2002 — 2004 |
Leinninger, Gina Marie |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Role of Jnk in Neuronal Apoptosis @ University of Michigan At Ann Arbor
DESCRIPTION (provided by applicant): The goal of this application is to determine the molecular mechanism underlying diabetic neuropathy in dorsal root ganglion (DRG) neurons. Our hypothesis is that neurons exposed to high glucose undergo apoptosis via activation of apoptosis signal-regulated kinase 1 (ASKI), which activates the c-Jun N-terminal kinase (JNK) pathway. Insulin-like growth factor I (IGF-I) is predicted to protect DRG from glucose-mediated apoptosis by blocking activation of a component of the JNK pathway. This application will analyze glucose-treated DRG by TUNEL analysis and western blotting to determine 1) apoptotic molecules induced by JNK activation, 2) the role of ASKI on JNK activation and apoptosis and 3) the effect of IGF-I on JNK pathway activation and apoptotic regulatory proteins. At the conclusion of these studies we will understand how the JNK pathway functions in a model of diabetic neuropathy and how IGF-I mediates neuroprotection. These findings will advance our understanding of neuronal injury and may suggest potential therapeutic interventions for treatment of diabetic neuropathy.
|
1 |
2010 — 2011 |
Leinninger, Gina Marie |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. |
Role of Lateral Hypothalamic Leptin Receptor-Neurotensin Neurons in Energy Balanc
DESCRIPTION (provided by applicant): Obesity-linked (type-2) diabetes exacts a significant health toll, but there are few disease-modifying treatments to stem this "diabesity epidemic." Better understanding of the mechanisms that regulate energy homeostasis are needed to identify potential pathways for therapeutic intervention. The adipose-derived hormone leptin acts via neurons in the brain that express the long form of the leptin receptor (LepRb) to decrease food intake and potentiate energy expenditure. Many aspects of leptin action via LepRb neurons of the medialbasal hypothalamus have been characterized, but they do not account for leptin's ability to modulate the incentive salience of food. A potential locus for this aspect of leptin action is the lateral hypothalamus (LHA), which contains Orexin (OX) neurons that project to and regulate the mesolimbic dopamine (DA) system to alter motivated behavior (including food intake and activity). My work in the laboratory of Dr. Martin Myers has begun to characterize LHA LepRb neurons, including a subpopulation that are discrete from, but synaptically connected with, OX neurons. This subpopulation of LHA LepRb neurons co-express opposing transmitters: the inhibitory neurotransmitter GABA and the excitatory neuropeptide neurotensin (Nts), a known regulator of the mesolimbic dopamine (DA) system;we therefore refer to this population as LHA LepRbNts neurons. I hypothesize that opposing GABA and Nts signaling from LHA LepRbNts neurons mediate distinct regulatory effects in energy homeostasis, particularly via the mesolimbic DA system. During the K99 mentored phase, I will explore this hypothesis in mice null for Nts signaling (Aim 1) while developing a novel mouse model (NtsFRT Neo-Cre mice) to selectively identify LHA LepRbNts neurons (Aim 2a) allowing for their functional interrogation. Dr. Myers has a substantial track record in creating novel mouse lines, and his mentorship during the K99 phase is essential for my ability to learn the molecular genetics skills necessary to create the NtsFRT Neo-Cre mice (and subsequent novel mouse models) that will be utilized for my independent research program. During the R00 phase, I will interbreed NtsFRT Neo-Cre mice and existing mouse models to generate mice that either selectively ablate all LHA LepRbNts neurons (Aim 2) or their GABA signaling (Aim 3) to identify the roles of these neurons overall and parse the specific role of GABA in energy homeostasis. Collectively, the scientific and career training facets of the mentored K99 phase will provide the tools to establish my independent research program in the R00 phase, supporting my transition to a productive research faculty position in the field of obesity. Overall, this line of research will determine the signaling mechanisms by which LHA LepRbNts neurons contribute to energy homeostasis, and their role in the pathogenesis of obesity PUBLIC HEALTH RELEVANCE: Obesity-linked diabetes is an increasing worldwide health problem, but limited understanding of the systems that regulate food intake and weight has hindered development of effective therapies for this disease. The studies herein will investigate the mechanisms by which a unique group of neurons in the lateral hypothalamus regulate food intake, weight, activity levels and hedonic or "craving" responses. This work will add to our understanding of the development of obesity, and characterization of these novel neurons may identify therapeutic intervention sites for treating obesity.
