Sangwon F. Kim - US grants

[unreadable] DESCRIPTION (provided by applicant): Schizophrenia is commonly recognized by its psychotic symptoms such as delusions and hallucinations, which often leads to social and functional impairment. Glutamate-NMDA neurotransmission has been strongly implicated in the genesis of schizophrenia. Recently, we have discovered that Dexrasl was found originally to bind to the Peripheral Benzodiazepine Receptor Associated Protein (PAP7), a protein of unknown function which binds to cyclic AMP dependent protein kinase and the peripheral benzodiazepine receptor. PAP7 also binds to the Divalent Metal Transporter (DMT1), an iron import channel. We have identified a novel signaling cascade in neurons whereby stimulation of glutamate-NMDA receptors activates nNOS, leading to S-nitrosylation of Dexrasl and a physiological increase in iron uptake through DMT1. In this proposal we plan to continue extensive investigations to further define the role of Dexrasl on brain iron homeostasis and study its implications in pathophysiological conditions and mental illness. We will employ both cellular and animal models to dissect out the detailed signaling cascades and the role of individual components. We will also extend our study to the Dexrasl homologous protein, Rhes (Ras Homologous Enriched in Striatum) which is enriched in striatum and up-regulated by thyroid hormone, which is known to influence the development and the function of CMS. We will employ molecular and cellular approaches to characterize the functions and roles of Rhes in the brain. The findings from our research will improve our understandings of CNS iron homeostasis and possibly lead to development of new strategies for treatment of patients with neurological dysfunctions and mental illness. [unreadable] [unreadable] [unreadable]

Schizophrenia is commonly recognized by its psychotic symptoms such as delusions and hallucinations, which often leads to social and functional impairment. Glutamate-NMDA neurotransmission has been strongly implicated in the genesis of schizophrenia. Recently, we have discovered that Dexrasl was found originally to bind to the Peripheral Benzodiazepine Receptor Associated Protein (PAP7), a protein of unknown function which binds to cyclic AMP dependent protein kinase and the peripheral benzodiazepine receptor. PAP7 also binds to the Divalent Metal Transporter (DMT1), an iron import channel. We have identified a novel signaling cascade in neurons whereby stimulation of glutamate-NMDA receptors activates nNOS, leading to S-nitrosylation of Dexrasl and a physiological increase in iron uptake through DMT1. In this proposal we plan to continue extensive investigations to further define the role of Dexrasl on brain iron homeostasis and study its implications in pathophysiological conditions and mental illness. We will employ both cellular and animal models to dissect out the detailed signaling cascades and the role of individual components. We will also extend our study to the Dexrasl homologous protein, Rhes (Ras Homologous Enriched in Striatum) which is enriched in striatum and up-regulated by thyroid hormone, which is known to influence the development and the function of CMS. We will employ molecular and cellular approaches to characterize the functions and roles of Rhes in the brain. The findings from our research will improve our understandings of CNS iron homeostasis and possibly lead to development of new strategies for treatment of patients with neurological dysfunctions and mental illness.

PROJECT SUMMARY (See instructions): Thyroid hormone is crucial to CNS development and function. A deficiency of thyroid hormone causes cretinism, a syndrome of severe impairment of physical and mental development. Relatively few genes in brain are known to be induced by thyroid hormone recently, we showed that one of these - Rhes (RasHomologous Enriched in Striatum, also called Dexras 2) - potently stimulates the brain iron transporter, or DMT1. The brain's iron requirement is relatively high. Intense brain metabolism and concomitant oxygen consumption depends upon a steady supply of iron to maintain cytochromes and mitochondrial function. Iron deficiency during pregnancy or postnatal life can result in brain maldevelopment. Administration of supplemental iron to children may not fully compensate for deprivation early in life: cognitive deficits are frequent in these youngsters. Conversely, iron excess can be neurotoxic, in part by favoring formation of reactive oxygen species (ROS). These observations indicate that iron transport into the CNS is a tightly ordered process that satisfies the need of the brain for this element without the imposition of a toxic burden. Our long-term goal is to elucidate the molecular basis and functional importance of iron brain trafficking. In this study, we will use molecular, cellular and biochemical approaches to characterize the function and regulation of Rhes. Our focus is to understand how this agents regulates iron transport and how this process affects neurotransmitter synthesis, which requires iron. Our research will provide insight into the mechanism(s) by which iron or thyroid deficiency hampers brain development. It also may lead to new strategies for the prevention of learning disabilities and for the management of children so affected.

