Roy V. Sillitoe, Ph.D. - US grants
Affiliations: | Neuroscience | Baylor College of Medicine, Houston, TX |
Area:
Cerebellum, circuit formationWe 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.
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High-probability grants
According to our matching algorithm, Roy V. Sillitoe is the likely recipient of the following grants.Years | Recipients | Code | Title / Keywords | Matching score |
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2014 — 2018 | Sillitoe, Roy Vincent | 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. |
Synaptic Origins of Cerebellar Disease @ Baylor College of Medicine DESCRIPTION (provided by applicant): The cerebellum is essential for motor behavior. Motor behavior is severely disrupted in ataxia, dystonia, and tremor. These diseases are defined by very distinct motor impairments, which raises an intriguing problem because the cerebellar circuitry that's affected is the same in each case. For instance, all Purkinje cells receive the same inputs, yet their outputs instigate all three diseases. The main focus of this research is to understanding how the same circuitry is capable of causing several different diseases. To address this problem we postulated that in each disease circuit behavior might be determined by how neuronal communication is altered. To test this we devised an experimental model that enables us to systematically block chemical communication in the main cerebellar synapses. Our model utilizes the Cre/loxP genetic approach to conditionally block the expression of the vesicular GABA transporter VGAT or the vesicular glutamate transporter VGLUT2 at every major synapse in the mouse cerebellum. We have generated compelling preliminary data showing that the inception of cerebellar disease may depend on damaged synapses rather than circuits. Now we would like to expand on this work by testing the hypothesis that loss of signaling at different cerebellar synapses will result in phenotypes that resemble a range of cerebellar diseases. In our first aim we will trace the path of a typical signal through the cerebellum and systematically silence each type of synapse starting from the sensory input stage through to the motor output. We will delineate how loss of synapse communication leads to motor disease by determining how each connection influences circuit morphogenesis and neuronal function, and how each one impacts motor behavior. In our second aim we will test whether obstructing synapse function during cerebellar development has a different pathogenic outcome to blocking the same synapse in the adult cerebellum. For this question we will manipulate synapses with spatial and temporal precision and then analyze circuit connectivity and neuronal function in behaving mice. This information has important consequences for therapy because different cerebellar synapses could be targeted to rescue movement in different diseases. |
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2014 — 2019 | Nelson, David Loren (co-PI) [⬀] Neul, Jeffrey L (co-PI) [⬀] Sillitoe, Roy Vincent |
U54Activity 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 differ from program project 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, with funding component staff helping to identify appropriate priority needs. |
@ Baylor College of Medicine Adult; Affect; Anatomy; Architecture; autism spectrum disorder; Behavior; Brain; brain malformation; Cells; Child; college; Data; Defect; Detection; Development; Disease; Drosophila genus; Electrons; Epilepsy; Equipment; experimental analysis; experimental study; Faculty; Functional disorder; Funding; Gene Expression; Gene Expression Profiling; Genetic Models; Goals; grasp; Histologic; Hour; Human; human disease; Image; Image Analysis; imaging capabilities; Impairment; In Situ Hybridization; in vivo; Individual; innovation; Institutes; Intellectual functioning disability; knowledge base; Label; Laboratories; Lead; Maps; Medicine; Mental Retardation and Developmental Disabilities Research Centers; Microscope; Microscopic; Microscopy; Mission; mRNA Expression; Nerve Degeneration; neural circuit; neural correlate; Neurologic; Neurons; neuropathology; Pattern; Population; Postdoctoral Fellow; Preparation; Process; quantitative imaging; Reporter; Reproducibility; Research Institute; Research Personnel; Resolution; Resources; RNA; robot assistance; Role; Science; Services; Signal Transduction; skills; Stains; Structure; student training; Synapses; synergism; Technology; Time; Tissue Embedding; Tissue imaging; Tissue Sample; Tissues; Training; translational study; Transmission Electron Microscopy; two-photon; Work; |
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2017 — 2021 | Sillitoe, Roy Vincent | 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. |
@ Baylor College of Medicine PROJECT SUMMARY/ABSTRACT Tremor is the most common movement disorder. It impairs voluntary actions by causing intense shaking during walking, eating, and speaking. The shaking is repetitive and highly rhythmic as the affected body parts ?oscillate? back and forth. Oscillation frequency is a defining feature of tremor; distinct tremors are found in Parkinson's disease, dystonia, and essential tremor (ET). Because tremor disorders have a neurological basis, it implies that specific brain oscillations drive the body to oscillate at the same frequency. However, it is still not clear where in the central nervous system the oscillations begin, and the processes that lead to oscillations in the connected brain regions remain unknown. In ET, which is the most prevalent form of pathological tremor, a hindbrain motor region called the cerebellum has been heavily implicated as the major source of abnormal activity. But, how abnormal cerebellar activity leads to oscillating motions has been challenging to test. This is largely because of the lack of an appropriate animal model. To address this problem, we identified a mouse genetic model that exhibits the core features of ET. We have generated compelling preliminary data showing that the loss of a Purkinje cell gene, Car8, causes an ET-like tremor that mimics the human condition in its frequency, progression with age, and responsiveness to alcohol. Here, we will expand on this work by testing the hypothesis that loss of Car8 function causes cerebellar oscillations that drive tremorgenic activity in the thalamocortical circuit. In our first aim, we will trace the path of the 4- 12Hz tremor oscillations from the cerebellum to the inferior olive, thalamus, and motor cortex in active mice. We will therefore identify the major brain oscillators