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You searched for +publisher:"University of Arizona" +contributor:("Streicher, John M"). Showing records 1 – 2 of 2 total matches.

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University of Arizona

1. Felemban, Razaz Abdulaziz. Remodeling the Interactions between TDP-43 and RNA for Development of Therapeutics for ALS .

Degree: 2019, University of Arizona

Developing effective treatment strategies for amyotrophic lateral sclerosis (ALS) that affect upper and lower motor neuron requires an understanding of the underlying cellular pathway that leads to motor neuron death and muscle atrophy. RNA dysregulation is a hypothesized disease mechanism in ALS. Studies have shown that pathological transactive response (TAR) DNA Binding Protein (TDP-43) binds irreversibly to RNA in stress granules and forms membraneless prion-like TDP-43 aggregates in cytoplasmic motor neurons1. These membraneless compartments can form in cells through liquid-liquid phase separation (LLPS). A recent study showed that mRNA secondary structure promotes LLPS to build membraneless compartments in cells.2 Based on a remodeling hypothesis by Coyne et al.,3 we hypothesized that remodeling the interactions between TDP-43 and RNA using small molecules would decrease motor neuron toxicity. Using in silico docking, we screened 50,000 compounds on the RNA recognition motifs 1 and 2 of TDP43 (RRM1 and RRM2). We identified rTRD001 that was able to bind to TDP-43 in the RRM1 domain, disrupt TDP-43 interaction with RNA, reduce cytoplasmic aggregate and cytotoxicity in motor neuron cell line NSC-34, and mitigate TDP-43 dependent phenotypes in an ALS fly model based on the overexpression of mutant TDP-43. Further studies are necessary in order to assess the mechanism and mode of action for this neuroprotective effect for this compound. Advisors/Committee Members: Vanderah, Todd W (advisor), Streicher, John M. (committeemember), Vaillancourt, Richard (committeemember), Khanna, May (committeemember).

Subjects/Keywords: ALS; mRNA; rTRD01; rTRDs; TDP-43

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Felemban, R. A. (2019). Remodeling the Interactions between TDP-43 and RNA for Development of Therapeutics for ALS . (Doctoral Dissertation). University of Arizona. Retrieved from http://hdl.handle.net/10150/633221

Chicago Manual of Style (16th Edition):

Felemban, Razaz Abdulaziz. “Remodeling the Interactions between TDP-43 and RNA for Development of Therapeutics for ALS .” 2019. Doctoral Dissertation, University of Arizona. Accessed August 24, 2019. http://hdl.handle.net/10150/633221.

MLA Handbook (7th Edition):

Felemban, Razaz Abdulaziz. “Remodeling the Interactions between TDP-43 and RNA for Development of Therapeutics for ALS .” 2019. Web. 24 Aug 2019.

Vancouver:

Felemban RA. Remodeling the Interactions between TDP-43 and RNA for Development of Therapeutics for ALS . [Internet] [Doctoral dissertation]. University of Arizona; 2019. [cited 2019 Aug 24]. Available from: http://hdl.handle.net/10150/633221.

Council of Science Editors:

Felemban RA. Remodeling the Interactions between TDP-43 and RNA for Development of Therapeutics for ALS . [Doctoral Dissertation]. University of Arizona; 2019. Available from: http://hdl.handle.net/10150/633221


University of Arizona

2. Olson, Keith Mathew. Atypical Opioid Interactions – Development of Selective Mu-Delta Heterodimer Antagonists, Clinical Opioids at Non-Mu Pain Targets and Endogenous Biased Signaling .

