2005 — 2009 |
Borodinsky, Laura |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Activity-Dependent Regulation of Early Stages in Synapse Formation @ University of California-San Diego
Laura N. Borodinsky Proposal # 0516871
Activity-dependent regulation of early stages in synapse formation
Nervous system function relies on the establishment of appropriate connections, called synapses. The hypothesis of the proposed project is that early events in synapse formation are shaped by electrical activity. Alterations in electrical activity modify neurotransmitter expression following a homeostatic paradigm (Borodinsky et al., 2004). This finding leads to the question whether altered neurotransmitter expression causes rerouting of axons in the spinal cord. Axonal pathfinding patterns for different neuronal types will be followed after activity has been perturbed.
The experiments will also address the hypothesis that neural activity influences the classes of neurotransmitter receptors expressed in postsynaptic cells. The ultimate goal of the project will be to test the hypothesis that novel synapses between neurons and target cells can be formed when activity is manipulated, i.e. that expression of different transmitters will be matched by the expression of corresponding receptors.
The proposed project is important for the field of developmental neuroscience because it challenges the view that early events in nervous system development are governed entirely by a predetermined genetic program, independent of electrical activity.
The information gained in this study could have significant implications for how we think about disorders in developmental wiring of the nervous system and related pathologies. The ability to regulate the number of neurons secreting particular transmitters and transmitter sensitivity in target cells has the power to be of substantial societal benefit, providing potential therapies for neurological disorders.
Support from NSF for the present proposal will be crucial in the advancement as an independent scientist of a member of an underrepresented group. This grant will allow continued training of students, and will allow the principal investigator to develop skills as a supervisor. NSF support will ensure publication of results in scientific journals, and participation in scientific meetings to disseminate the results from this proposal and enhance understanding of nervous system development.
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1 |
2011 — 2017 |
Borodinsky, Laura |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Interaction Between Electrical Activity and Bone Morphogenetic Proteins: Consequences to Spinal Cord Differentiation @ University of California-Davis
Connections among neurons and with target cells enable the plethora of nervous system tasks. The establishment of these connections relies on the specialization of neurons during development, which in the spinal cord is regulated by a family of proteins known as bone morphogenetic proteins (BMPs). The current view is that these proteins trigger a genetically hardwired program that establishes the fate of cells along the dorsoventral axis of the developing spinal cord. However, differentiation of embryonic neurons is also sensitive to electrical activity, which manifests spontaneously in these developing cells. This study will test the hypothesis that a gradient of BMPs across the dorsoventral axis of the nervous system contributes to establish a gradient of calcium-dependent electrical activity in immature spinal neurons that, in turn, regulates neuronal differentiation. A multi-approach study using molecular, pharmacological, biochemical and physiological techniques will be implemented. This investigation may lead to new ways of thinking on how the nervous system develops and will challenge the idea that nervous system development is exclusively genetically driven. Results from this project may identify novel mechanisms of action of BMPs of relevance to many research fields, including developmental biology, neuroscience, stem cells and tissue repair. Overall, this study will contribute to the understanding of how to induce restorative plastic events in a pathological context of loss or impaired nervous system function.
The PI will serve as role model for female and latino students and colleagues. This award will support both graduate and undergraduate students, and the PI will institute a multistep research experience for the Sacramento High School District in the context of outreach activities coordinated by the Center for Biophotonics. The PI will also continue to support international Neuroscience research in developing countries such as Argentina, through participation in argentine scientific meetings and training courses.
