2011 — 2012 |
Orr, Anna Goldshmidt |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Astrocytic A2a Receptors: Novel Roles and Mechanisms in Alzheimer?S Disease @ J. David Gladstone Institutes
DESCRIPTION (provided by applicant): Adenosine is a potent regulator of brain function. Accumulation of adenosine activates the adenosine receptor A2A-R, which modulates neuronal activity. Expression of A2A-R is high in certain types of neurons, but low in astrocytes. We found that expression of A2A-R is abnormally high in astrocytes in patients with Alzheimer's disease (AD) and in an AD mouse model. A2A-R levels in postmortem human brains strongly correlated with the levels of AD pathology. Based on these unexpected results, we hypothesize that astrocytic A2A-R is involved in AD pathogenesis. To test our hypothesis, we will examine AD-related cognitive dysfunction in mice after manipulating astrocytic A2A-R expression levels. We will also investigate the mechanisms by which astrocytic A2A-R may influence neuronal function. A2A-R signals through the intracellular Gs-coupled pathway and has been implicated in retraction of astrocytic processes, which are lost in postmortem AD brain and AD mouse models. Indeed, both adenosine and activators of Gs-coupled signaling induce process retraction in cultured astrocytes. Notably, astrocyte retraction is linked to changes in neuronal function. However, few studies have addressed the causes of astrocytic retraction or its possible role in AD-related neuronal dysfunction. We will determine whether Gs-coupled signaling by A2A-R triggers retraction in astrocytes and alters neuronal activity. In summary, we propose to examine whether elevated levels of A2A-R, through intracellular Gs-coupled signaling, induce aberrant astrocytic retraction and contribute to AD-related neuronal dysfunction. Investigating this novel astrocyte-neuron interaction may uncover new roles for astrocytes and adenosine receptors in AD and offer new therapeutic targets for alleviating AD-related cognitive decline. These studies may also reveal a novel mechanism by which astrocytes regulate neuronal activity and contribute to normal brain function. The proposed aims and experimental approaches are driven by the working hypothesis that adenosine activates astrocytic A2A-R and leads to Gs-coupled intracellular signaling, which induces morphological changes in astrocytes and downstream changes in neuronal activity. Diverse techniques will be used to test this working hypothesis, including behavioral assessment in mice, live time-lapse confocal imaging, and electrophysiology. Alternative strategies are outlined to ensure success in the event of technical difficulties with particularly challenging experiments. The proposed research promises to enhance our understanding of normal brain function and may pave the path towards an effective strategy for the prevention or treatment of AD. The research plan will also provide a rigorous scientific training opportunity for the candidate in the fields of neurodegeneration and glial-neuronal interactions. PUBLIC HEALTH RELEVANCE: The research project will examine how astrocytes-the non-neuronal cells of the brain-are influenced by adenosine and whether adenosine, by affecting astrocytic function, regulates normal brain activity and cognitive decline in a mouse model of Alzheimer's disease. This research project promises to reveal new information about normal brain function and the possible causes of abnormal brain function in a prevalent neurological disease.
