1998 — 1999 |
Jordan, Bryen A |
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.). |
Regulation of Kappa Opioid Receptors @ New York University School of Medicine
DESCRIPTION: (Applicant's Abstract) The exposure of an opioid receptor to opioid peptides or opiate alkaloids initiates a biological response. A long-term or repeated exposure to opioids causes a decreased sensitivity to the drug, leading to a reduced cellular response; this desensitization is regulated by multiple mechanisms which have been implicated in the generalized development of tolerance and addiction. Acute opioid treatments result in a rapid desensitization by functional uncoupling of the receptor from the effector system. In addition, this treatment results in a rapid internalization of the receptor into intracellular compartments. Chronic opioid treatment results in longer desensitization due to receptor down-regulation with a net loss of binding sites from the cell. Relatively little is known about the molecular mechanisms underlying these events. The objective of the studies proposed here is to explore the agonist-mediated events that lead to receptor internalization and degradation. These studies propose to explore the molecular mechanisms of opioid receptor internalization and dimerization in order to understand the functional significance of these events. The specific aims are: (i) to characterize kappa opioid receptor trafficking in neuronal cells, and (ii) to explore the role of dimerization in kappa opioid receptor function. This work will provide critical information about the early agonist-mediated events that modulate opioid receptor function. A thorough understanding of the cellular mechanisms involved in the modulation of receptor desensitization is crucial for the development of a therapeutic basis for drug addiction.
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0.954 |
2005 — 2007 |
Jordan, Bryen A |
K01Activity Code Description: For support of a scientist, committed to research, in need of both advanced research training and additional experience. |
Synapse-to-Nucleus Signaling Components in Psds @ New York University School of Medicine
The candidate, Dr. Bryen A. Jordan holds a Ph.D. degree from the Dept of Pharmacology at the NYU School of medicine. He is currently a research assistant professor at the Dept of Biochemistry at NYU School of Medicine. The career goals of the candidate are to obtain sufficient skills and knowledge during the award period to become an independent researcher at a medical or academic institution. The scientific goal of the proposal is to better understand the role of the postsynaptic density (PSD) in synaptic function. The proposed aims of the K01 will allow the candidate to master skills in mass spectrometry/proteomics, imaging analysis and electrophysiology which will greatly enhance the ability of the candidate to do independent research. The candidate will also gain important experimental and theoretical knowledge in the fundamentals of neurobiology to pursue a career in neuroscience. Dr. Edward Ziff will advise and guide the candidate to become an independent scientist. Dr. Ziff has previously trained a number of highly successful researchers including Dr. Michael Greenberg and Dr. Thomas Kouzarides. Additionally, Dr. Moses Chao, Dr. Bernardo Rudy and Dr. Thomas Neubert wilf serve as co-mentors and provide general and specific guidance throughout the term of the proposal. NYU Medical Center and Dr. Edward Ziff provide a exemplary environment to conduct research for the candidate to obtain further training. A specialized cellular structure known as the PSD lies in direct apposition to active zones in most excitatory synapses. Assembled at the PSD are proteins that mediate and transmit presynaptic input, such as ionotropic glutamate receptors, scaffolding proteins and kinases and phosphatases. However recent proteomic studies demonstrate that the PSD is far more complex than previously thought. The long-term objective of this grant is to explore the molecular composition of PSDs and identify novel components that regulate synaptic function. Preliminary work has identified 452 proteins from PSDs purified from whole brains. This work has uncovered a novel set of proteins with nuclear localization signals that are highly enriched in PSDs. One of these can shuttle rapidly into the nucleus in response to NMDA receptor stimulation. Specific aims are to 1)- Identify region-specific differences in PSD composition by liquid chromatography and mass spectrometry of purified PSDs from hippocampus, striatum and cerebellum. 2)- To characterize the nuclear translocation of our identified targets in dissociated neurons and in slice cultures by chemical and electrical stimulation 3)- to explore the mechanisms and components of nuclear translocation in response to synaptic stimulation and to assess the function of these proteins in the nucleus. This project will provide an in-depth look at the complexity of the PSD and identify region specific factors. Furthermore, this project will analyze novel proteins that can shuttle to the nucleus in response to synaptic stimulation. This work will increase our understanding of synaptic function which is critical in learning and memory.
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0.954 |
2011 — 2015 |
Jordan, Bryen Alexander |
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. |
Aida-1 in App Metabolism and Synaptic Function @ Albert Einstein College of Medicine, Inc
DESCRIPTION (provided by applicant): Deposition of beta-amyloid peptide (Aß) within neuritic plaques is a hallmark pathology of Alzheimer's disease (AD). Processing of the Amyloid Precursor Protein (APP) by ß and ?-secretases results in the generation of Aß peptides. Excess Aß is believed to be a main contributor to the dysfunction and degeneration of neurons that underlies AD. As such, preventing Aß deposition or clearing excess pathogenic Aß remains an important therapeutic target in AD. APP internalization is required for Aß production and there is evidence that general endocytic dysregulations underlie sporadic AD and AD- like pathophysiologies. Therefore a better understanding of the mechanisms that regulate APP internalization would guide more selective strategies for developing AD therapies. In this proposal we will use biochemical, cell biology and imaging analysis of primary neuronal cultures to test the hypothesis that the novel APP adaptor AIDA-1 regulates Aß production by promoting APP internalization. To determine if AIDA-1 regulates APP metabolism in vivo we will quantify APP proteolytic fragments in newly generated AIDA-1 knockout mice, and determine if loss of AIDA-1 can rescue AD-like phenotypes in mouse models of AD. Moreover we will evaluate the therapeutic potential of cell-permeable peptides that block AIDA-1/APP interactions by determining their effects on excess Aß production in AD mouse models. We will also determine how loss of AIDA-1 affects synaptic function in cell cultures and in acute hippocampal slices from AIDA-1 knockout mice and determine if loss of AIDA-1 can revert the synaptic deficits observed in AD mouse models. With the tools developed here, we will be able to address the chronic and acute effects of loss of AIDA-1 and endogenous Aß production on neurotransmission. This is important given AD has been increasingly viewed as a synaptic dysfunction caused by excess Aß production.
