Michael J. Iadarola - US grants
Institution:
Duke University Medical School, Durham, NC, United StatesDepartment:
Duke-VA Neurology Research LaboratoriesArea:
pain, pain control, TRPV1We are testing a new system for linking grants to scientists.
The funding information displayed below comes from the NIH Research Portfolio Online Reporting Tools and the NSF Award Database.The grant data on this page is limited to grants awarded in the United States and is thus partial. It can nonetheless be used to understand how funding patterns influence mentorship networks and vice-versa, which has deep implications on how research is done.
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High-probability grants
According to our matching algorithm, Michael J. Iadarola is the likely recipient of the following grants.Years | Recipients | Code | Title / Keywords | Matching score |
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1997 — 2012 | Iadarola, Michael J | Z01Activity Code Description: Undocumented code - click on the grant title for more information. ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Integrative and Molecular Studies of Pain and Pain Control @ Dental &Craniofacial Research Overview: This research program addresses basic molecular and physiological processes of nociceptive transmission in the central and peripheral nervous systems and new ways to effectively control pain. The molecular research is performed using animal and in vitro, cell-based models. We concentrate on primary afferent pain-sensing neurons located in dorsal root ganglion (DRG) that innervate the skin and deep tissues and their connections in the dorsal spinal cord, which is the first site of synaptic information processing for pain. Our research has identified the DRG and spinal cord as loci of neuronal plasticity and altered gene expression in persistent pain states. The mechanisms of transduction of physical pain stimuli are also under investigation through examination of events and molecules in damaged or inflamed peripheral tissue and using reductionistic approaches such as cloned thermal and chemo-responsive ion channels expressed in heterologous cell systems or naturally expressed in primary cultures of dorsal root ganglion. Our goals are (1) to understand the molecular and cell biological mechanisms of acute and chronic pain at the initial steps in the pain pathway, (2) to investigate mechanisms underlying human chronic pain disorders, and (3) to use this knowledge to devise new treatments for pain.[unreadable] New Treatments for Pain: We address the new treatment goal by a translational research and human clinical trials program aimed at developing new analgesic treatments for severe pain. The current approach, based on our studies of pain transduction through the vanilloid receptor 1 ion channel, now called TRPV1, has resulted in a clinical trial of resiniferatoxin (RTX) as a new treatment for advanced cancer pain. RTX activates TRPV1, which is a heat-sensitive calcium/sodium ion channel that normally converts painful heat into nerve action potentials by opening the pore of the ion channel. The influx of ions depolarizes pain-sensing nerve endings and triggers an action potential that is conducted to the spinal cord. Capsaicin, a vanilloid chemical and the active ingredient in hot pepper, also stimulates TRPV1 opening, which is why it feels hot. RTX is a very potent vanilloid that will prop open the TRPV1 ion channel, thereby causing calcium cytotoxicity and death of a specific class of pain-sensing neurons. This has proved to be a very effective means of pain control in several pre-clinical models and by several routes of administration. Some routes lead to cell death (e.g. intraganglionic injections) other routes do not, such as application to nerve endings in skin, deep tissue and joints. Through the efforts of an inter-institute working group, established with NIDA's Division of Pharmacotherapies and Medical Consequences of Drug Abuse, we are bringing this novel treatment to human clinical trial. The working group consists of experts on chemistry and manufacture, toxicological, neurobiological, medical, and regulatory affairs as well as anesthesiologists, pain management specialists and pharmacologists from our group. We have (a) established procedures for isolation, purification of RTX and formulation of the drug product, which was tested for stability, (b) conducted preclinical pharmacology, (c) conducted a complete toxicology study, and (d) submitted a clinical protocol to our Institutional Review Board and to the FDA as part the Investigational New Drug Application (IND). The RTX cell deletion treatment will first be tested for its ability to control cancer pain in patients with advanced disease. If it is safe and effective, we shall conduct a second protocol for treatment of head and neck cancer and then work on controlling other acute and chronic pain conditions such as post-surgical pain, joint pain, trigeminal neuralgia, arthritis and neuropathic pain. [unreadable] Basic Pain Mechanisms: Underlying the translational studies are our investigations of molecular regulation of gene expression, neuronal function, behavior, and mechanisms of pain transduction. We are systematically investigating the first three