Patrick W. Mantyh - US grants
Affiliations: | University of Minnesota, Twin Cities, Minneapolis, MN |
Area:
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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, Patrick W. Mantyh is the likely recipient of the following grants.Years | Recipients | Code | Title / Keywords | Matching score |
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1987 — 1989 | Mantyh, Patrick W | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Peripheral Nociceptors in Inflammatory Pain @ University of California Los Angeles Dorsal root ganglion (DRG) neurons are involved in the transmission of nociceptive information from peripheral tissues to the central nervous system. A class of these sense organs differ from all others in that they display a property called "sensitization" wherein the response to successive noxious stimuli increases and the threshold is lowered - the opposite of "adaptation". Recently several neuropeptides known as tachykinins (substance P, substance K, and neuromedin K) have been shown to be synthesized by mammalian DRG neurons. Recent data has strongly implicated these neuropeptides in the afferent transmission of nociceptive information and in the efferent regulation of inflammation and sensitization in peripheral tissues. In addition another powerful vasodilator, calcitonin gene related peptide (CGRP), has been shown to co- exist with substance P containing DRG neurons and appears to potentiate the nociceptive actions of substance P in the rat spinal cord. The hypothesis we will test in the present proposal is whether tachykinin and CGRP-containing DRG neurons change biochemically and pharmacologically in response to an inflammatory pain state, and if so, to what extent these changes are associated with the phenomena of sensitization. The model system we will use to investigate this will be a standard experimental arthritis in the rat which will serve as a simple, reproducible and humane animal model of a chronic pain syndrome of high incidence in man. The goal of the present proposal is clear; to understand how peripheral tachykinin and CGRP containing neurons are involved in the genesis of chronic pain and inflammation in arthritis and to determine the effectiveness of the 30 known putative tachykinin antagonists in ameliorating the pain or inflammation associated with the arthritic condition. We feel the proposed work is the most tangible, direct and quantitative approach for studying those factors which might activate nociceptors in ordinary innocuous joint movement; obviously a problem of practical importance. |
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1990 — 2000 | Mantyh, Patrick W | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Peripheral Nociceptors in Inflammation @ University of Minnesota Twin Cities The long-term objective of the proposed studies is an enhanced understanding of the cellular mechanisms of nociception and analgesia. The transmission of noxious stimuli from peripheral nociceptors to the spinal cord is dependent in large part on the interaction of substance P (SP), a peptide released from sensory nerve endings, and substance P receptors (SPR) which are expressed by neurons in the spinal cord and dorsal column nuclei (DCN). Recently, we have shown that SP release from primary afferents drives SPR internalization in spinal cord neurons and provides a specific image of the cells activated by SP in the spinal cord in vivo. Building on this and related observations we will: (1) Determine the somatosensory stimuli that induce SP release in the spinal cord and DCN in the normal rat, determine how different anesthetic agents influence the release of SP and the SP-induced SPR internalization, and determine whether morphologically distinct classes of SPR- immunoreactive neurons and glia in the spinal cord and DCN are activated by different modalities of somatosensory stimulation. (2) Determine the neuronal and glial cell types that show an up- regulation of the SPR after nerve injury or in an inflammatory pain state. (3) Determine whether, after nerve injury or in inflammatory pain, there is an increased release or diffusion of SP in the spinal cord or DCN in response to noxious and non-noxious stimuli or nerve stimulation and whether an additional subset of neurons and glia is now activated by SP released from primary afferents. (4) Determine whether opiates, prostaglandins and other ligands that target receptors expressed on the presynaptic terminals of primary afferent neurons differentially modulate the release of SP from sensory neurons in the normal animals vs. animals with nerve injury or persistent inflammatory pain. (5) Using similar techniques that we have successfully employed to raise antibodies to the SPR, raise antibodies that recognize; a subtype of the SPR that has a truncated C-terminus, the neurokinin-2 and neurokinin-3 receptors and determine what role these tachykinin receptors play in nociception and analgesia. The goal of the proposal is to explore the cellular basis of pain perception and discover targets in the signal transduction pathway that may be the most effective points for interventions in the control of pain. |
