1995 — 1997 |
Petitto, John M |
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. |
Molecular Pharmacology of Brain Il-2 Receptors |
1 |
1999 — 2002 |
Petitto, John M |
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. |
Il-2 Gene Deletion: Neurodevelopment and Behavior
DESCRIPTION (Adapted from applicant's abstract): Elucidating the role of IL-2 in the brain during development could have important implications for understanding processes involved in autoimmune diseases affecting the brain, as well as neurodevelopmental diseases such as schizophrenia. This proposal will test the hypothesis that deletion of the IL-2 gene in the CNS produces spatial learning deficits resulting from alterations in hippocampal neurodevelopment and function. IL-2 mRNA transcripts and IL-2-like immunoreactivity have been identified in rodent and human brain and IL-2 has been implicated as both a neurotrophic factor and neuromodulator. To determine how and where IL-2 works in the brain, we have cloned and sequenced the full-length cDNAs for the alpha, beta, and gamma subunits of the brain IL-2 receptor complex. Our data and the work of others show that IL-2 receptor gene expression is enriched in the hippocampal formation, which is the only brain region where specific IL-2 receptor binding has been detected. Our preliminary studies using IL-2 knockout mice are the first to demonstrate that IL-2 gene deletion produces robust impairments in spatial learning. Thus, we propose to characterize the nature of the learning impairment in IL-2 knockout mice, focusing on the effects of IL-2 gene deletion on the neurodevelopment and function of the hippocampus. The specific aims will: 1) Characterize the neurobehavioral phenotype resulting from IL-2 gene deletion, 2) Test the hypothesis that the neurobehavioral phenotype of IL-2 knockout mice results principally from the absence of the IL-2 gene in the CNS, rather than in the periphery, and 3) Test the hypothesis that the spatial learning deficit produced by IL-2 gene deletion will be accompanied by alterations in hippocampal cytoarchitecture and neurobiology. The proposed studies will be the first to determine the consequences of the absence of IL-2 on these aspects of brain development and behavior. We believe that the proposed research is timely and will lay an essential foundation on which to build in future studies.
|
1 |
2001 — 2004 |
Petitto, John M |
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. |
Neuroimmunology of Il-15
IL-15 and IL-2 are members of the 4alpha-helix bundle family of cytokines. Heterotrimeric receptors for both cytokines on lymphocytes share the same constitutively expressed pair of signal transducing subunits. IL-2 and IL-15 can bind the dimeric IL-2/15Rbeta,gammac receptor and transmit intracellular signals. To differentiate signals by IL-15 and IL-2, "private" accessory alpha subunits (IL-15Ralpha and IL-2Ralpha) are expressed forming trimeric receptors that confer specificity for each cytokine. Whereas numerous studies have documented various actions of IL-2 in the CNS such as its neuromodulatory and neurotrophic actions in septal and hippocampal neurons, the neural and immunological actions of IL-15 in the brain are largely unknown. Several lines of evidence have led investigators to hypothesize that functional effects ascribed to endogenous IL-2 may well be attributable to endogenous IL-15. Moreover, in the immune system these cytokines have both shared and distinctly different actions. Of particular relevance to the studies outlined in this proposal, IL-15 is powerful T-cell chemoattractant, a characteristic not shared by IL-2. Although studies have implicated IL-2 signaling through IL-2/15Rbeta,gammac in the hippocampal formation and related limbic regions, the effects of IL-15 on these neurons is unknown and will be examined in the proposed studies. In the brain, some classical immune cytokines have been found to have neuromodulatory and neurotrophic effects that are limited to very specific neural pathways, while exerting more general effects on the brain's endogenous immune cells (e.g., microglia). We postulate that IL-15 also has this characteristic. Recent observations including our preliminary data suggest that the IL- 15/IL-15R system may orchestrate interactions between T- lymphocytes, microglia and regenerating neurons following axotomy. Using this model in the proposed studies, we will test the hypothesis that IL-15 plays a key role in neuronal regeneration. Thus, the proposed Specific Aims will: 1) test the hypothesis that IL-15Ralpha and IL-15 are enriched in the hippocampus and related limbic regions, and are expressed by neurons; 2) determine which neuromodulatory and neurotrophic effects of IL-15 on septal and hippocampal neurons are different from those of IL-2, and; 3) test the hypothesis that glial- derived IL-15 plays an essential role in motor neuron regeneration following nerve axotomy.
