Iain L. Campbell - US grants
Affiliations: | Neuropharmacology | Scripps Research Institute, La Jolla, La Jolla, CA, United States |
We 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.
You can help! If you notice any innacuracies, please sign in and mark grants as correct or incorrect matches.
High-probability grants
According to our matching algorithm, Iain L. Campbell is the likely recipient of the following grants.Years | Recipients | Code | Title / Keywords | Matching score |
---|---|---|---|---|
1993 — 2000 | Campbell, Iain Leslie | 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. |
Cytokines and Aids Dementia Complex @ Scripps Research Institute This proposal focuses on the hypothesis that cytokines produced systemically and by infiltrating immune cells or resident brain cells, contribute to CNS injury during HIV-infection. To test this hypothesis, a well defined transgenic approach was employed in which the expression of the cytokines IL-6 and IL-3 was targeted to astrocytes using glial fibrillary acidic protein (GFAP)-fusion gene constructs. This has provided us with unique and powerful models to study the neuropathogenic consequences of the constitutive production of cytokines from astrocytes in the intact CNS. Initial characterization of GFAP-IL6 and GFAP-IL3 transgenic mice has unveiled wide-ranging molecular, cellular and functional alterations of the CNS-many of which share similarities to those seen in HIV encephalopathy. Significantly, these studies directly implicate cytokines in having a causal role in the genesis of HIV encephalopathy and other neurodegenerative diseases. Here we propose to develop transgenic mice with expression of the cytokine TNF-alpha targeted to the CNS. Detailed neuropathological assessment in this new model as well as in existing GFAP-cytokine mice will employ an established battery of tests to examine CNS alterations at the molecular and cellular levels, including RNase protection assays, in situ hybridization, northern blot hybridization, protein immunoblot assay, conventional light and laser confocal microscopy of immunolabeled brain sections and electron microscopy. Functional CNS alterations in the GFAP- cytokine mice will be determined at the behavioral and electrophysiological and levels and where possible be linked to specific molecular and cellular alterations. The identification of primary pathogenetic and functional milestones associated with the cerebral expression of the various cytokines will be determined by: i) detailed developmental studies and comparative analysis of the different GFAP- cytokine models, and ii) analyzing the CNS alterations resulting from the grafting of cytokine producing transgenic astrocytes in the normal mouse brain. The neurological impact of additional pathogenetic factors will be assessed: i) in cross-breeding experiments to develop biogenic mice expressing combinations of cytokines (i.e. IL-6+IL-3), and ii) by back- cross breeding GFAP-cytokine mice with SCID mice to develop immunodeficient GFAP-cytokine transgenic animals. These studies will develop models that recapitulate the multi-factorial pathogenetic and immunodeficient environments thought to underlie HIV encephalopathy. Finally, the well characterized GFAP-transgenic mice will be used to identify and assess in vivo the efficacy of drugs targeted at harmful individual cytokine-CNS interactions. This study provides a unique and powerful approach to elucidate the molecular and cellular basis for the CNS pathobiology of cytokines in vivo and can be expected to advance our understanding of HIV-associated neurological disease, help identify critical targets for therapeutic interventions and facilitate the preclinical evaluation of therapeutic strategies. |
1 |
1996 — 2000 | Campbell, Iain Leslie | P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
The Role of Cytokines in the Pathogenesis of Aids Dementia Complex @ Scripps Research Institute HIV-1 infection is commonly accompanied by injury to the central nervous system. Affected individuals frequently exhibit serious, progressive behavioral and neurological complications. Although the precise molecular and cellular pathogenetic processes associated with HIV encephalopathy remain unknown, accumulating evidence suggest toxicity tot he CNS amy be mediated indirectly, in part, by host derived factors such as cytokines, produced in response to the viral infection. This proposal focuses on the hypothesis that a key antiviral cytokine IFN-alpha, produced systemically and by infiltrating immune cells or resident brain cells, contributes to CNS injury during HIV-infection. To test this hypothesis, a well defined transgenic approach was employed in which the expression of IFN-alpha was targeted to astrocytes using a glial fibrillary acidic protein-IFNalpha1 fusion gene construct. This approach has provided a unique and powerful model to study the neuropathogenic consequences of the constitutive production of IFN-alpha from astrocytes in the intact CNS. Preliminary pathological characterization of so-called GIFN transgenic mice has unveiled wide-ranging structural and molecular alterations of the CNS thereby directly supporting the view that IFN-alpha, and likely therefore, other members of the IFN family, may have a causal role in the genesis of HIV encephalopathy. Here, we propose to further expand the scope and detail of the neuropathological assessment in an existing as well as in new stable lines of GIFN mice to be developed. This assessment will employ an established battery of tests to examine CNS alterations the molecular and cellular levels., including RNase protection assay, in situ hybridization, northern blot hybridization, protein immunoblot assay, conventional light and laser confocal microscopy of immunolabeled brain sections and electron microscopy. Functional CNS alterations in the GIFN mice will be determined at the behavioral, electrophysiological and neuroendocrine levels and where possible be linked to specific molecular and cellular alterations. The neurological impact of different pathogenetic factors will be assessed in the GIFN mice by: i) cross-breeding of the GFAP-IFN mice with mice from other transgenic backgrounds (e.g. GFAP-IL6 or GFAP-gp120), ii) intra- neural infection with neurotropic viruses and, iii) back-cross breeding with SCID mice to develop immunodeprived GFAP-cytokine transgenic animals. These studies will recapitulate the multi-factorial nature of the pathogenetic process the thought to underlie HIV encephalopathy. Finally, the well characterized GIFN mice will be used to identify and assess in vivo the efficacy of drugs targeted at harmful IFN-CNS interactions. This study provides a unique and powerful approach to elucidate the molecular and cellular basis for the CNS pathobiology of IFN-alpha in vivo and will facilitate the development and testing of therapeutic strategies to alleviate the toxic CNS actions of this cytokine. |