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0.985 |
2018 — 2019 |
Jordan, Bryen Alexander |
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. |
Aida-1 in Nmda Receptor Function and Anxiety @ Albert Einstein College of Medicine
As the most prevalent group of psychiatric diseases, anxiety disorders are chronic and disabling conditions that impose enormous costs on individuals and society. Anxiety disorders have complex polygenic etiologies with poorly understood underlying brain circuitries. Structures in the amygdala such as the basolateral complex are widely implicated in anxiety, but additional regions include insula cortex, medial prefrontal cortex, bed nucleus of stria terminalis, and hippocampus. Among several candidate genes, NMDA receptors (NMDARs), and GluN2B subunits in particular have been associated with anxiety. However, there is no clear picture of unique or converging molecular mechanisms that underlie these disorders. The lack of a mechanistic understanding precludes the identification of novel therapeutic targets and development of useful mouse models. These factors contribute to languishing efforts to develop drugs for pathological anxiety. This proposal seeks to test a novel molecular pathway that regulates anxiety in rodents, and test whether manipulations of this pathway can be anxiolytic. The hypothesis being tested is that Amyloid Precursor Protein Intracellular Domain Associated-1 (AIDA-1) regulates anxiety-related behaviors by controlling NMDAR function in ventral hippocampus (VH). AIDA-1 is a synaptic protein that controls GluN2B subunit function and NMDAR- dependent plasticity in the hippocampus. Preliminary findings indicate that AIDA preferentially regulates GluN2B function in VH. Behavioral testing reveals that AIDA-1 forebrain knockout mice (AIDA-1 cKO) only display reduced anxiety, and not the deficits in spatial and episodic memory expected from deficits in NMDAR function and hippocampal synaptic plasticity. Selective AIDA-1 knockdown in VH, but not in amygdala, recapitulate the reduced anxiety phenotype observed in AIDA-1 cKO mice. Our data support longstanding evidence of VH function in emotionality. The proposed studies will provide insight into AIDA-1 and NMDAR biology, and into functional differences present along the dorso-ventral axis of the hippocampus. Importantly, these experiments will provide insights into anxiety disorders, and may identify novel therapeutic targets for their treatment.
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0.985 |
2021 |
Jordan, Bryen Alexander |
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. |
Anks1b Haploinsufficiency in a Novel Brain Disorder @ Albert Einstein College of Medicine
Neurodevelopmental disorders (NDDs) are highly prevalent brain diseases with enormous social and economic impacts. Failure to understand their causative molecular and cellular mechanisms is largely responsible for the paucity of available therapies. However, NDDs are highly heritable and the identification of causative single gene mutations in patients will help define underlying genetic risk factors and molecular abnormalities. We recently identified patients around the world harboring heterozygous and monogenic deletions of the ANKS1B gene. Clinical analyses reveal that affected individuals present with a spectrum of neurodevelopmental phenotypes, including autism, and speech and motor deficits. Our findings formalize a link between ANKS1B haploinsufficiency and a previously undefined syndrome we term AnkSyd. Because the mechanisms linking ANSK1B to essential cellular functions dysregulated in AnkSyd are unknown, elucidating ANKS1B function represents a key opportunity to define molecular mechanisms contributing to NDDs and normal brain function. The long-term goal of the proposed research is to define the mechanisms underlying AnkSyd and identify therapeutic targets. ANKS1B encodes for AIDA-1, a brain specific protein that is one of the most abundant proteins at neuronal synapses. Our lab found that AIDA-1 is specifically enriched at postsynaptic densities where it controls NMDA receptor (NMDAR) function by regulating the synaptic localization and function of GluN2B subunits of NMDARs. The proposed research will test the hypothesis that NMDAR dysfunction contributes to AnkSyd. Toward this purpose, we generated induced pluripotent stem cells (iPSCs) and neurons from patients and unaffected family members, as well as a transgenic mouse model that displays behavioral correlates of patient phenotypes. Overall, this proposal seeks to understand the pathophysiology of AnkSyd, a newly identified genetic syndrome presenting with autism and neurodevelopmental delays. As a monogenic disease with confirmed ANKS1B haploinsufficiency, studying AnkSyd will allow us to clearly link AIDA-1 dysfunction to cellular and behavioral outcomes. The successful completion of these experiments will reveal that NMDAR dysfunction contributes to AnkSyd pathophysiology and that ANKS1B haploinsufficiency disrupts a specific mechanism linking AIDA-1 to GluN2B. Finally, these experiments will determine the therapeutic potential of rescuing GluN2B function or other abnormal molecular pathways identified in AnkSyd models.
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0.985 |