we have been involved with studies in coronary artery disease and transplant vascular disease. Lastly, we found an important role for mononuclear phagocytes in the regulation of VEGF production and biological activity and are interested in how this may apply to cancer growth and spread.

My laboratory is divided into three modules:

1. Signaling and cell survival/differentiation
2. Lung repair and remodeling
3. Angiogenesis

My goal is to help people in my laboratory grow and become independent scientists/investigators. In addition, I hope that we uncover some of the basic mechanisms underlying mononuclear phagocyte-induced inflammation and translate these findings to novel approaches to patients with disease.

O’Brien, James

Dr. O’Brien is the assistant director for clinical research for the Division of Pulmonary, Allergy, Critical Care and Sleep Medicine.  He is funded by the NHLBI to study the effect of excess body wieght on outcomes and processes of care for mechanically ventilated patients.  He is interested in the effect of processes and structures of care on outcome for ICU patients and long-term outcomes for patients surviving critical illness. 

Parinandi, Narasimham

Parinandi is currently working on regulation of phospholipase D in vascular endothelium and airway epithelium in response to agonists including oxidants, bioactive lipid signal mediators, toxicants, drugs, and growth factors. In this context, the cross-talks among phospholipases D and A2 and C and other lipases is being explored. The main focus of this investigation is to establish the regulation of endothelial and epithelial barrier functions and also the regulation of secretory phenomena in cells by phospholipase-derived bioactive lipid mediators. In addition, Parinandi is also investigating the role of cardiolipin and oxidized cardiolipin in mitochondrial lipid mediator generation and signaling.  Overall, the goal of Parinandi’s research is to investigate the role of membrane phospholipid-derived signal mediators in cellular dysfunction, cytotoxicity, and cell death. 

Pfeiffer, Douglas

Our research activities pertaining to mitochondria have included aspects of steroidogensis and lipid metabolism, various transport processes, and the phenomenon now referred to as the mitochondrial permeability transition.  The permeability transition is important in mechanisms of cell death; however, we maintain that its primary function is to initiate the degradation and replacement of mitochondria that are functioning poorly because they contain mutated DNA, have excessive levels of oxidized proteins and lipids, or for other reasons.  We have recently discovered a large Ca2+ independent phospholipase A2 whose activity promotes the transition.  It is not active in well energized mitochondria but becomes active upon deenergization.  Thus this activity may help the cell identify which mitochondrion to replace.  We are currently attempting to isolate and clone the phospholipase, and to understand how it is regulated by energetic status.  We are also attempting to ascertain the molecular properties of a Ca2+ conducting channel that is located in the inner membrane (Ca2+ uniporter).  Were this to be accomplished the channel would become an attractive target for drug development directed at influencing cell death arising from necrosis or apoptosis. 

Williams, Joseph

As part of a large collaborative effort with colleagues from 4 other universities, our lab is looking at the linkages between physiology and life history of birds in the tropics and in temperate environments. We are testing the idea that tropical birds have a lower basal metabolism, a better immune system, and longer survival, than do temperate birds. In addition we are investigating the association between metabolism and life-history attributes of birds, such as clutch size, the number of clutches laid per year and the rate of nestling growth. Research in the tropics takes place at the Smithsonian Tropical Research Institute, Gamboa, Panama, whereas our work on temperate birds occurs in Ohio and Michigan. 

Yong, Xia

The overall research interest of the Xia laboratory is in the molecular mechanisms of cardiovascular regulation and diseases. Specifically, we focus on the function and regulation of nitric oxide synthase (NOS).  Our previous studies identified superoxide generation as a novel function of NOS. This new superoxide generation pathway has now been found to play important roles in cell injury and signal transduction. Current studies in Dr. Xia’s group include the regulation of NOS by protein-protein interactions, protein phosphorylation, and critical enzyme cofactors. These studies take multi-disciplinary approaches ranging from molecular biology, biochemistry, biophysics, to physiology and pharmacology. Other research in the laboratory includes the studies on the mechanism of endothelial dysfunction, a common manifestation of various cardiovascular diseases.

Yoon, Sung Ok

Although it may not be the direct cause, mitochondrial dysfunction is a widespread phenomenon observed in almost all the neurodegenerative diseases. One major project in the lab is investigating the role of JNK3 and Pin1 in regulation of mitochondrial homeostasis. We have discovered that Pin1 binds HtrA2, a mitochondrial protease, which plays a critical role in Parkinson’s disease based on genetic studies]. HtrA2 itself is hyperphosphorylated in Parkinson’s patients, suggesting phosphorylation of HtrA2 plays a role in regulating its activity. We are currently employing MPTP model of Parkinson’s disease in Pin1 knockout mice to understand the role of Pin1 in Parkinson’s disease.