steps in the pain pathway beginning with injured peripheral tissue, the dorsal root ganglion and the dorsal (sensory) spinal cord. The goal of this approach is to obtain a comprehensive and informative understanding of nociceptive process. The dorsal root ganglion is quite small but its analysis is made possible by the extensive use of reverse-transcription-PCR, which allows us to make multiple measurements on such small tissue samples. Our studies reveal a complex, dynamic modulation of gene expression at all three steps. We have examined novel molecules as well as neuropeptide, cytokine and chemokine expression and identified prominent roles for new, key molecules with distinct combinatorial patterns of expression among the three tissues. The functional implications of our studies on cytokines suggest a new role for monocyte chemoattractant protein 1 in nociceptive DRG neurons. Our recent work shows that this molecule is quantitatively enriched in the superficial layers of the dorsal spinal cord where it likely functions to affect intercellular communication. Thus, this small protein can affect a specific endpoint in the sensory half of the spinal cord. Further studies demonstrated that this protein was highly enriched in the choroid plexus where it may have a more broad action on the entire nervous system by influencing the epithelial cells that manufacture the cerebrospinal fluid. The above studies were conducted in the laboratory rat, we do not know is whether this molecule is made in the same nociceptive sensory neurons in human DRG and shows the same enrichment in human spinal cord. To answer this question we have established collaboration with the Neuropathology Section of the Clinical Brain Disorders Branch of NIMH to collect human trigeminal ganglia and the spinal trigeminal nucleus when they collect brains for their brain bank. These tissues samples can be used for analysis of specific peptides or proteins and for more expression profiling studies for bridging the gap between rodent and the human spinal circuits and connections with the sensory ganglia. Through this research in animals and humans we hope to obtain a fundamental understanding of the relationships between tissue damage, inflammation and pain sensation. In a broader framework, these studies explore the fundamental molecular basis of synaptic plasticity. We hypothesize modularity in neuronal responses when a new level of synaptic or pharmacological input occurs that will be relevant not only to pain but also to situations such as learning, neurological disorders like epilepsy, and drug abuse. A set of "generic" alterations is combined with circuit-specific genes to meet the demands of new stimulation or activity. Understanding the molecular repertoire and its dynamic interactions will lead to a deeper understanding of mechanisms that trigger and sustain chronic pain and other disorders of the nervous system. [unreadable] Early Translational Investigations: A final set of studies concerns the identification of small chemicals that enhance the action of vanilloid agonists on TRPV1. This ligand-gated ion channel is one of the most important molecular transducers of painful stimuli and understanding how TRPV1 can be blocked, activated or sensitized is of primary importance in understanding pain. We have identified a new action on the TRPV1 molecule via screening of a chemical library. This activity is manifested as an enhancement of calcium influx upon agonist activation of TRPV1. These studies suggest an allosteric modulation of the open state of the TRPV1 ion channel and the presence of a reserve level of activity that can be accessed for pain transmission as well as the existence of a new class of pharmacological agents for pain modulation and pain control. |
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2008 — 2012 | Iadarola, Michael J | Z01Activity Code Description: Undocumented code - click on the grant title for more information. ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Mechanisms of Pain and Immune Processes @ Dental &Craniofacial Research Overview: Chronic neuropathic pain can affect any part of the body, including the oral cavity and facial nerves. Neuropathic pain can occur due to a variety of insults, infections, autoimmune disorders such as Sjogrens Syndrome, or metabolic disorders such as diabetes (diabetic neuropathy). We are testing the hypothesis that, in some patients, chronic pain is maintained by immunopathological processes related to autoantibodies generated against proteins in peripheral nerve. Autoantibodies are known culprits in certain large fiber peripheral neuropathies. Where pain is a component, we hypothesize the presence of autoantibodies to proteins found in nerve endings arising from small diameter, pain-sensing (nociceptive) C-fiber or A-delta nerve fibers. In support of this idea, it has been reported that approximately 30% of Sjogrens syndrome (SjS) patients exhibit a small fiber neuropathy that produces painful paresthesias in the upper and lower extremities. Similar neuropathic pain occurs prominently in Type II diabetes and in cancer patients treated with certain chemotherapeutic agents. To test the hypothesis that painful neuropathic conditions have an autoimmune component we