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1 |
2011 — 2015 |
Borodinsky, Laura Noemi |
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. |
Spinal Cord Development: Interplay Between Electrical Activity and Sonic Hedgehog @ University of California At Davis
DESCRIPTION (provided by applicant): Nervous system development encompasses generation of neural cells, followed by their positioning and differentiation to culminate with establishment of specific connections that enable the execution of innumerable functions. Although both the developing and mature nervous system exhibit tremendous plasticity, comparatively, the former has a greater capacity for remodeling. When the neural tissue is injured or its function is imbalanced, as for patients suffering from spinal cord injury or epilepsy, recreating the remarkable plasticity of the developing nervous system towards repairing and regenerating damaged cells and connections is the ultimate goal. Understanding developmental processes becomes crucial to devising therapies targeting nervous system regeneration and repair. Two major developmental cues are key for nervous system development, the morphogentic protein, Sonic hedgehog (Shh), and early electrical activity. Although many aspects of their action are known, there has been no previous consideration of the interaction between them. This research project wil study the molecular mechanisms underlying the interplay between Shh and electrical activity and how their interaction affects nervous system development and maturation. This study will test the hypothesis that the Shh gradient across the dorsoventral axis of the nervous system contributes to establish a gradient of calcium-dependent electrical activity across the dorsoventral developing spinal cord that in turn regulates neuronal differentiation. Pharmacological and molecular manipulations of Shh gradient and signaling wil be implemented in developing Xenopus embryos. Calcium dynamics will be imaged in neurons on the dorsal and ventral surfaces of the neural tube of control and experimentally perturbed embryos. Reciprocally, manipulations of calcium spike activity will be carried out and the consequences to Shh signaling in the developing spinal cord will be assessed. To investigate the functional consequences of the interplay between Shh signaling and calcium spike activity, a crucial biological outcome will be studied: dorsoventral differentiation of developing spinal neurons. The involvement of calcium spike activity-dependent pathways in this process will be studied in vivo following pharmacological and molecular perturbations of Shh signaling and electrical activity. This project may lead to new ways of thinking of how the nervous system develops and how different pathways interact to promote its formation and maturation. When generation and differentiation of neural cells is needed to reestablish lost connections, the ability to direct the affected system toward the production of appropriate number and type of cells is paramount. This investigation of mechanisms underlying neuronal differentiation may set the basis for devising treatments for neurological disorders such as pediatric epilepsy and spinal cord injury, in which both the reestablishment of balanced excitability and the reposition of damaged cells are key events for promoting recovery. PUBLIC HEALTH RELEVANCE: This project investigates the complex developmental process of neuronal specification and differentiation during nervous system development. We will elucidate the interaction between two major developmental cues, electrical activity and the morphogenetic protein Sonic hedgehog. When the neural tissue is injured or its function is imbalanced, as for patients suffering from spinal cord injury or epilepsy, recreating the remarkable plasticity of the developing nervous system towards repairing and regenerating damaged cells and connections is the ultimate goal. The knowledge of how different patterns of activity are established during development and how they relate to other regulatory factors will help devising therapies aimed at inducing restorative plasticity in a pathological context of loss or impaired synaptic connectivity. This study wil contribute to the understanding of how to direct the affected system toward the production of appropriate number and type of cells when generation and differentiation of neural cells are needed. Moreover, results from this project may identify novel non-canonical mechanisms of action of Sonic hedgehog that may be of relevance to many fields of research, including developmental biology, neuroscience, cancer, stem cells and tissue repair.
