MECHANISMS OF ACTION OF DRUGS THAT PREVENT EXPERIMENTAL DIABETIC RETINOPATHY
Gerhardinger Chiara
Schepens Eye Research Institutecity: Boston country: United States (us)
Grant 5R01EY017637-04 from National Eye Institute
Keywords: Address; Affect; Age; Aldehyde Reductase; Animals; Apoptosis; Apoptotic; Aspirin; Atherosclerosis; Attenuated; Autopsy; Back; base; Blood capillaries; Blood Vessels; Candidate Disease Gene; capillary; Cause of Death; Cell Cycle; Cell Death; Cessation of life; Characteristics; Clinical; clinical application; Complications of Diabetes Mellitus; connective tissue growth factor; Data; Development; Diabetes Mellitus; diabetic; Diabetic Nephropathy; diabetic rat; Diabetic Retinopathy; Drug Delivery Systems; drug development; Drug effect disorder; efficacy testing; Elements; Endothelial Cells; Experimental Diabetes Mellitus; Extracellular Matrix; Eye; Family; Gender; Gene Expression; Gene Expression Profile; Genes; Genetic; glycemic control; Goals; Growth Factor; Histopathology; Human; human TGFB1 protein; Hyperglycemia; Hypertension; Individual; Inflammation; inhibitor/antagonist; interest; Investigation; Kidney; Kidney Diseases; Lead; Learning; malformation; Measures; Medicine; member; Messenger RNA; Molecular; Molecular Target; Names; non-diabetic; novel; Oral cavity; Oxidative Stress; Pathology; Pathway interactions; Pericytes; Pharmaceutical Preparations; Phosphotransferases; preclinical study; prevent; Prevention; Prevention strategy; Process; Proteins; Rattus; receptor; research study; Residual state; Retina; retina blood vessel structure; Retinal; Retinal Diseases; Role; Signal Transduction; small molecule; sorbinil; Staging; Streptozocin; Syndrome; Testing; TGF-beta type I receptor; Tissues; Transforming Growth Factor beta; Vision; Work
Relevance: Narrative The studies proposed address diabetic retinopathy, the most common and dreaded complication of diabetes. We seek to identify processes that are active at early stages of the development of retinopathy, so that we may develop the best drug strategy for prevention of the damage inflicted by diabetes to the retinal vessels. Such work has now uncovered a possible role in diabetic retinopathy of a multifunctional growth factor named TGF-beta. TGF-beta has been known to be involved in several vascular pathologies, but has never before been associated with diabetic retinopathy. This project intends to test whether reducing the increased TGF-beta caused by diabetes will protect the retinal vessels from damage and ultimately death. The project is exciting for three reasons. First, it will test a new inhibitor of TGF-beta that can be administered by mouth, and therefore would accelerate potential clinical application. Second, if the results show that returning to normal levels the excess TGF-beta activity caused by diabetes does in fact protect the retinal vessels, we will have a precise molecular target to be brought to test for the prevention of human diabetic retinopathy. Third, being TGF-beta implicated in multiple vascular pathologies --from kidney disease in diabetic and nondiabetic individuals, to vascular malformations in genetic syndromes, to abnormal vascular wall remodeling in hypertension and atherosclerosis--, the development of drug strategies to modulate the activity of TGF-beta will find interest and use in several fields of medicine
Project start date: 2009-01-01
Project end date: 2012-12-31
Budget start date: 1-JAN-2012
Budget end date: 31-DEC-2012
5R01EY017637-04 (2012): $460944
Sponsored Links Excellgen http://Excellgen.com
MECHANISMS OF ACTION OF DRUGS THAT PREVENT EXPERIMENTAL DIABETIC RETINOPATHY
Gerhardinger Chiara, Senior Scientist/professor
Schepens Eye Research Institutecity: Boston country: United States (us)
Grant 5R01EY017637-03 from National Eye Institute