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1994 — 1996 | Mantyh, Patrick W | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Aggregation/Deposition of B Amyloid in Alzheimer Disease @ University of Minnesota Twin Cities |
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1996 — 2001 | Mantyh, Patrick W | T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Minnesota Pain Research Training Program @ University of Minnesota Twin Cities |
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1998 — 2002 | Mantyh, Patrick W | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
@ University of Minnesota Twin Cities Description: (Applicant's Abstract) Management of chronic painful syndromes presents a tremendous challenge to the medical field as current pain management approaches with narcotics, such as morphine, carry adverse side effects such as sedation, constipation, tolerance and addiction. Therefore, a greater understanding of pathophysiological mechanisms that lead to a chronic pain state is needed for development of novel and effective therapies with minimal side effects. Recently, we demonstrated that when a conjugate of substance P (SP) and the ribosome-inactivating protein saporin (SAP) is infused into the spinal cord, the SP-SAP conjugate is specifically internalized and cytotoxic to lamina I spinal cord neurons that express the substance P receptor (SPR). This treatment leaves responses to mild noxious stimuli unchanged, but profoundly attenuates responses to highly noxious stimuli and to mechanical and thermal hyperalgesia. Using the intrathecal infusion of SP-SAP in the rat spinal cord as our model we propose: to investigate whether this treatment can alleviate inflammatory and/or neuropathic persistent pain states (Aim 1); to further define the rostral brain areas these neurons project to and the other receptors and neurotransmitters that are expressed by lamina I SPR-expressing neurons (Aim 2); to determine the functional role of neurons that express the SPR in nociceptive processing and hyperalgesia, and whether these SPR expressing neurons are functionally different from nociceptive neurons that do not express the SPR (Aim 3); and to determine whether reorganization of the spinal cord and dorsal root ganglia occurs following SP-SAP treatment and whether morphine is still effective in attenuating nociceptive responses (Aim 4). Information from these investigations will provide significant insight into the neurochemistry of spinal nociceptive signaling and whether SP-SAP treatment shows promise for developing non-opioid therapies to control chronic pain in humans. |
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2001 — 2019 | Mantyh, Patrick William | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
Peripheral Nociceptors in Persistent Pain @ University of Arizona ? DESCRIPTION (provided by applicant): Chronic skeletal pain is a frequent companion of aging. In large part this is because the mass, quality, and strength of human bone peaks at 25-30 years of age and declines thereafter. Thus, by the time most humans are 60, normally non-traumatic, low impact falls can result in fracture of the hip, wrist, or vertebrae. Fractures in oler individuals are frequently painful and heal at significantly slower rates than in the young. For example, in older individuals with hip fractures the fractured bone usually never fully heals, is frequently accompanied by chronic skeletal pain, and most individuals never fully recover their pre-fracture functional status and quality of life. Currently, disorders and aging of the bone are one of the most common causes of chronic pain and long-term physical disabilities in the United States and the world. In large part this is because we know very little about the mechanisms that drive age-related bone pain and bone healing. As a result, we have remarkably few mechanism-based analgesics to control the pain or anabolic therapies to accelerate healing following an age- related bone fracture. In the present proposal, our goal is to begin to develop a mechanism-based understanding of what drives age-related fracture pain and bone healing. To accomplish these goals we will use a model of bone fracture pain and bone healing in the young vs. old male and female mice. This model will allow us to simultaneously explore bone fracture healing, skeletal pain behaviors, changes in sensory and sympathetic nerve fiber expression and sprouting, and the bone microenvironment in the normal and fractured