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0.958 |
2019 — 2021 |
Borodinsky, Laura Noemi |
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. |
Mechanisms of Folate Action During Nervous System Development @ University of California At Davis
Project summary Neural tube defects (NTDs) are among the most common serious birth defects diagnosed in human fetuses and newborns with a combined incidence of ~1/1,000 in the United States and an estimated of 300,000 or more newborns worldwide each year. NTDs result from the failure of neural tube closure during the early fetal development. A combination of genetic and environmental factors appears to regulate the formation of the neural tube. Notably, folate supplementation during pregnancy prevents NTDs by unclear mechanisms. Our recently published study demonstrates that folate receptor 1 (Folr1), one of folate uptake systems, localizes to the apical surface of Xenopus laevis neural plate and is necessary for neural plate cell apical constriction during neural plate folding. Moreover, we find that Folr1 interacts with adherens junction components, C-cadherin and ?- catenin suggesting that folate signaling might regulate neural plate cell-cell adhesion during neural tube formation. Our overall research goal is to elucidate the cellular and molecular mechanisms underlying neural tube formation. We will test the hypothesis that folate participates in the changes in cell shape that neural cells undergo during neurulation by recruiting its receptor and triggering a novel and dynamic signaling pathway. The first specific aim will consist in determining the molecular mechanisms underlying folate/Folr1 promotion of neural plate cell apical constriction during neural tube formation. We will identify the molecular mechanisms of Folr1 regulation of cell adhesion remodeling necessary for neural tube formation. In the second specific aim we will discover the signaling pathways recruited by folate/Folr1 that are necessary for neural plate cell apical constriction and neural tube formation. We will interrogate the ubiquitination pathway through gain and loss of function approaches and epistasis experiments. We will assess the role of folate in cell adhesion molecule and cytoskeletal dynamics by live imaging embryos expressing fluorescently tagged proteins or reporters of cell adhesion and cytoskeletal components during neural tube formation. We will use state-of-the-art methodologies including proteomics of immunoprecipitates, super resolution microscopy, reporters of cytoskeletal and cell adhesion dynamics and optogenetic approaches to manipulate signaling pathways. Although folate fortification has been a highly effective public health measure in reducing NTDs, the lack of mechanism-based understanding of NTD prevention leads to general concerns regarding unintended consequences resulting from supplementation. Optimal folate supplementation, risk groups and treatment of folate-insensitive NTDs are some of the unsolved clinical aspects awaiting for the full elucidation of the molecular and cellular mechanisms underlying folate action in neural tube formation.
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0.958 |
2020 — 2021 |
Borodinsky, Laura Noemi |
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. |
Mechanisms of Neural Activity During Neural Tube Formation @ University of California At Davis
Project summary One of the first steps in nervous system development consists in the folding of the neural plate and closure of the neural tube to originate the brain and spinal cord. Failure of neural tube formation leads to neural tube defects (NTDs), which are one of the most common serious birth defects. The causes of NTDs are multiple and both genetic and environmental factors have been identified. Among these factors, the use of antiepileptic drugs during pregnancy increases the incidence of NTDs by unknown mechanisms. In the mature nervous system, antiepileptic drugs decrease excitability by targeting diverse effectors. However, most studies have argued that off-target effects of these drugs are responsible for inducing NTDs in epileptic patients? offspring. Instead, the effect of antiepileptic drugs on embryonic neural excitability remained mostly unexplored because of the prevailing view that neural activity is not apparent at neural plate stages. In contrast, our recently published study demonstrates that glutamate signaling is present in the folding neural plate and is necessary for neural tube formation. Downregulating glutamate signaling directly or by incubating Xenopus laevis embryos with the antiepileptic drug valproic acid causes NTDs. In this study we will discover the molecular mechanisms of neurotransmitter signaling during neural tube formation. Challenging the prevailing view, we hypothesize that vesicular glutamate release from neural plate cells is necessary for neural tube formation. Released glutamate elicits calcium transients in neural plate cells that control expression and function of regulatory neural cell cycle proteins like Sox2, which is a pivotal transcription factor for modulating neural stem cell renewal, proliferation and neurogenesis, depending on its level of expression and posttranslational modifications. By using state-of- the-art imaging and molecular approaches, we will discover the molecular mechanisms and spatiotemporal profile of glutamate release and signaling during neural tube formation. We will identify downstream molecules to glutamate release that control neural plate cell proliferation, their mechanisms of action and impact in the formation of the neural tube. We will examine the role of glutamate signaling on the regulation of Sox2 expression and function during neural plate folding. This study proposes a novel paradigm-shifting model in which neurotransmitter signaling is functional at neural plate stages and is crucial for the formation of the neural tube. The significance of the mechanistic knowledge gained form this study is based on the contribution it will make to the field of NTDs and to the molecular understanding of the regulation of neural stem cell cycle progression, which in turn will be relevant to research on brain tumors, brain and spinal cord injuries, neurogenesis in neurodegenerative and neurodevelopmental disorders. This study, by advancing our mechanistic understanding of neural activity-driven neural tube formation will improve preventative measures for epileptic pregnant women.
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0.958 |