Abstract: The ultimate goal of our work is to develop drug strategies for the prevention of diabetic retinopathy. Prevention has been brought within reach by the progressively wider implementation of intensive glycemic control, and we anticipate that the addition of drugs that are effective in pre-emptying the tissue effects of residual hyperglycemia and are safe for long-term administration will make prevention a reality. There are no adjunct drugs usable clinically, and there are no rigorous positive or negative information on the type of drugs that may be effective in the prevention of human diabetic retinopathy. We thus sought to learn from drugs that prevent experimental diabetic retinopathy which molecular processes must be silenced in the retinal vessels in order to prevent the sight-threatening damage induced by diabetes. We tested two drugs with different mechanisms of action (an aldose reductase inhibitor and aspirin at low-intermediate concentrations) reasoning that molecular targets common to the two drugs would identify candidate pathogenic pathways to be investigated further. The experiments showed that, in rats, (i) diabetes changes the expression of multiple genes in retinal vessels, (ii) the TGF-¿ pathway was the single functional pathway mostly affected by diabetes, and (iii) the two drugs had private as well as common targets, with the TGF- ¿ pathway being one of the two common functional targets. Given that overactivity of the TGF- ¿ pathway could explain much of the vascular histopathology of diabetic retinopathy, and based on additional results documenting increased TGF- ¿ signaling in diabetic retinal vessels, we plan to test the hypothesis that excess TGF- ¿ signaling contributes to the characteristic vascular pathology of diabetic retinopathy. The project is made especially exciting by the opportunity to use a new small molecule inhibitor of TGF- ¿ type I receptor kinase, named SM16, that is orally active, a most appealing feature for translational steps. We aim to develop and validate in diabetic rats a drug strategy based on SM16 for non-invasive, long-term, and on-target prevention of the excess TGF- ¿ signaling in retinal vessels. The precise aim is to bring TGF- ¿ signaling back to control values without reducing basal TGF- ¿ activity. We will use the inhibitor to learn the molecular effects of excess TGF- ¿ signaling on diabetic retinal vessels. We will then test whether by taking away such effects, the retinal capillaries are protected from the cell death and remodeling that lead to their final demise in diabetes. In the same rats we will also examine the effects of SM16 on the development of the typical renal pathology. Finally, we will examine the TGF- ¿ pathway in human diabetic retinal vessels (postmortem eyes). A combination of positive results in the preclinical studies and the human diabetic retina will identify excess TGF- ¿ signaling as a contributor to the vascular pathology of diabetic retinopathy and will stimulate investigation and development of drugs to modulate safely TGF- ¿ activity in humans. In addition, the studies are poised to generate a paradigm for applications of anti-TGF- ¿ therapy to other pathologies. The studies proposed address diabetic retinopathy, the most common and dreaded complication of diabetes. We seek to identify processes that are active at early stages of the development of retinopathy, so that we may develop the best drug strategy for prevention of the damage inflicted by diabetes to the retinal vessels. Such work has now uncovered a possible role in diabetic retinopathy of a multifunctional growth factor named TGF- ¿. TGF- ¿ has been known to be involved in several vascular pathologies, but has never before been associated with diabetic retinopathy. This project intends to test whether reducing the increased TGF- ¿ caused by diabetes will protect the retinal vessels from damage and ultimately death. The project is exciting for three reasons. First, it will test a new inhibitor of TGF- ¿ that can be administered by mouth, and therefore would accelerate potential clinical application. Second, if the results show that returning to normal levels the excess TGF- ¿ activity caused by diabetes does in fact protect the retinal vessels, we will have a precise molecular target to be brought to test for the prevention of human diabetic retinopathy. Third, being TGF- ¿ implicated in multiple vascular pathologies - from kidney disease in diabetic and nondiabetic individuals, to vascular malformations in genetic syndromes, to abnormal vascular wall remodeling in hypertension and atherosclerosis -, the development of drug strategies to modulate the activity of TGF- ¿ will find interest and use in several fields of medicine
