Research into the physiologic functions and diseases involving liver, kidney and pancreas.
Labs in This Area
Role of mitochondria and metabolic processes in cancer growth, cardiac disease and metabolic disorders
Our lab focuses on three major areas of research:
Role of proteins involved in cellular and systemic metabolism
TTP is a protein that binds to AU-rich regions in the 3’ UTR of mRNA molecules and causes their degradation. It has been studied extensively in the field of inflammation. We recently showed that it also plays a role in cellular iron conservation. We have also shown that TTP is a key mediator of cellular metabolic processes. Our studies have demonstrated that TTP regulates glucose, fatty acid and branched-chain amino acid metabolism in the liver and muscle tissue. We also have evidence that TTP directly regulates mitochondrial electron transport chain (ETC) by targeting specific proteins in the ETC complexes. Finally, recent studies demonstrated that TTP also regulates systemic metabolism by targeting FGF-21 expression. We have both TTP Floxed mice (for the generation of tissue specific TTP knockout mice) and TTP knockout mice in the background of TNF-alpha receptor 1/2 knockout mice (to reduce the inflammatory burden). Current studies include: 1) role of TTP in liver metabolism of fatty acids and glucose, 2) effects of TTP on mitochondrial proteins, 3) mechanism of TTP regulation of branched-chain amino acid levels and 4) role of TTP in cardiac metabolism.
Adult cardiomyocytes regenerate at a very low rate, but neonatal cardiomyocytes grow and replicate at a high rate. We have identified specific tandem zinc-finger (TZF) proteins that bind to mRNAs to regulate cardiac regeneration and cardiac development. Our studies suggest that these proteins may alter DNA repair in response to damage by regulating p53 and helicases. Current projects include: 1) identifying the mechanism by which TZF proteins regulate p53 and DNA damage, 2) characterization of the role of helicases in cellular proliferation and regeneration and 3) role of TZF proteins in cardiac development.
Characterization of cellular and mitochondrial iron regulation
Our lab has identified a novel mitochondrial protein, ATP-Binding Cassette-B8 (ABCB8), which plays a role in mitochondrial iron homeostasis and mitochondrial iron export. Mice with ABCB8 knocked out in the heart develop cardiomyopathy and mitochondrial iron accumulation. In addition, we have shown that a pathway involving mTOR and tristetraprolin, treatment with doxorubicin (an anticancer drug that also causes cardiomyopathy) and SIRT2 protein also impact cellular and/or mitochondrial iron regulation. Current studies in this area include: 1) further characterization of ABCB8 in iron homeostasis in other organs and disorders, 2) characterization of the mechanism for iron regulation by SIRT2, 3) identification of the mechanism by which mTOR is regulated by iron, 4) role of iron in viral infection, particularly HIV, 5) characterization of the effects of iron on mitochondrial dynamics and 6) identification of novel mitochondrial-specific iron chelators.
For more information, see Dr. Ardehali's faculty profile.
See Dr. Ardehali's publications in PubMed.
Circadian and metabolic gene networks in the development of diabetes and obesity
An epidemic of obesity and diabetes has continued to sweep through the industrialized world, already posing a risk to over one-third of the US population who are overweight or obese. Although both physical inactivity and overnutrition are tied to “diabesity,” recent evidence indicates that disruption of internal circadian clocks and sleep also play a role. The primary research focus in our laboratory is to apply genetic and biochemical approaches to understand the basic mechanisms through which the circadian clock regulates organismal metabolism. We anticipate that a better understanding of clock processes will lead to innovative therapeutics for a spectrum of diseases including diabetes, obesity, autoimmunity and cancer.
Studies of Clock Function in Beta Cell Failure and Metabolic Disease
Glucose homeostasis is a dynamic process subject to rhythmic variation throughout the day and night. Impaired glucose regulation leads to metabolic syndrome and diabetes mellitus, disorders that are also associated with sleep-wake disruption, although the molecular underpinnings of circadian glucose regulation have been unknown. Work from our laboratory first demonstrated an essential role of the intrinsic pancreatic clock in insulin secretion and diabetes mellitus and present efforts focus on dissecting the genomic and cell biologic link between clock function and beta cell failure (Nature, 2010, 2013).
