1999 — 2003 |
Tosini, Gianluca |
S11Activity Code Description: To promote increased faculty and interdepartmental collaboration through programs that focus on specific research themes or scientific disciplines at developing minority institutions. These grants are intended to strengthen the biomedical research capability in defined areas and to attract other competent biomedical scientists through an improved research environment. |
Plasticity of Mammalian Circadian Axis @ Morehouse School of Medicine
Circadian rhythms show considerable plasticity: they synchronize to environmental light cycles, shift phase in response to single light pulses, and alter their free-running periods and their sensitivity to fight as a function of their light exposure history. The mechanisms underlying much of this plasticity are incompletely understood. We propose to investigate two instances of plasticity at the cellular level: one in the pineal and the other in the suprachiasmatic nucleus (SCN). We have discovered that mammalian pineal gland, although not normally photosensitive, may become photosensitive when cultured. Our first aim is to describe the changes produced by culturing the gland, define the optimal culture conditions for producing them and to test the hypothesis that these changes do not occur in vivo because they are suppressed by endogenous norepinephrine from sympathetic input to the developing pineal. We have recently observed dramatic changes in the distribution of cell bodies visualized with antisera to serotonin (5HT) as a consequence of light exposure history. Such cell bodies, which are normally found only in the raphe nuclei, appear in large numbers in the SCN of hamsters that have been held for 16-20 weeks in constant darkness. Our second aim is to explore this observation further by testing two hypotheses: 1) that the effect is caused either by the complete absence of light or by the absence of a daily environmental entraining signal; 2) that the 5HT in SCN cells is a consequence of changes in the uptake mechanism. If we are able to block 5HT uptake and eliminate the 5HT cell bodies in the SCN we will assess the effects of such blocking treatments on circadian physiology and behavior. Because the pineal and the SCN are both centrally important components of the mammalian circadian axis, changes in their morphology (and physiology) produced by the environment may well be involved in circadian behavioral plasticity. Light 5HT and circadian rhythmicity have all been shown to be important mediators of mental state. Our findings are most likely to relate to the biological basis of mood disorders. The collaborative work described in this proposal will extend and deepen the ties that already exist between the Neuroscience Institute at Morehouse School of Medicine and the neuroscience community at University of Virginia and will provide the principal investigator with opportunities for continued training and development.
|
0.997 |
2003 — 2006 |
Tosini, Gianluca |
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. |
Photic and Circadian Regulation of Retinal Melatonin. @ Morehouse School of Medicine
DESCRIPTION (provided by applicant): The presence of melatonin rhythmicity in the retina of mammals has been demonstrated by several in vivo and in vitro studies, but many aspects of its synthesis and regulation in this tissue are still obscure. The goals of the present research proposal are to identify the cell type(s) that synthesizes melatonin and to elucidate the role of environmental light and of the circadian clock in regulating melatonin synthesis in the retina of mammals. The first specific aim will test the hypothesis that cone photoreceptors contain the melatonin synthesizing machinery as well as the circadian clock components to regulate it. The second aim will test the hypothesis that rod photoreceptors and/or inner retinal neurons contain the circadian clock(s) that drives retinal melatonin biosynthesis in cones. Finally, the third aim will test the hypothesis that cone photopigments mediate the suppression of retinal melatonin that follows exposure nocturnal exposure to light. In our research we will use a wide array of new and technologically advanced techniques such as dual in situ hybridization, quantitative real time PCR and Laser Capture Dissecting Microscopy. Retinal melatonin is involved in the modulation of several aspects of retinal physiology; thus the understanding of how this hormone (neuromodulator) is regulated will likely improve our understanding of retinal physiology and pathologies. Modem life style has tremendously changed our daily exposure to light and darkness and thus it is important to understand the effect that such exposure may have on the organism and, in particular, retinal function.
|
0.997 |
2007 — 2015 |
Tosini, Gianluca |
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. R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Photic and Circadian Regulation of Retinal Melatonin @ Morehouse School of Medicine
DESCRIPTION (provided by applicant): The mammalian retina contains circadian clocks that regulate multiple aspects of retinal function by driving circadian rhythms of gene expression, photoreceptor outer segment membrane turnover, and visual sensitivity. Our long term goal is to understand how light and the circadian clocks control retinal and central nervous system functions, and the effects that disruption of this photic and circadian control has on the health and viability of neurons, especially photoreceptor cells. Our hypothesis is that a hierarchical network of clocks regulates circadian rhythms in the mammalian retina and the pacemaker controlling melatonin synthesis is the master circadian clock. Furthermore, we believe that melatonin plays and important role in photoreceptors viability and functioning. In the last few months we have developed a unique in vitro preparation and a series of transgenic mice in which the role of melatonin in the retina can be tested. Three specific aims are designed to test this hypothesis. In specific aim 1, we will determine if mouse photoreceptors contain the circadian pacemaker that drives melatonin synthesis. In Specific aim 2, we will investigate the roles of melatonin in the generation of retinal rhythmicity by comparing melatonin proficient mice (C3H/f+/+) and melatonin receptor knock-out mice (MT1-/-, MT2-/- and MT1-/-MT2-/-) in C3H/f+/+. Finally, in specific aim 3 we will use melatonin receptor knock-out mice in C3H/f+/+ background to test the hypothesis that melatonin is important for photoreceptor functioning and viability. In our research, we will use a wide array of new and technologically advanced techniques, such as quantitative real time RT-PCR, laser capture dissecting microscopy, microarray analysis as well as real-time monitoring of bioluminescence rhythmicity in photoreceptor layers or isolated photoreceptor. Significance. Retinal circadian clock are involved in the modulation of many aspects of retinal physiology. Thus, understanding the cellular and molecular basis of retinal clock function will greatly improve our knowledge of retinal physiology and pathologies. Modern life style has tremendously changed the time at which we expose ourselves to light;hence, it is important to understand the effect that such exposure may have on retinal physiology and pathology.