bone. Importantly, the mouse model closely mirrors the pain and bone healing that occurs in humans. A key aspect of the application is that we will be focusing on old mice, as with age there is a marked increase in bone fractures, skeletal pain, and bone fracture associated morbidity / mortality. Our specific aims are: 1) begin to elucidate the specific cells and factors that drive age-related fracture pain and bone healing; 2) determine the role that stromal cell factors, including nerve growth factor (NGF) and sclerostin, play in driving fracture pain and reducing fracture healing in the young vs. old bone. Our experience in working at the nerve / bone interface, the robust nature of the mouse bone fracture model, and the comparison of young vs. old offers a unique opportunity to increase our understanding of the mechanisms that drive age-related fracture pain / bone healing. If successful, these studies may help in the development of novel therapies that can more effectively treat age-related bone fractures. RELEVANCE: Skeletal pain is a frequent companion of aging. This project will focus on exploring the mechanisms that drive bone fracture pain / bone healing. If successful, this proposal has the potential to fundamentally transform our understanding of skeletal pain and how we treat and prevent age-related pain and bone fractures. |
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2004 — 2007 | Mantyh, Patrick William | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cancer Pain and Breast Tumor Metastasis to Bone @ University of Minnesota Twin Cities DESCRIPTION (provided by applicant): Bone cancer significantly decreases the quality of life of millions of cancer patients each year. A major problem in designing new therapies to treat this chronic pain was that until recently there was not a model available to define the mechanisms that generate and maintain bone cancer pain. The major thrust of this proposal is to use a rat tumor model that is mixed in nature (in that it induces both bone formation and destruction) to define the mechanisms that give rise to bone cancer pain that arises from mixed tumors such as breast or prostate when they metastasize to bone. Rat mammary carcinoma cells, stably transfected with green fluorescent protein, will be injected and confined to the intramedullary space of the rat femur. Over a twenty eight day period these tumor cells proliferate and induce bone formation, bone destruction, bone cancer related pain behaviors and a set of neurochemical changes in both sensory and spinal cord neurons that appears to be involved in generating and maintaining bone cancer pain. Using this model we will define: the time course and extent of tumor growth, bone formation, bone destruction, osteoclastogenesis, and bone cancer pain related behaviors (Aim 1): how the sensory and sympathetic innervation of bone changes as the tumor fills the intramedullary space, the bone is remodeled and bone cancer pain develops (Aim 2); the neurochemical changes that occur in primary afferent sensory neurons, sympathetic neurons, the spinal cord and dorsal column nuclei as the tumor grows, tumor induced bone remodeling occurs and bone cancer pain develops (Aim 3); whether systemic or intrathecal administration of morphine, COX-2 inhibitor, gabapentin or endothelin A receptor antagonist reduce specific aspects of bone cancer pain related behaviors, tumor growth, bone remodeling, osteoclastogenesis and the neurochemical changes that occur in the peripheral and central nervous system (Aim 4). Information from these investigations should expand our understanding of the mechanisms that generate and maintain bone cancer pain and lead to the development of more effective therapies for treating bone cancer pain. |
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2011 — 2015 | Mantyh, Patrick William | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Metastatic Prostate Cancer-Induced Bone Pain @ University of Arizona DESCRIPTION (provided by applicant): Prostate cancer is unique among cancers as although it is highly metastatic, bone is frequently the only clinically detectable site of metastasis. Fortunately, patients with metastatic prostate cancer usually have a long survival time. Unfortunately, prostate metastasis to bone frequently causes a severe, chronic pain that reduces quality of life, functional status, and greatly increases health care utilization. The goals of this application are to understand the mechanisms that drive prostate cancer-induced bone pain and use this information to develop therapies that can better prevent and/or treat this chronic pain. In preliminary studies, we have refined a mouse model of prostate cancer bone pain so that it closely mirrors many of the pathological features observed in humans with prostate metastasis to bone in terms of: the tumor being