Keywords: 2-(Acetyloxy)benzoic Acid; 2-Deoxy-2-((methylnitrosoamino)carbonyl)amino-D-glucose; 2-deoxy-2-(3-methyl-3-nitrosoureido)-D-glucopyranose; 2-deoxy-2-[[(methylnitrosamino)-carbonyl]amino]-D-glucopyranose; Acetylsalicylic Acid; Address; Adventitial Cell; Affect; Age; Aldehyde Reductase; Alditol[{..}]NAD(P)+ 1-oxidoreductase; Aldose Reductase; Animals; Apoptosis; Apoptosis Pathway; Apoptotic; Aspergum; Aspirin; atheromatosis; Atheroscleroses; Atherosclerosis; Atherosclerotic Cardiovascular Disease; atherosclerotic vascular disease; Attenuated; Autopsy; Back; base; biological signal transduction; Blood capillaries; Blood Pressure, High; Blood Vessels; Body Tissues; Buccal Cavity; Candidate Disease Gene; Candidate Gene; Capillaries; Capillary; capillary; Capillary, Unspecified; Cause of Death; Cavitas Oris; Cell Communication and Signaling; Cell Cycle; Cell Death; Cell Death, Programmed; Cell Division Cycle; Cell Signaling; Cell-Extracellular Matrix; Cessation of life; Characteristics; Clinical; clinical applicability; clinical application; Common Rat Strains; Complications of Diabetes Mellitus; connective tissue growth factor; CTGF; D-6-fluoro-spiro(chroman-4, 4`-imidazolidine)-2`, 5`-dione; Data; Death; Development; diabetes; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes, Experimental; Diabetes-Related Complications; diabetic; Diabetic Complications; Diabetic Kidney Disease; Diabetic Nephropathy; diabetic rat; diabetic rat model; Diabetic Retinopathy; Dorsum; drug action; Drug Delivery; Drug Delivery Systems; drug development; Drug effect disorder; Drug Targeting; Drug Targetings; drug/agent; Drugs; EC 2.7; ECM; Ecotrin; efficacy testing; Elements; Empirin; Endothelial Cells; Entericin; experiment; Experimental Diabetes Mellitus; experimental research; experimental study; Extracellular Matrix; Extren; Eye; Eyeball; Family; fisp12 protein; Gender; Gene Expression; Gene Expression Profile; gene expression signature; gene product; Genes; Genetic; GFAC; glycemic control; Goals; Growth Agents; Growth Factor; Growth Factors, Proteins; Growth Substances; Head and Neck, Buccal Cavity; Health; heavy metal lead; heavy metal Pb; Histopathology; Human; Human, General; Hyperglycemia; hyperglycemic; hyperpiesia; hyperpiesis; Hypertension; hypertensive disease; IGF-binding protein-related protein-2; IGFBP-8; IGFBP-rP2; Individual; Inflammation; INFLM; inhibitor; inhibitor/antagonist; insulin-like growth factor binding protein 8; interest; Intracellular Communication and Signaling; Investigation; Kidney; Kidney Diseases; kidney disorder; Kinases; Lead; Learning; malformation; Mammals, Rats; Man (Taxonomy); Man, Modern; Measures; Measurin; Medication; Medicine; member; Messenger RNA; Molecular; Molecular Target; Mouth; mRNA; Names; necrocytosis; necropsy; Nephropathy; non-diabetic; nondiabetic; novel; Oral cavity; Oxidative Stress; Pathology; pathway; Pathway interactions; Pb element; Pericapillary Cell; Pericytes; Perivascular Cell; Pharmaceutic Preparations; Pharmaceutical Preparations; Phosphotransferases; postmortem; preclinical study; prevent; preventing; Prevention; Prevention strategy; Preventive strategy; Process; Proteins; Rat; Rat model of diabetes; Rattus; receptor; Receptor Protein; renal; Renal Disease; renal disorder; research study; Residual; Residual state; Retina; retina blood vessel structure; retina disease; retina disorder; Retinal; Retinal Blood Vessels; Retinal Diseases; Retinal Disorder; Retinal Vessels; retinopathy; RNA, Messenger; Role; Rouget Cells; Science of Medicine; Sight; Signal Transduction; Signal Transduction Systems; Signaling; small molecule; social role; sorbinil; Staging; Streptozocin; Streptozotocin; Structure of blood vessel of retina; STZ; Syndrome; Testing; Tissues; transcriptome; Transphosphorylases; Urinary System, Kidney; vascular; Vascular Hypertensive Disease; Vascular Hypertensive Disorder; Vision; Work; Zanosar