Studies of Clock Regulation of Metabolic Epigenetics
In 2009 we first reported discovery that the circadian system plays a central role in metabolism through regulation of NAD+ biosynthesis (Science, 2009). NAD+ is a precursor of NADP+ and is required for macromolecule biosynthesis, in addition to functioning as an oxidoreductase carrier. NAD+ is also a required cofactor for the class III histone deacetylases (silencer of information regulators, SIRTs), nutrient-responsive epigenetic regulators Biochemical analyses show that SIRT1 deacetylates substrate proteins generating O-acetyl-ADP-ribose and nicotinamide, which is then regenerated to NAD+ by the enzyme nicotinamide phosphoribosyl transferase (NAMPT). We originally showed that CLOCK/BMAL1 directly control the transcription of Nampt and in turn control the activity of SIRT1—identifying a feedback loop composed of CLOCK/BMAL1-NAMPT/SIRT1. More recently, we have identified a role for the clock-NAD+ pathway in mitochondrial respiration (Science, 2013), and our present efforts include the analysis of clock-NAD+ regulation of cellular redox and epigenetic regulation, with the ultimate aim of applying such knowledge to studies of cell growth and stress response.
See Dr. Bass' publications in PubMed.
Focusing on the renin angiotensin system as it relates to the understanding of human diabetic kidney disease and rodent models of diabetic kidney disease and hypertension
Dr. Batlle’s lab currently focuses on the renin angiotensin system as it relates to the understanding of this system in rodent kidney physiology. Of particular focus are the pathways and mechanisms that determine the enzymatic cleavage and degradation of Angiotensin II and other peptides within the system by ACE2-dependent and independent pathways. The lab uses a holistic approach involving ex vivo, in vitro and in vivo studies using various rodent models of diabetic and hypertensive kidney disease.
The lab is also involved in the search for biomarkers of kidney disease progression as part of the NIDDK Consortium on CKD. Other areas of research interest include nocturnal hypertension and the physiology and pathophysiology of electrolyte disorders such as distal renal tubular acidosis.
For more information, please see Dr. Batlle's faculty profile.
See Dr. Batlle's publications in PubMed.
The Green Lab investigates the genetics and molecular biology of cholestatic liver diseases and fatty liver disorders. The major current focus is on the role of ER Stress and the Unfolded Protein Response (UPR) in the pathogenesis of these hepatic diseases.
Dr. Green’s laboratory investigates the mechanisms of cholestatic liver injury and the molecular regulation of hepatocellular transport. Current studies are investigating the role of the UPR in the pathogenesis and regulation of hepatic organic anion transport and other liver-specific metabolic functions. We employ genetically modified mice and other in vivo and in vitro models of bile salt liver injury in order to better define the relevant pathways of liver injury and repair; and to identify proteins and genes in these pathways that may serve as therapeutic targets for cholestatic liver disorders.
The laboratory also investigates the mechanisms of liver injury in fatty liver disorders and the molecular regulation of hepatic metabolic pathways. The current focus of these studies includes investigations on the role of the UPR in the pathogenesis of non-alcoholic steatohepatitis and progressive fatty liver disease. We employ several genetically modified mice and other in vivo and in vitro models of fatty liver injury and lipotoxicity. Additional studies include the application of high-throughput techniques and murine Quantitative Trait Locus (QTL) analysis in order to identify novel regulators of the UPR in these disease models.
See Dr. Green's publications in PubMed.
For more information, please see Dr. Green's faculty profile.
Contact Dr. Green at 312-503-1812 or the Green Lab at 312-503-0089
David Hillburn, MD
Xiaoying Liu, PhD
Genetic determinants of maternal metabolism and fetal growth
A major interest of the Lowe laboratory is genetic determinants of maternal metabolism during pregnancy and the interaction between the intrauterine environment and genetics in determining size at birth. This interest is being addressed using DNA and phenotype information from ~16,000 mothers and their babies who participated in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. A genome wide association study using DNA from mothers and babies from four different ancestry groups has been performed, with several different loci demonstrating genome-wide significant association with maternal and fetal traits. Replication studies have confirmed the identified associations. Studies are now underway now to identify the causal variants and their functional impact. In related studies performed with investigators at Duke, targeted and untargeted metabolomic studies are underway to determine whether metabolic signatures characteristic of maternal obesity and/or hyperglycemia can be identified in mothers and babies. Integration of metabolomic and genomic data is also planned to more fully characterize maternal metabolism during pregnancy and its interaction with fetal growth. Finally, a HAPO Follow-Up Study has been initiated in which a subset of the HAPO mothers and babies (now 8-12 years of age) will be recruited to examine the hypothesis that maternal glucose levels during pregnancy are positively correlated with metabolic measures in childhood, including adiposity, lipidemia, glycemia and blood pressure.