primarily osteoblastic, the pattern of tumor colonization in bone, the individual tumor colonies forming sclerotic bone lesions, the robust vascularization, and viability of the tumor. While these prostate cancer cells do not express nerve growth factor (NGF), preliminary data suggest their associated stromal cells release NGF that induces dramatic sprouting of tropomyosin receptor kinase A (TrkA)+ sensory and sympathetic nerve fibers in the tumor-bearing bone that may play a major role in driving chronic prostate cancer-induced bone pain. Based on these observations, we hypothesize that: (1) NGF released from specific populations of stromal cells induces marked sprouting and neuroma formation by TrkA+, but not TrkA-, sensory and sympathetic nerve fibers in the tumor-bearing bone and that the extent of this pathological reorganization will predict the severity of prostate-induced pain behaviors;(2) newly sprouted sensory and sympathetic nerve fibers have a distinct morphology and express pathologically high levels of pro-algesic neurotransmitters, channels/receptors, and mitogen-activated protein kinases that are never observed in nerve fibers that innervate the normal bone;and (3) early preventive administration of anti-NGF or anti-TrkA attenuates the tumor-induced nerve sprouting, the pro-algesic phenotype of sensory and sympathetic nerve fibers, and bone cancer pain. In contrast, late administration of anti-NGF or anti-TrkA will only partially reverse the pro-algesic phenotype of the nerve fibers and have little or no effect on the pathological sprouting or neuroma formation that has already occurred. The overarching hypothesis is that the earlier preventive blockade of the NGF/TrkA pathway is initiated, the more effectively the pathological nerve changes and pain can be controlled. If correct, data from this project may fundamentally change our understanding and treatment of prostate cancer-induced bone pain. PUBLIC HEALTH RELEVANCE: Prostate cancer is unique among cancers as although it is spreads to different organs, bone is frequently the only clinically detectable site of metastasis. Fortunately, patients with metastatic prostate cancer usually have a long survival time. Unfortunately, prostate metastasis to bone frequently causes a severe, chronic pain that reduces quality of life, functional status and greatly increases health care utilization. The goals of this application are to understand the mechanisms that drive prostate cancer-induced bone pain and to use this information to develop therapies that can better treat this chronic pain. |
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2011 — 2015 | Mantyh, Patrick William | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Preventive Analgesia For Bone Cancer Pain @ University of Arizona DESCRIPTION (provided by applicant): Bone cancer pain significantly decreases the quality of life and functional status for millions of cancer patients each year. Currently, our vision of how sensory nerve fibers change when tumors metastasize and grow in bone is that nerve fibers are first sensitized and activated by factors released by tumor/stromal cells, then injured as tumor and stromal cells proliferate and remodel the tumor bearing bone. However, preliminary data we have generated suggests that tumor and tumor-associated stromal cells also induce dramatic sprouting and neuroma formation of sensory and sympathetic nerve fibers that innervate the bone. Our hypothesis is that tumor and stromal cells induce a marked reorganization of TrkA+ nerve fibers and that the pathological reorganization of these nerve fibers plays a significant role in driving bone cancer pain. Based on these observations, we hypothesize that: (1) nerve growth factor (NGF) released from tumor and stromal cells induces marked sprouting and neuroma formation in TrkA+, but not TrkA-, sensory and sympathetic nerve fibers; (2) newly sprouted sensory nerve fibers have a distinct morphology and pathologically high expression levels of neurotransmitters, ion channels, receptors and mitogen-activated protein kinases, which is different from nerve fibers that innervate the normal bone, and (3) early administration of anti-NGF or TrkA antagonist will block these pathological changes and the severity of bone cancer pain more effectively than late administration. The overarching hypothesis is that the earlier administration of anti-NGF or TrkA blockade is begun, the more likely these therapies will block tumor-induced nerve sprouting, neuroma formation, inappropriate up-regulation of ion channels, and pain. If correct, data generated from this project has the potential to fundamentally change our understanding of the mechanisms that drive bone cancer pain and promote the use of preventive analgesia for managing bone cancer pain. |
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