Relevance: Narrative The studies proposed address diabetic retinopathy, the most common and dreaded complication of diabetes. We seek to identify processes that are active at early stages of the development of retinopathy, so that we may develop the best drug strategy for prevention of the damage inflicted by diabetes to the retinal vessels. Such work has now uncovered a possible role in diabetic retinopathy of a multifunctional growth factor named TGF-¿. TGF-¿ has been known to be involved in several vascular pathologies, but has never before been associated with diabetic retinopathy. This project intends to test whether reducing the increased TGF-¿ caused by diabetes will protect the retinal vessels from damage and ultimately death. The project is exciting for three reasons. First, it will test a new inhibitor of TGF-¿ that can be administered by mouth, and therefore would accelerate potential clinical application. Second, if the results show that returning to normal levels the excess TGF-¿ activity caused by diabetes does in fact protect the retinal vessels, we will have a precise molecular target to be brought to test for the prevention of human diabetic retinopathy. Third, being TGF-¿ implicated in multiple vascular pathologies --from kidney disease in diabetic and nondiabetic individuals, to vascular malformations in genetic syndromes, to abnormal vascular wall remodeling in hypertension and atherosclerosis--, the development of drug strategies to modulate the activity of TGF-¿ will find interest and use in several fields of medicine
Project start date: 2009-01-01
Project end date: 2012-12-31
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
PFA/PA: PA-07-070
5R01EY017637-03 (2011): $433249
Grants awarded to Gerhardinger Chiara
INFLAMMATORY CYTOKINES IN DIABETIC RETINOPATHY
Gerhardinger Chiara, Assistant Scientist
Schepens Eye Research Institutecity: Boston country: United States (us)
Grant 5R01EY016206-04 from National Eye Institute
Abstract: Diabetic retinopathy is the leading cause of blindness in the US adult population. To develop, effective approaches to prevent this disease, there is a crucial need for a better understanding of the mechanisms of diabetes-induced retinal damage. We have recently found that glial Muller cells mount an acute-phase response in diabetes, which is accompanied by retinal induction of the inflammatory cytokine interleukin 1¿ (IL-1¿). In this project, we intend to investigate the hypothesis that IL-1¿ upregulation contributes to the glial and vascular abnormalities of the diabetic retina. The specific aims are 1. To identify the cell type/s that upregulate IL-1¿ and characterize the IL-1¿ system in the diabetic retina. The retinal cell type/s expressing IL-1¿ in diabetes will be identified by in situ hybridization and immunohistochemistry. To investigate the effect of diabetes on the IL-1¿ system, we will study the retinal expression and cellular distribution of the two IL-1¿ endogenous inhibitors - decoy receptor IL-1RII and receptor antagonist IL-1ra - and of the two components of the IL-1¿ signaling receptor - IL-1RI and IL-1RAcP. 2. To determine the mechanisms and consequences of IL-1¿ upregulation in retinal cells. We will perform in vitro studies to determine whether high glucose upregulates IL-1¿ in cell culture models. We will then investigate whether IL-1¿ is sufficient to mimic the effect of diabetes on Muller cells, and the interaction of IL-1¿ with other diabetes-induced factors. 3. To determine whether inhibition of IL-1¿ activity can prevent the development of diabetic retinopathy. As conclusive evidence for a role of IL-1¿ in diabetic retinopathy, we will evaluate the effect of retinal overexpression of IL-1ra in preventing retinal abnormalities in diabetic rats. Identifying IL-1¿ as a mediator of diabetes-induced retinal damage would open new avenues for the prevention of retinopathy. Recombinant IL-1ra or other anti-IL-1¿ drugs could become powerful tools to prevent retinopathy - with possible applications to other diabetic complications with an inflammatory component such as atherosclerosis