For further information visit Dr. Lowe's faculty profile page
View Dr. Lowe's publications at PubMed
Tolerance mechanisms in autoimmune diabetes and transplantation
1. Tolerance mechanisms for transplantation. We use rodent as well as non-human primate models. These models include allogeneic islet, heart and kidney and xenogeneic islet transplantation. Transplant tolerance is induced by infusion of donor cells treated with the chemical cross-linker ethylcarbodiimide (ECDI). Using a stringent full MHC-mismatched strain combination, we have shown in an allogeneic islet cell transplant model that two infusions of ECDI-treated donor cells prior to and after transplantation led to indefinite graft survival in over 90% of the transplant recipients in the absence of any immunosuppression. This tolerance strategy takes advantage of the tolerogenic recognition of apoptotic donor cells by recipient CD11c dendritic cells and is associated with up-regulation of Tregs and down-regulation of anti-donor T and B cell responses. The same strategy has been applied to allogeneic heart and kidney transplant, as well as xenogeneic islet transplant (rat-to-mouse, pig-to-mouse) with robust tolerance efficacy. We are currently applying the same strategy to monkey-to-monkey (allogeneic) and pig-to-monkey (xenogeneic) islet transplantation. Our ultimate goal is to test this tolerance strategy in human-to-human (allogeneic) and pig-to-human (xenogeneic) solid organ and/or tissue transplantation. Additional ongoing efforts in the lab also focus on: (1) understanding how viral infections at various stages (acute, chronic, latent) can influence tolerance efficacy and stability; (2) collaborating with Shea lab in designing nanoparticle-based cell-free tolerance strategies for allogeneic and xenogeneic transplantation.
2. Proteins with post-translational modifications (PTMs) as neoantigens for autoimmune diabetes. We use the non-obese diabetic (NOD) mouse model to study the role of proteins with PTMs in the pathogenesis of type 1 diabetes. Beta cell secretory proteins are subjected to post-translational modifications such as deamidation and di-sulfide bond formation among others. Such modified proteins/peptides may become neoantigens that can activate endogenous T cells and lead to beta-cell directed autoimmunity. Ongoing efforts in the lab focus on: (1) temporal correlation between the appearance of humoral immunity to proteins/peptides with PTMs and diabetes development; (2) the role of cellular immunity to proteins/peptides with PTMs in the development of diabetes; (3) the role of endogenous enzymatic pathways for the formation of such neoantigens; (4) the role of neoantigens as a diagnostic tool for autoimmune diabetes; (5) the role of neoantigens for more effective tolerance induction strategies for autoimmune diabetes.
3. Circadian Clock regulation in immune cell function and autoimmune diabetes. Disruption of circadian rhythms has been linked to inflammatory diseases, however the precise roles of core clock proteins in the function of immune cells have not been elucidated. Collaborating with the Bass lab, we are investigating the role of BMAL1, one of the core clock proteins, in controlling several fundamental aspects of the immune system. Ongoing efforts in the lab focus on: (1) defining the phenotypic and functional alterations in immune cells caused by disruption of circadian gene regulation; (2) defining the role of circadian gene regulation at the immune cell/beta cell interface and its contribution to the development of autoimmune diabetes; (3) defining the role of circadian gene regulation at the immune cell/transplanted graft interface and its contribution to the development transplant graft rejection.
For more information visit Dr. Luo's faculty profile page
View Dr. Luo's publications at PubMed
Basic and translational research focused on the endocrine regulation of mineral metabolism.
Investigation focuses on the relationship between mineral homeostasis, skeleton biology and secretion of the hormone Fibroblast Growth Factor (FGF)-23 by the bone that translates to several acquired and hereditary diseases, such as hypophosphatemic rickets or chronic kidney disease (CKD), in which abnormally elevated production of FGF23 is responsible for various adverse outcomes.
Her laboratory uses a combination of histology, cell biology, molecular biology and mouse genetics tools to study the bone response to impaired mineral metabolism. The main focus of her research is to understand the bone regulatory mechanisms of FGF23 transcription and cleavage in health and in CKD. The lab currently studies the role of two specific bone factors, PHEX and Dentin Matrix Protein (DMP)-1, which are generally involved in the process of bone mineralization. PHEX and DMP1 mutations lead to hereditary rickets and hypophosphatemia caused by elevated production of FGF23. To date, PHEX and DMP1 contribution to elevated FGF23 production in CKD is unclear and represent a possible therapeutic target for patients with CKD.
Dr. Martin’s laboratory is funded by the National Institute of Health, National Institute of Diabetes and the National institute of Digestive and Kidney Diseases (NIDDK).
For more information view Dr. Martin's Faculty Profile
View publications by Aline Martin in PubMed
Elucidation of mechanisms of pathogenesis and immune regulation of autoimmune disease, allergy and tissue/organ transplantation
The laboratory is interested in understanding the mechanisms underlying the pathogenesis and immunoregulation of T cell-mediated autoimmune diseases, allergic disease and rejection of tissue and organ transplants. In particular, we are studying the therapeutic use of short-term administration of costimulatory molecule agonists/antagonists and specific immune tolerance induced by infusion of antigen-coupled apoptotic cells and PLG nanoparticles for the treatment of animal models of multiple sclerosis and type 1 diabetes, allergic airway disease, as well as using tolerance for specific prevention of rejection of allogeneic and xenogeneic tissue and organ transplants.