established, a sensitive, quantitative, liquid phase luminescence assay, that uses recombinant antigen tracers expressed in mammalian cells, in order to measure the presence of antibodies in serum, saliva, or other body fluids. This translational research program addresses molecular and pathophysiological processes of nociceptive transmission and new ways to investigate chronic pain conditions in human patients. Our goals are to understand (1) the molecular and cell biological mechanisms underlying human chronic pain disorders, and (2) to use this knowledge to devise new treatments and diagnostics for pain disorders. In order to obtain sufficient throughput to examine large cohorts of normals and patients for multiple candidate antigens, we adapted the assay from a single tube format to a 96 well microtiter plates operating on our robotic pipeting platform. We also formed collaborations and assembled cohorts of different patient populations to establish baseline values in autoimmune disorders, infectious diseases and chronic pain and nervous system disorders. We have examined a known central nervous system autoimmune disorder called Stiff Person Syndrome. These patients have high titer autoantibodies to the enzyme glutamic acid decarboxylase (GAD65), which catalyzes the formation of the inhibitory neurotransmitter gamma-aminobutyric acid. We tested the major antigens (IA2, IA2b and GAD65) in Type 1 diabetes, which is the juvenile autoimmune form. These studies demonstrated that the non-radioactive luciferase immunoprecipitation assay is superior to the gold-standard radioactive assay in terms of sensitivity and specificity. We also performed an extensive analysis of autoantigens in Sjogrens Syndrome (SjS) patients (Ro52, Ro60 and La, and about 7 other antigens). We discovered two new antigens in sub-populations of SjS. One was against a nervous system protein, and another was against a gastric parietal cell protein. Over the past year we have extended the SjS study to include a comparison of salivary antibody levels to those in serum. Using only 5 microliters, the LIPS assay readily detected the major SjS autoantigens in saliva, yielding the same sensitivity and specificity as in serum. These results highlight the feasibility of establishing non-invasive, saliva based assays for many types of human diseases and for monitoring of vaccine immune status for large populations of people. In many neural autoimmune disorders the major autoantigens are frequently plasma membrane receptors or ion channels. To establish the basic parameters of receptor-based autoimmune disorders, we initiated a study on Myasthenia Gravis patients. This is a neurological autoimmune disorder against a membrane-bound, ligand-gated ion channel, the muscle nicotinic receptor (AChR). We established collaboration with the Myasthenia group at Johns Hopkins and demonstrated that LIPS detected autoantibodies that reacted with specific truncation mutants suggesting antigenic presentation of the extracellular domain in depends on intracellular folding of the second intracellular loop. These data provide a heuristic template for further studies of the AChR. We are currently working on several additional inter-institute and inter-institutional collaborations (such as the above Myasthenia study) to obtain well-characterized patients with Complex Regional Pain Syndrome (CRPS, a neuropathic pain disorder), other neuropathies, and other CNS and PNS disorders and infectious diseases that have neurological manifestations. We are working closely with groups at Rochester and Hopkins on SjS and salivary diagnostics and SjS patients with neurological symptoms, respectively. We have begun the analysis of neuropathic pain patients with CRPS using samples obtained from Rush University. We also are using this assay to explore the interrelationships between HIV, the virus causing Kaposis sarcoma and HIV-associated malignancies and painful peripheral neuropathies. The latter studies formed the basis of a Bench-to-Bedside award from the NIH Clinical Center. One of the most compelling aspects of this project is the progressive layering and evolution of the data set. As we increase the number of test antigens and assay across conditions and diseases, we assemble a comprehensive assessment of autoimmune responses. This is accomplished by determination of (a) the extent and specificity of immune response to orthologous proteins and protein fragments, (b) overlap in antigen profiles indicative of a common denominator or general mechanism, and (d) antigenicity within entire signaling pathways involved in inter- or intracellular communication. As time progresses, full multiple antigen profiling can be implemented to obtain a new level of understanding of many complex human disease states. In order to meet the increased demands of such broad spectrum autoimmunome profiling and take advantage of the layering, we are in the process of scaling up the throughput of the assay from 96 well plates to 384 well plates and then to 1536 well plates in collaboration with the NIH Chemical Genomics Center and the TRND group. This will conserve serum and allow us to examine individuals in much greater depth than what is presently possible. |
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