Keywords: 21+ years old; Acute-Phase Proteins; Acute-Phase Reaction; Acute-Phase State; Adhesion Molecule; Adult; adult human (21+); Affect; anakinra; Apoptosis; apoptosis of neuronal cells; Apoptosis Pathway; Astroprotein; atheromatosis; Atheroscleroses; Atherosclerosis; Atherosclerotic Cardiovascular Disease; atherosclerotic vascular disease; Atrophic Arthritis; Blindness; Blood; Blood Vessels; CD54 (ICAM 1); CD54 Antigens; Cell Adhesion Molecules; cell adhesion protein; Cell Communication; Cell Culture Techniques; Cell Death, Programmed; Cell Interaction; cell type; Cell-to-Cell Interaction; Cell/Tissue, Immunohistochemistry; Cells; clinical practice; Complement; Complement Proteins; Complications of Diabetes Mellitus; Conditioned Culture Media; Conditioned Medium; Culture Media, Conditioned; cytokine; D-Glucose; Deposit; Deposition; Development; Dextrose; diabetes; Diabetes Complications; Diabetes Mellitus; Diabetes-Related Complications; diabetic; Diabetic Complications; diabetic rat; diabetic rat model; Diabetic Retinopathy; Disease; disease/disorder; Disorder; drug/agent; Drugs; Dysfunction; ELISA; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; experiment; experimental research; experimental study; Functional disorder; gene product; Gene Transfer; Genetics, in situ Hybridization; GFA-Protein; GFAP; Glia; Glial Cells; Glial Fibrillary Acid Protein; Glial Fibrillary Acidic Protein; Glial Intermediate Filament Protein; Glucose; Glycoprotein ICAM 1 (human clone pHRVr1 deblocked protein moiety reduced); Human; Human, Adult; Human, General; ICAM-1; IHC; IL-1 inhibitor, urine; IL-1 RII; IL-1ra; IL-1RII; IL1 febrile inhibitor; IL1 Receptors; IL1RN; Immunohistochemistry; Immunohistochemistry Staining Method; In Situ Hybridization; in situ Hybridization Staining Method; In Vitro; Inflammatory; Inflammatory Arthritis; Inflammatory Response; inhibitor; inhibitor/antagonist; Intercellular adhesion molecule 1; interleukin 1 inhibitor, urine; interleukin 1 receptor antagonist protein; Interleukin-1 Receptor Antagonist; interleukin-1 receptor type II; interleukin-1 receptor, type 2; Interleukin-1 Receptors; Interleukins; Investigators; Kolliker`s reticulum; Label; Man (Taxonomy); Man, Modern; Measures; Mediator; Mediator of Activation; Mediator of activation protein; Medication; Modeling; Muller`s cell; nerve cement; Nervous; neural; Neuroglia; Neuroglial Cells; neuron apoptosis; neuronal apoptosis; Non-neuronal cell; overexpression; pathophysiology; Pharmaceutic Preparations; Pharmaceutical Preparations; Physiopathology; Play; Population; prevent; preventing; Prevention; Production; programmed cell death of neuronal cells by apoptosis; programmed cell death of neurons by apoptosis; programmed cell death, neuronal cells; programmed cell death, neurons; programs; Programs (PT); Programs [Publication Type]; Proteins; Rat model of diabetes; Reactants, Acute-Phase; receptor; Receptor Protein; Receptor Signaling; Receptors, IL-1; Receptors, Interleukin-1; Recombinants; relating to nervous system; Research; Research Personnel; research study; Researchers; Response, Acute-Phase; Reticuloendothelial System, Blood; Retina; retina disease; retina disorder; Retinal; retinal damage; Retinal Diseases; Retinal Disorder; retinopathy; Rheumatoid Arthritis; Role; social role; Source; System; System, LOINC Axis 4; tool; transfer of a gene; United States; unspecified interleukin; Up-Regulation; Up-Regulation (Physiology); Upregulation; urine-derived IL1 inhibitor; vascular; Viral Vector
Project start date: 2006-04-01
Project end date: 2010-03-31
Budget start date: 1-APR-2009
Budget end date: 31-MAR-2011
5R01EY016206-04 (2009): $428211