|
0.997 |
2010 — 2011 |
Tosini, Gianluca |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Circadian Regulation of the Per2::Luc Bioluminescence Rhythm in the Mouse Rpe @ Morehouse School of Medicine
DESCRIPTION (provided by applicant): The retinal pigment epithelium (RPE) plays an important role in the maintenance of photoreceptors health and functioning. Previous studies have shown that RPE is also involved in the regulation of the disc shedding, a process that is that is vital for the health of the photoreceptors. This process has been shown to be under circadian control, albeit the mechanisms controlling this circadian rhythm are still poorly understood. Our laboratory has developed a novel preparation in which circadian rhythms in RPE can be easily monitored using the PER2::LUC mouse. Our preliminary data indicate that a circadian rhythm in PER2::LUC bioluminescence can be recorded from cultured RPE and the phase of such a rhythm is different from the phase observed in the retina. Light does phase-shift the circadian rhythm in the RPE, and SCN lesion does not affect the phase of this rhythm. Interestingly, we discovered that Dopamine application can shift the circadian rhythm in the RPE. In this exploratory application, we propose to investigate the role of Dopamine and Dopamine receptors in the regulation of the circadian rhythms in the RPE and the circadian regulation of the RPE transcriptome. PUBLIC HEALTH RELEVANCE: The retinal pigment epithelium (RPE) plays an important role in the maintenance of photoreceptors health and functioning. Previous studies have shown that RPE is also involved in the regulation of the disc shedding, a process that is that is vital for the health of the photoreceptors. This process has been shown to be under circadian control, albeit the mechanisms controlling this circadian rhythm are still poorly understood. Modern life style has tremendously changed the time at which we expose ourselves to light;hence, it is important to understand how the circadian clock controls the rhythmic event in this organ. Indeed, the national plan for the eye and vision research of the National Eyes Institute states as one of its primary program objective the understanding of the mechanisms controlling the circadian shedding of photoreceptor outer segments and their phagocytosis by the RPE. In this grant application, we propose first to determine the role of DA in the entrainment of PER2::LUC circadian rhythm in the RPE and then to identify genes showing a circadian pattern of expression in RPE. This effort could prove a valuable tool to discovering genes and molecular pathways regulating rhythmic event in the RPE.
|
0.997 |
2010 — 2015 |
Quarshie, Alexander Tosini, Gianluca |
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. |
Msm Interdisciplinary Sleep/Clinical Cardiovascular Research Training Program @ Morehouse School of Medicine
The overall goal of this training program is to attract and train talented under-represented minority pre- doctoral students to MSM and prepare them to pursue independent research career opportunities in Clinical and Translational Research (CTR) thereby augmenting the number of highly skilled investigators pursuing CTR related to clinical cardiovascular disease and sleep disorders. The following aims will drive the overall goal of this program: Aim 1: Develop a multidisciplinary clinical cardiovascular and sleep-disorders research training program that will recruit URM candidates across the ACTSI and its partner institutions (MSM, Emory, and Georgia Tech). We will target PhD graduate students interested in cardiovascular and sleep disorders research for enrollment in the PhD/MSCR track in the MSM MSCR program, and target medical students interested in cardiovascular and sleep disorders research for enrollment in the MD/MSCR track in the MSM MSCR program. Aim 2: Enhance the clinical and translational research training environment in cardiovascular and sleep disorders for minority T32 trainees. We will promote interdisciplinary discourse and scientific exchange among T32 trainees, faculty and mentors. We will harnesses the diversity and strength of MSM graduate medical education programs, the basic science research excellence ofthe Cardiovascular and Neuroscience institutes, the outstanding clinical research resources and mentorship ofthe Atlanta Clinical and Translational Science Institute (ACTSI) to address the above aims. RELEVANCE (See instructions): This training program addresses the critical need for development of a sustainable pool of minority scientists as leading investigators for the 21 st century, by developing and implementing innovative strategies and collaborations that build upon the strengths of existing programs such as the ACTSI.