|
1 |
2012 — 2014 |
Leinninger, Gina Marie |
R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
Lateral Hypothalamic Leptin Receptor-Neurotensin Neurons in Energy Balance @ Michigan State University
Project Summary / Abstract Obesity-linked (type-2) diabetes exacts a significant health toll, but there are few disease-modifying treatments to stem this diabesity epidemic. Better understanding of the mechanisms that regulate energy homeostasis are needed to identify potential pathways for therapeutic intervention. The adipose-derived hormone leptin acts via neurons in the brain that express the long form of the leptin receptor (LepRb) to decrease food intake and potentiate energy expenditure. Many aspects of leptin action via LepRb neurons of the medialbasal hypothalamus have been characterized, but they do not account for leptin's ability to modulate the incentive salience of food. A potential locus for this aspect of leptin action is the lateral hypothalamus (LHA), which contains Orexin (OX) neurons that project to and regulate the mesolimbic dopamine (DA) system to alter motivated behavior (including food intake and activity). My work in the laboratory of Dr. Martin Myers has begun to characterize LHA LepRb neurons, including a subpopulation that are discrete from, but synaptically connected with, OX neurons. This subpopulation of LHA LepRb neurons co-express opposing transmitters: the inhibitory neurotransmitter GABA and the excitatory neuropeptide neurotensin (Nts), a known regulator of the mesolimbic dopamine (DA) system; we therefore refer to this population as LHA LepRbNts neurons. I hypothesize that opposing GABA and Nts signaling from LHA LepRbNts neurons mediate distinct regulatory effects in energy homeostasis, particularly via the mesolimbic DA system. During the K99 mentored phase, I will explore this hypothesis in mice null for Nts signaling (Aim 1) while developing a novel mouse model (NtsFRT Neo-Cre mice) to selectively identify LHA LepRbNts neurons (Aim 2a) allowing for their functional interrogation. Dr. Myers has a substantial track record in creating novel mouse lines, and his mentorship during the K99 phase is essential for my ability to learn the molecular genetics skills necessary to create the NtsFRT Neo-Cre mice (and subsequent novel mouse models) that will be utilized for my independent research program. During the R00 phase, I will interbreed NtsFRT Neo-Cre mice and existing mouse models to generate mice that either selectively ablate all LHA LepRbNts neurons (Aim 2) or their GABA signaling (Aim 3) to identify the roles of these neurons overall and parse the specific role of GABA in energy homeostasis. Collectively, the scientific and career training facets of the mentored K99 phase will provide the tools to establish my independent research program in the R00 phase, supporting my transition to a productive research faculty position in the field of obesity. Overall, this line of research will determine the signaling mechanisms by which LHA LepRbNts neurons contribute to energy homeostasis, and their role in the pathogenesis of obesity. .
|
0.979 |
2014 — 2021 |
Leinninger, Gina Marie |
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. |
Role of Lateral Hypothalamic Neurotensin Neurons in Energy Balance @ Michigan State University
DESCRIPTION (provided by applicant): Neurons in the lateral hypothalamic area (LHA) exert opposing control of feeding and energy balance via incompletely understood neuronal circuits. Many LHA neurons express orexigenic neuropeptides and regulate limbic brain regions, including midbrain dopamine (DA) neurons, to induce hedonic feeding and promote weight gain. A separate population of LHA neurons expresses the anorectic neuropeptide neurotensin (Nts) and these LHA Nts neurons are selectively activated by stimuli that suppress feeding. Loss of action via LHA Nts neurons promotes overeating and blunts energy expenditure and DA signaling that leads to obesity, suggesting that LHA Nts neurons interface with DA circuits to regulate energy balance. Indeed, LHA Nts neurons synaptically regulate the midbrain, where many DA neurons express the receptors for neurotensin, neurotensin receptor-1 (NtsR1) and neurotensin receptor-2 (NtsR2). Nts acts via these receptors to activate DA neurons and suppress feeding, but loss of Nts action via NtsR1 promotes hedonic feeding and obesity. Collectively, these data implicate a novel LHA Nts neuronal circuit that synergizes anorectic cues and DA signaling to promote weight loss. To determine the mechanism(s) by which LHA Nts neurons regulate energy balance this proposal combines the use of novel genetic reagents and state of the art molecular tools to interrogate the constituent neurons within the LHA Nts neuronal circuit. Aim 1 will establish the LHA Nts neuronal mechanisms that coordinate physiologic cues and behavior to adaptively regulate energy balance. Aim 2 will determine how LHA Nts neurons interface with DA circuits, testing the hypothesis that Nts action via midbrain NtsR1 and/or NtsR2 neurons modulates DA signaling to regulate energy balance. Aim 3 will selectively activate LHA Nts neurons to test the hypothesis that action via the LHA Nts neuronal circuit suppresses hedonic intake and promotes locomotor activity to induce weight loss. Collectively, these studies will determine the precise mechanisms by which LHA Nts neurons regulate DA- mediated feeding and energy expenditure, and the potential for modulation of this circuit in treating obesity.
|
0.979 |