|
1 |
2005 — 2008 |
Petitto, John M |
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. |
Immunodeficiency and Neuronal Function
DESCRIPTION (provided by applicant): Recent data demonstrates that the peripheral immune system has important effects on neuronal integrity and function in the CNS. This data includes work from our lab and others showing that deficits in neurobehavioral performance and motor neuron regeneration following axotomy are associated with the absence of functional T and B lymphocytes in immunodeficient mice. Moreover, alterations in neuronal function in immunodeficient mice can be prevented if normal lymphocytes from wild-type mice of the same genetic background are adoptively transferred to reconstitute a functional immune system in these animals. The proposed studies are designed to elucidate the neurobiological and immunological mechanisms that modulate these important processes in both limbic and motor neurons. The Specific Aims will identify critical mechanisms that determine whether immunological processes are involved in modulating parameters of brain function and behavior, and may have proregenerative effects on injured neurons. These aims are: 1) Test the hypothesis that immune status during development serves as a determinant of behavior; 2) Test the hypothesis that immunodeficiency results in alterations in septal and hippocampal neurons; and 3) Test the hypotheses that the proregenerative effects of immune reconstitution are mediated principally by T lymphocytes, and that their proregenerative function may be augmented by prior exposure to neuronal damage.
|
1 |
2007 — 2011 |
Petitto, John M |
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. |
Il-2 Deficiency Associated Neuropathology: Development and Autoimmunity
DESCRIPTION (provided by applicant): The role of IL-2 as a neuromodulator and trophic factor in the brain has been the focus of much research. IL- 2 has been implicated in the pathogenesis of multiple sclerosis and several major neuropsychiatric disorders including Alzheimer's disease, schizophrenia, and Parkinson's disease. IL-2 is an immunoregulatory cytokine that is indispensable for maintaining immunological homeostasis. IL-2 is also expressed by brain cells, and exerts potent effects on acetylcholine release from septohippocampal cholinergic neurons and trophic effects on fetal septal and hippocampal neurons. Our lab has previously cloned and sequenced the IL-2 heterotrimeric receptor complex in brain, and shown that IL-2 receptors are enriched in the hippocampus and related limbic regions. Using IL-2 knockout mice, we have found that IL-2 gene deletion results in septohippocampal pathology in adult mice. Our data and the literature suggest that these alterations are due to both the loss of IL-2's trophic effects on neurons, and to unique characteristics of autoimmunity caused by IL-2 deficiency in the peripheral immune system. The proposed studies are designed to disentangle which components of the septal and hippocampal neuropathology are due to the absence of IL-2 in the brain versus peripheral immune cells. Our working hypotheses that we will test are that the loss of medial septal neurons that we have observed in IL-2 knockout mice is due principally to autoimmunity, whereas the hippocampal pathology is due the loss of the neurotrophic actions of brain IL-2. These and other important objectives will be achieved by successful completion of the following Specific Aims. The experiments proposed in Aim 1 will assess the development of: 1) peripheral autoimmunity, 2) the neuroimmunological status of the septum and hippocampus, and 3) septal and hippocampal neuropathology in IL-2 knockout mice. Aims 2 and 3 will use a combination of novel congenic mice and adoptive transfer manipulations to test our working hypotheses. The research proposed in Aim 2 will test the hypothesis that loss of medial septal neurons results from peripheral IL-2 deficiency-induced autoimmunity. Experiments proposed in Aim 3 will test the hypothesis that brain IL-2 is essential for the normal development and survival of neurons in the dentate gyrus. Learning and memory will also be tested in Aims 2 and 3 to determine the functional significance of the neuropathology. These studies will provide essential new insight into brain IL-2's intrinsic actions in the septohippocampal system. This unique mouse model will also provide much needed new data elucidating neuroimmunological and autoimmune processes involved in brain development and disease. Such information may ultimately provide critical new insight into the role of brain cytokines and autoimmunity in prominent neurological and neuropsychiatric diseases (e.g., multiple sclerosis, Alzheimer's disease, schizophrenia).
|
1 |