DESCRIPTION (provided by applicant): Antipsychotic drugs relieve symptoms of schizophrenia as well as manic-depressive illness. The first generation drugs, however, were ineffective in many patients and failed to alleviate features such as emotional withdrawal reflecting the negative symptoms of schizophrenia. A new generation, atypical antipsychotic drugs (AAPDs), help non-responders, ameliorate negative symptoms, have fewer side-effects and so have emerged as some of the most widely used of all drugs. However, their use has been hampered by adverse metabolic side effects including severe weight gain elicited by some of those agents, sometimes doubling patient weights and with no clear cut explanation. We have found that the drugs that cause weight gain potently and selectively activate the enzyme AMP-kinase (AMPK) in the hypothalamic area of the brain in discrete nuclei which regulate eating behavior. This activation occurs secondary to the drugs' blocking the histamine H1 receptor for histamine, which, besides its roles in allergy, is a neurotransmitter in the feeding centers of the hypothalamus. Our preliminary studies indicate that inositol polyphosphate multikinase (IPMK), which utilizes one of the downstream molecules (inositol 1,4,5-triphosphate) produced upon histamine H1 receptor activation, is required for AMPK regulation. Also, the expression level of IPMK in the hypothalamus is modulated by energy balance. These intriguing observations led us to hypothesize that IPMK is the main mediator between histamine H1 receptor and AMPK regulation in the hypothalamus. Hence, in this proposal we will investigate the novel role of IPMK on AMPK modulation and energy homeostasis. We will characterize the molecular mechanism by which IPMK regulates AMPK modulation in the hypothalamus (Aim1). Moreover, we will investigate the posttranslational modification of IPMK, which can lead to a change of eating behavior via AMPK modulation (Aim 2). Finally, the contribution of IPMK in energy homeostasis and AAPDs-mediated weight gain in animal model will be investigated utilizing ipmkloxP/loxP mice (Aim3). Together, these studies will unveil not only the molecular basis of AAPD-mediated weight gain but also a novel signaling mechanism by which appetite is regulated in the hypothalamus. Accordingly, more efficient and effective strategies could be developed to manage the patients experiencing APPD-related metabolic side effects.

? DESCRIPTION (provided by applicant): Smoking is the largest preventable cause of death and disease in the United States, with about 46 million U.S. adults currently smoking. Though there are medications approved by the FDA to treat nicotine addiction, they are minimally effective and at least 80% of those seeking treatment relapse within one year. Rewarding aspects of nicotine as well as aversive properties, such as those associated with abstinence, may act synergistically to direct the behavior of smokers toward tobacco consumption. Symptoms associated with nicotine withdrawal include increased anxiety and cognitive deficits. To date, few studies have investigated the molecular and cellular changes that occur during chronic exposure to nicotine and how these molecules are altered during withdrawal. Previously, we and others have established that the transcription factor CREB is a central mediator of addictive behaviors. We now made the discovery that one of the targets of CREB in the brain is the LKB1/AMPK pathway. AMP-activated kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that has a major role in the periphery in sensing cellular energy status and regulating fuel availability. Its role in the brain is virtually unknown. Preliminary data indicates that the AMPK pathway and its downstream targets are misregulated during nicotine exposure and withdrawal. The proposed mechanistic and translational studies will determine the functional role of this protein on nicotine reward behavior and withdrawal symptoms and will afford the development of novel or repurposed pharmacological treatments designed to promote smoking cessation.