that contribute to ET pathophysiology. In our second aim, we define the cellular origin of the tremor by testing if genetically and optogenetically altering Purkinje cell firing modulates tremor in Car8 mice. Because cerebellar inhibitory interneurons are also implicated in ET, we will also test if modulating their activity onto Purkinje cells influences tremor. This experiment will address how local circuit wiring impacts network-wide oscillations. Next we will take advantage of the robust connectivity of the cerebellar nuclei with the rest of the motor system, plus the efficacy of deep brain stimulation (DBS). In our third aim, we will use the Car8 mice to test whether the cerebellar nuclei are an effective target for DBS. We hypothesize that directing the DBS to the cerebellar nuclei will prevent the spread of pathological oscillations away from the source. The utility of Car8 as a preclinical model shows promise towards uncovering the mechanisms for how DBS works. Our research has importance to human health because we introduce a multi-disciplinary approach to study a broad spectrum of tremors that are all challenging to define, diagnose, and treat. |
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2020 — 2021 | Sillitoe, Roy Vincent | 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. |
Cellular and Tissue Pathogenesis @ Baylor College of Medicine Intellectual and developmental disabilities (IDDs) are common and have a devastating impact on child health around the world. Unfortunately, there are no effective treatments for the vast majority of IDDs and our understanding of the pathogenic mechanism for majority of IDDs is incomplete. A major impediment to solving how to better treat IDDs is our limited knowledge of how cells and tissues are impacted in each IDD. As a direct response to this problem, we have assembled the Cell and Tissue Pathogenesis Core (CTP Core) to study how brain anatomy and its associated pathologies arise. Our guiding rationale is that, solving how brain structure is wired in typical development will place us in an ideal position to uncover how faulty brain circuits eventually disrupt the ability to perform different behaviors in IDDs. Indeed, the pathological consequences of altering brain development typically present as severe motor or cognitive difficulties in children. The goal of the CTP Core is to provide our IDDRC Investigators with a centralized resource for comprehensive pathological examination of tissue, high-resolution two-photon and confocal imaging, ultra-structure tracking by electron microcopy, and the generation and characterization of human disease cellular models that are relevant to IDDs. By combining human cellular models, such as iPSC-derived neurons or glia, with deep structural and functional phenotyping of how the brain is mis-wired in different diseases or disease models, the CTP Core will provide a unique opportunity to address how distinct genetic and environmental factors may impact the brain and lead to alterations in cellular structure, connectivity and function. To accomplish these goals, we have divided the CTP Core into three sub-Cores that operate in parallel, but with the common goal of resolving brain structure as it relates to function and disease. The Neuropathology Sub-Core provides expertise in neuronal tissue analysis from basic histology and transmission electron microscopy to in-depth circuit analysis; the Microscopy Sub-Core provides access and training to state-of-the-art confocal and two-photon microscopy; and the Human Disease Cellular Models Sub-Core provides expertise for studies requiring reprogramming, characterization and genome editing of human induced pluripotent stem cells (iPSCs) and their progeny derived from IDD patients. Therefore, a major feature of the CTP Core is investigator access to both classic and modern analytical techniques using human tissue, in vivo model systems such as mouse, rat, drosophila, and in vitro assays such as 3-dimensional brain organoids and neurons and glia derived from human iPSCs. The ultimate goal of the CTP Core is to forge new avenues to improve the behavioral outcomes of IDD by correcting brain function and restoring various motor and cognitive functions. The availability of major equipment such as transmission and two-photon microscopes, existing effective workflow of services, and the collective experience with many disease models highlight the arsenal of tools available to BCM IDDRC investigators. |
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2021 | Sillitoe, Roy Vincent | 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. |
Cerebellar Deep Brain Stimulation @ Baylor College of Medicine PROJECT SUMMARY/ABSTRACT Neurological and neuropsychiatric diseases are a growing concern worldwide as the consequences are often lethal, or at best they leave patients incapacitated. Unfortunately, most patients with these diseases do not respond to the current medications, and in the few cases that do work, they too can eventually develop drug resistance. Deep brain stimulation (DBS), a neurosurgical approach, has become an effective treatment when traditional medicines are not an option. However, even DBS has its limitations, as a large number of people do not respond to the treatment. Research using humans and animal models suggests that the current brain locations into which DBS is directed are not always adequate. As a first step towards identifying better targets for brain repair, we designed a genetic toolkit in mice that provides a versatile method for generating mouse models for severe motor disease. The toolkit is based on controlling the function of neural circuits in a brain region called the cerebellum, a structure involved in motor and cognitive function and a susceptibility site in a growing list of brain diseases. In Aim1, we will use a combination of these genetic models, high-resolution anatomy and in vivo electrophysiology conducted in behaving mice to define neural signatures for different motor diseases. In Aim2, we will use these neural signatures as biomarkers to test the feasibility of providing targeted close-loop cerebellar DBS to eliminate motor deficits with fast moment-to-moment precision. The ultimate goal of this work is to reverse the behavioral outcomes of disease by correcting brain function and restoring mobility. The availability of additional treatment options for incurable neurological and neuropsychiatric diseases will provide alternate healthcare considerations for reducing the impact of disease and improving the quality of life of affected patients. |
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