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2013 |
Orr, Anna Goldshmidt |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Astrocytic A2a Receptors: Novel Roles and Mechanisms in Alzheimers Disease @ J. David Gladstone Institutes
DESCRIPTION (provided by applicant): Adenosine is a potent regulator of brain function. Accumulation of adenosine activates the adenosine receptor A2A-R, which modulates neuronal activity. Expression of A2A-R is high in certain types of neurons, but low in astrocytes. We found that expression of A2A-R is abnormally high in astrocytes in patients with Alzheimer's disease (AD) and in an AD mouse model. A2A-R levels in postmortem human brains strongly correlated with the levels of AD pathology. Based on these unexpected results, we hypothesize that astrocytic A2A-R is involved in AD pathogenesis. To test our hypothesis, we will examine AD-related cognitive dysfunction in mice after manipulating astrocytic A2A-R expression levels. We will also investigate the mechanisms by which astrocytic A2A-R may influence neuronal function. A2A-R signals through the intracellular Gs-coupled pathway and has been implicated in retraction of astrocytic processes, which are lost in postmortem AD brain and AD mouse models. Indeed, both adenosine and activators of Gs-coupled signaling induce process retraction in cultured astrocytes. Notably, astrocyte retraction is linked to changes in neuronal function. However, few studies have addressed the causes of astrocytic retraction or its possible role in AD-related neuronal dysfunction. We will determine whether Gs-coupled signaling by A2A-R triggers retraction in astrocytes and alters neuronal activity. In summary, we propose to examine whether elevated levels of A2A-R, through intracellular Gs-coupled signaling, induce aberrant astrocytic retraction and contribute to AD-related neuronal dysfunction. Investigating this novel astrocyte-neuron interaction may uncover new roles for astrocytes and adenosine receptors in AD and offer new therapeutic targets for alleviating AD-related cognitive decline. These studies may also reveal a novel mechanism by which astrocytes regulate neuronal activity and contribute to normal brain function. The proposed aims and experimental approaches are driven by the working hypothesis that adenosine activates astrocytic A2A-R and leads to Gs-coupled intracellular signaling, which induces morphological changes in astrocytes and downstream changes in neuronal activity. Diverse techniques will be used to test this working hypothesis, including behavioral assessment in mice, live time-lapse confocal imaging, and electrophysiology. Alternative strategies are outlined to ensure success in the event of technical difficulties with particularly challenging experiments. The proposed research promises to enhance our understanding of normal brain function and may pave the path towards an effective strategy for the prevention or treatment of AD. The research plan will also provide a rigorous scientific training opportunity for the candidate in the fields of neurodegeneration and glial-neuronal interactions.
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2014 — 2019 |
Orr, Anna Goldshmidt |
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. 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. |
Roles of Astrocytic G Protein-Coupled Signaling in Memory @ J. David Gladstone Institutes
DESCRIPTION (provided by applicant): Memory loss is prevalent in the aging population and is a key feature of Alzheimer's disease (AD), the most common age-related neurodegenerative disorder. As the global population ages, we must define the mechanisms underlying memory and find effective strategies to prevent memory loss. The roles of astrocytes in memory are poorly understood. The candidate's preliminary findings suggest that G protein-coupled signaling in astrocytes affects long-term memory. In mice, the activation of astrocytic Gs-coupled receptors interfered with long-term memory, while reduction in the expression of an astrocytic Gs-coupled adenosine receptor enhanced long-term memory. The levels of this receptor were found to be increased in postmortem human brain tissue from AD patients. These findings raise the intriguing possibilities that astrocytic Gs-coupled receptors regulate long-term memory and contribute to memory loss. However, it is not known how these astrocytic receptors regulate memory. The main objective of the proposed research is to determine how astrocytic Gs-coupled signaling affects the neural processes underlying memory. By using established transgenic mice and chemogenetic techniques, the proposed studies will determine if astrocytic Gs-coupled receptor signaling influences neuronal immediate early gene expression (Aim 1), neural network oscillations (Aim 2) and neuronal plasticity (Aim 3), all of which have been implicated in the mechanisms that underlie memory. The studies will also define the signaling mechanisms downstream of astrocytic Gs-coupled receptors (Aim 3). These studies promise to reveal novel memory-linked neurobiological processes, advance our understanding of astrocytic functions and uncover new therapeutic strategies for memory loss in aging and disease. Mentored research will enable the candidate to link astrocytic signaling with complex neural processes and determine the effects of astrocytic signaling at the synaptic, cellular and network levels. The short-term goals of the candidate are to 1) obtain additional training related to the mechanisms of memory, 2) obtain career training and secure an independent tenure-track faculty position, and 3) receive funding to support her independent research on the roles of astrocytic receptor signaling in memory. The long-term goals of the candidate are to advance research efforts that elucidate the nature and functions of astrocytic signaling in cognition, brai aging and neurological deficits, and to develop novel therapeutic strategies that target astrocytic receptor signaling mechanisms to modulate disease processes. The proposed research and career training will enable the candidate to develop a strong independent research program focusing on the roles of astrocytic-neuronal interactions in health and disease. The Gladstone Institutes and UCSF will provide an ideal academic environment for carrying out the proposed training. A primary mentor and an advisory committee will provide the candidate with the pertinent expertise, resources and guidance for carrying out the proposed research and becoming an independent investigator.
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