Promising Results in Early Trial of Novel MS Treatment: Listen to a Science Friday interview with Dr. Miller regarding the Phase 1 clinical trial in multiple sclerosis patients. Read the article in Science Translational Medicine Antigen-specific tolerance by autologous myelin peptide-coupled cells: a phase 1 trial in multiple sclerosis.
For lab information and more, see Dr. Miller's faculty profile.
See Dr. Miller's publications on PubMed.
Contact Dr. Miller at 312-503-7674 or the lab at 312-503-1449.
Signal Transduction In Fibrogenesis
Our laboratory examines the signals that modulate fibrogenesis. This process is important in promoting normal healing but, when uncontrolled, leads to excessive scar formation such as occurs in chronic progressive cardiovascular or kidney disease. Our studies center upon the role of the Smad signal transduction pathway in extracellular matrix accumulation. We are investigating the mechanism(s) by which transforming growth factor (TGF)-ß stimulates collagen accumulation by the human kidney mesangial cells that are central to the scarring of the renal filter in disease states.
We have determined that the TGF-ß-specific Smad pathway is modulated by interaction with multiple additional signaling mechanisms, including those related to ERK MAP kinase, phosphatidyl inositol-3-kinase, protein kinase C and cytoskeletal rearrangement. Cross-talk amongst these pathways provides a complex milieu for the cellular regulation of fibrogenesis. Characterizing the precise patterns of interaction among signaling pathways that are usually studied in isolation offers our lab the opportunity to define unique events that determine tissue specificity.
Presently, we have two major projects in the lab. In one, we are examining the role of Smad anchor for receptor activation (SARA) in regulating cell phenotype and function. In the other, we are examining how cell interaction with the extracellular matrix leads to the activation of specific signaling pathways that promote fibrogenesis. We recently reported that integrin-mediated, cell adhesion-dependent activation of focal adhesion kinase (FAK) plays an essential role in specific phosphorylations of the Smad3 molecule and in TGF-ß-stimulated collagen expression.
View Dr. Schnaper's publications at PubMed
Organ and tissue engineering, 3D scaffold systems, induced pluripotent stem cells, stem and progenitor cell differentiation in 3D matrices, regenerative medicine applications
The major area of interest in my laboratory is advancing the state of art in organ regeneration and tissue engineering to develop methods to grow livers and kidneys as a cutting-edge solution to the organ shortage dilemma. Nationally, over 120,000 patients are waiting for solid organ transplantation, yet the number of transplants performed annually falls short of this need by 75%. In the absence of suitable donors for transplantation, organ failure leads to associated health problems, increased healthcare expenditures and death. Organ shortage is a national issue with local impact. In 2010 there were just over 1,050 solitary kidney, liver or heart transplants performed in Illinois, yet 311 patients in the state and more than 6650 nationwide died waiting for an organ.
Our research proposes a multidisciplinary solution to organ shortage by utilizing a tissue engineering approach to rehabilitate the extracellular matrix of organs that are not initially suitable for transplantation. Just-in-time organs, reconstituted with recipient derived progenitor cells, would abrogate the need for long waitlist times and associated waitlist mortality, reduce the reliance on organs from living donors and obviate the need for immunosuppression. Conceptually, these organs would be prepared from a donor matrix using a recipients own cells at the first signs of organ dysfunction. The re-engineered organ would then be ready for implantation when progressive organ failure indicates the need for transplantation.
The traditional paradigm in tissue engineering has been to grow cells on synthetic, polymer scaffolds to recreate the organ or tissue of interest. The limitation of this approach is the scale-up. Beyond a critical distance, diffusion of nutrients and oxygen is not sufficient to support cellular life and a vascular system must be incorporated into the tissue to supply nutrients. It has been technically difficult to design a synthetic micro-vasculature resembling small, terminal capillaries and to combine these structures with functional cells. Our approach challenges this paradigm by using the natural extracellular matrix as a scaffold to support the growth of new cells capable of repopulating the three-dimensional matrix. We have established protocols to remove parenchyma cells from livers and kidneys with a high efficiency of cellular removal and adequate retention of extracellular matrix molecules. We have further repopulated the vasculature of these matrix structures with endothelial cells derived from induced pluripotent stem cell technology. Together, we have partnered with the McCormick School of Engineering at Northwestern University and other leading academic and industrial centers to advance this fast moving field and address the problem of organ shortage.
View publications by Jason Wertheim at PubMed
Lab Phone 312-695-0257