|
0.997 |
2016 — 2020 |
Tosini, Gianluca |
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. |
Circadian Regulation of Rpe Functions @ Morehouse School of Medicine
The retinal pigment epithelium (RPE) is involved in many processes necessary to maintain photoreceptor function and health. The RPE is also involved in the regulation of the photoreceptor outer segment turnover (disk shedding and phagocytosis) a process that has been shown to be under circadian control. We have recently developed an RPE-choroid preparation in which we can monitor, in real-time, the circadian clock using the PER2::LUC knock-in mouse, a transgenic mouse model where the PER2 oscillation is faithfully reported via a firefly luciferase. This model is unique in that it reflects both transcription and post-translational events, providing a powerful tool to investigate circadian clock function in a specific tissue and/or cell. Using this new preparation we have demonstrated that the mouse RPE contains a circadian clock that is entrained by the neuromodulator dopamine (DA). In the present proposal (Specific Aim 1) we will test the hypothesis that DA, via D2-like receptors located in the RPE, entrains the circadian clock in the RPE, thus synchronizing the daily burst in phagocytosis of rod outer segment disks. Then we will identify the molecular mechanisms by which DA synchronizes the circadian clock in the RPE. In Specific Aim 2 we will test the prediction that removal of D2R signaling will affect the daily rhythm of phagocytosis thus leading to lipofuscin accumulation and reduced photoreceptor viability during aging. Finally, in Specific Aim 3 we will define the roles of RPE and inner retinal clocks in the regulation of the daily rhythm in RPE phagocytic activity. To reach this goal we will disrupt circadian clocks selectively in RPE and neural retina and assess the consequences on the daily rhythm of phagocytosis. The experiments described in this research proposal will determine the role that DA and its associated receptors play in the regulation of the circadian rhythms in the RPE and the role of retinal/RPE circadian clocks in the regulation of the daily rhythm of RPE phagocytic activity.
|
0.997 |
2017 — 2021 |
Quarshie, Alexander Tosini, Gianluca |
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. |
T32 Training Program For Institutions That Promote Diversity From Morehouse School of Medicine @ Morehouse School of Medicine
Abstract The overall goal of this training program is to attract and train talented under-represented minority pre- doctoral and post-doctoral students to Morehouse School of Medicine (MSM) and prepare them to pursue independent research career opportunities in Clinical and Translational Research (CTR) thereby augmenting the number of highly skilled investigators pursuing CTR related to clinical cardiovascular disease and sleep disorders. The following aims will drive the overall goal of this program: Aim 1: Develop a multidisciplinary clinical cardiovascular and sleep-disorders research training program that will recruit URM candidates across the Atlanta Clinical and Translational Science Institute (ACTSI) and its partner institutions (MSM, Emory, and Georgia Tech). We will target PhD graduate students interested in cardiovascular and sleep disorders research for enrollment in the PhD/MSCR track in the MSM MSCR program, and target post-doctoral students interested in cardiovascular and sleep disorders research for enrollment in the MSM MSCR program. Aim 2: Enhance the clinical and translational research training environment in cardiovascular and sleep disorders for minority T32 trainees. We will promote interdisciplinary discourse and scientific exchange among T32 trainees, faculty and mentors. We will harnesses the diversity and strength of MSM graduate medical education programs, the basic science research excellence of the Cardiovascular and Neuroscience institutes, the outstanding clinical research resources and mentorship of the ACTSI to address the above aims.
|
0.997 |
2021 |
Tosini, Gianluca |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Melatonin Signaling in Photoreceptors @ Morehouse School of Medicine
Melatonin is an important player in the regulation of many physiological functions within the body and within the retina. Several studies have shown that melatonin synthesis in the retina primarily occurs during the night and its levels are low during the day. Melatonin exerts its influence by binding to G protein-coupled receptors named melatonin receptor type 1 (MT1) and type 2 (MT2). MT1 and MT2 receptors activate a wide variety of signaling pathways and both receptors are present in the vertebrate photoreceptors where they may form MT1/MT2 heteromers (MT1/2h). Previous studies have also demonstrated that melatonin may play an important role in protecting photoreceptors from oxidative stress and can protect photoreceptors from apoptosis. Critically, melatonin signaling is involved in the modulation of photoreceptor functioning and viability during aging. Finally, new experimental evidence indicates that high fat diet (HFD) leads to a significant decrease in the amplitude of a- and b-wave of the scotopic ERGs in mice lacking MT1 signaling. The goal of this application is to elucidate the role of melatonin signaling plays in in the modulation of photoreceptor functioning and to determine if melatonin may represent a useful tool in the fight against retinal disorders. The present application comprises two specific aims. In specific aim 1 we will produce a rod specific MT1 knock out mice in a melatonin proficient genetic background. In specific aim 2 we will investigate the mechanism(s) by which MT1/2h signaling protects photoreceptor cells HFD. In our research, we will use a wide array of new and technologically advanced techniques as well as we will develop new lines of transgenic mice. Our proposal will provide important insights about the role of melatonin signaling in the modulation of photoreceptor health.
|
0.997 |