1 |
1998 — 2001 | Campbell, Iain Leslie | 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. |
Inflammatory Neurological Diseases @ Scripps Research Institute DESCRIPTION: This is a new proposal to study the role of IL12 in a variety of models of neurological disorders and in a variety of systems. His studies are to be divided into three specific aims. In the first aim he proposes to study IL12 expression and induction in a variety of in vivo systems using mice. For each of these systems he will include members of both susceptible and resistant strains to define if IL12 is a critical distinguishing feature that might be linked to susceptibility or resistance. The systems to be examined are: LPS endotoxemia, MHV infection, Listeria infection, Plasmodium berghii infestation, and EAE. In these systems he will examine a number of time points during the development of the illness, at it's peak and during recovery or chronic phases. His "read out" will be analysis by RNase protection assay of mRNa for p35 and embedded brains. He details the methods for all of these systems and studies. Finally, he will also examine the CNS tissues and extracts from them for a wide variety of other pro- and anti-inflammatory cytokines by PCR and in situ hybridization. The second specific aim is to analyze tissue cultures of astrocytes and microglial cells (both of which he has demonstrated to make IL12 on LPS stimulation) and peritoneal macrophages. He will define the time course of IL12 induction by LPS, attempt to define the mechanism of secretion being de novo synthesis by blocking protein assembly with cyclohexamide, and try to elucidate if the LPS induction is via a direct effect of the substance on gene transcription. Assays to be used here include analysis of p35 and p40 RNA induction, an anti-IL12 ELISA system, and a bioassay for IL12 using a human lymphoblastoid cell line generated from himself or an associate! The third aim is the creation of a stable transgenic IL12 producing transgenic mouse. He will use the GFAP promoter system he has successfully used in the past. AT this time he does possess the transgenic founders and is the process of breading them to establish a stable bigenic transgenic with consistent IL12 expression. He will use slot blots or PCR to follow the transgenes in the offspring. Once stable lines of IL12 expressing transgenics are established, he will use them in a wide number of experimental systems and manipulations to define whether and how IL12 may influence the standard changes typically attending the particular model. First he will analyze the clinical phenotype and behavior of the transgenics vs normals. He will describe the developmental and anatomic distribution of IL12 expression in the CNS, the degree of gliosis, microglial density and myelin and oligodendroglial changes (if any). Detailed anatomic examination of the neuronal distribution and its alterations will be defined using a variety of neuronal markers assisted by computer assisted image analysis. Ultrastructural studies will also be done to examine the CNS fine structure for changes in any cellular constituent not histo-logically seen with the light microscope. The nature, distribution, onset and type of CNS inflammation will be defined. He has enlisted the effort of two neuropathologists to help in this effort, and includes a table listing the numerous parameters to be examined. Since the founder mice have shown CNS inflammation spontaneously, he will do a detailed immunohistochemical analysis of the endothelium of the brain to determine which adhesion molecules are there. In the third part of the third aim he will attempt to define ability to participate in or deviate from normal neuroimmunological reactions. These will include EAE induction, putting the IL12 transgene on the SCID background or |
1 |
2000 — 2002 | Campbell, Iain Leslie | P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
@ Scripps Research Institute Individual's infected with the human immunodeficiency virus (HIV-1) frequently exhibit serious, progressive behavioral, cognitive and motor deficits (termed NeuroAIDS) in association with pathological changes (including gliosis, encephalitis and vacuolar myelopathy) in the brain. Current evidence strongly indicate the pathogenesis of this disorder (also known as NeuroAIDS) involves neurotoxic pathways mediated by: (1) HIV-1 related products e.g. the envelope protein gp120 and (2) products of the host response exemplified by cytokines such as IL-6, IFN- and TNF, release from activated macrophage/microglia and astroglia. Methamphetamine (METH) abuse which is frequently accomplished by significant acute and long-term neuronal damage is prevalent amongst HIV-1 infected individuals. We hypothesize here that the combination of these viral, host and METH insults produce additive or even synergistic actions that result in the worsening of the neuropathological sequelae and an accelerated progression to the functional neuropsychiatric deficits of NeuroAIDS. To determine the nature and mechanisms by which the central stimulant drug METH interacts with host-derived and HIV-1 related products to influence the degree and progression of structural and functional central nervous system (CNS) injury. Dysregulated peripheral immune function resulting from HIV-1 infection as well as infection from additional infectious agents is observed in individuals with AIDS. Therefore, we will define the interactions between METH and peripheral immune stimulation (achieved by intraperitoneal injection of the potent immune stimulant lipopolysaccharide) to influence the severity and progression of both CNS host responses and neuropathology. Transgenic mice with cerebral expression of IL6, TNF-, TNF- or gp120 recapitulate many of the structural and functional features of NeuroAIDS and will be used in the proposed studies to elucidate the interactions between METH and the central production of host- or HIV-1- related products to the development and progression of CNS host responses and neuropathology. Finally, transgenic mice with over-expression of Cu/Zn superoxide dismutase (SOD) or deficient expression of tissue-type plasminogen activator (tPA) that may underlie the pathogenic interactions between METH and products of the host response or HIV-1. This research plan integrates analysis of drug effects on the CNS as it relates to components of HIV disease progression is an important question for pre clinical and clinical research, as substance abusers have a high risk for exposure to the virus. The proposed studies should go far in identifying critical viral- and host-derived factors associated with increased susceptibility to the pathological effects of drugs of abuse such as METH and consequent neurotoxicity. |
1 |