Degree: 2017, University of Arizona

Most clinical opioids produce analgesia through the Mu Opioid Receptor (MOR) providing the only effective treatment for chronic pain patients. These studies explore three pre-clinical strategies to improve MOR analgesia and minimize side effects: 1) compounds that target G-protein Coupled Receptors (GPCRs) heterodimers, such as heterodimerization between the Delta Opioid Receptor (DOR) and MOR (MDOR); 2) multi-functional compounds that target multiple receptor systems for synergistic effects, such as a MOR agonist and a the serotonin reuptake transporter (SERT) inhibitor; or 3) biased agonists that preferentially activate one signaling pathway associated with analgesia over another associated with side effects at the same receptor. First, several indirect lines of evidence indicate the MOR-DOR heterodimer (MDOR) can regulate MOR opioid tolerance and withdrawal. However, studying MDOR remains difficult because no selective MDOR antagonists are available. To address this need, we created a novel series of bivalent MDOR antagonists by connecting a low affinity MOR antagonist (H-Tyr-Pro-Phe-D1Nal-NH2) to a moderate affinity DOR (H- Tyr-Tic-OH) antagonist with variable length polyamide spacers (15-41 atoms). In vitro radioligand binding and [35S]-GTPγS coupling assays in MOR, DOR, and MDOR expressing cell lines show bivalent ligands produce a clear length dependence in MDOR but not MOR or DOR cell lines. The lead compound – D24M with a 24-atom spacer – displayed high potency (IC50MDOR = 0.84 nM) with 91-fold selectivity for MDOR:DOR and 1,000-fold MDOR:MOR selectivity. Second, clinicians have long appreciated subtle but distinct differences in analgesia and side effects of MOR opioids. A variety of non-MOR targets including DOR, Kappa Opioid Receptor (KOR), the Cannabinoid Receptor-1 (CB1), the Sigma-1 Receptor (σ1R), the Dopamine- (DAT), Serotonin- (SERT) and Norepinephrine- Reuptake Transporters (NET) induce analgesia and/or modulate MOR mediated side effects. To determine if different opioid profiles arise from non-MOR interactions, we evaluated the binding and function of nine clinical analgesics at the nine aforementioned targets revealing several clinical opioids contain previously unidentified affinity’s or activity’s. Hydrocodone displayed low affinity at the MOR (KI = 1800 nM) and only ~2 fold less affinity at the σ1R (KI = 4000 nM). Second buprenorphine promoted monoamine influx at DAT, SERT and NET with EC50 > 1,000 nM. These novel interactions suggest the nuanced differences of clinical opioids may arise from previously unappreciated off-target effects. Future studies will assess whether these in vitro results predict hydrocodone and buprenorphine activity in vivo. Finally, the unique function of the numerous endogenous opioid peptides at a given receptor remains unclear. How endogenous ligands interact with ORs produces obvious drug design consequences. These studies show two endogenous Dynorphin analogues – Dynorphin A and Dynorphin B – differentially regulate two ubiquitous signaling modules – βarrestin2… Advisors/Committee Members: Hruby, Victor J (advisor), Streicher, John M (advisor), Hruby, Victor J. (committeemember), Streicher, John M. (committeemember), Ghosh, Indraneel (committeemember), Montfort, William (committeemember), Porreca, Frank (committeemember).

Subjects/Keywords: Bivalent; Delta Opioid Receptor; Functional Selectivity; MDOR Heterodimer; Mu Opioid Receptor; Opioid Signaling

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Olson, K. M. (2017). Atypical Opioid Interactions – Development of Selective Mu-Delta Heterodimer Antagonists, Clinical Opioids at Non-Mu Pain Targets and Endogenous Biased Signaling . (Doctoral Dissertation). University of Arizona. Retrieved from http://hdl.handle.net/10150/626669

Chicago Manual of Style (16th Edition):

Olson, Keith Mathew. “Atypical Opioid Interactions – Development of Selective Mu-Delta Heterodimer Antagonists, Clinical Opioids at Non-Mu Pain Targets and Endogenous Biased Signaling .” 2017. Doctoral Dissertation, University of Arizona. Accessed August 24, 2019. http://hdl.handle.net/10150/626669.

MLA Handbook (7th Edition):

Olson, Keith Mathew. “Atypical Opioid Interactions – Development of Selective Mu-Delta Heterodimer Antagonists, Clinical Opioids at Non-Mu Pain Targets and Endogenous Biased Signaling .” 2017. Web. 24 Aug 2019.

Vancouver:

Olson KM. Atypical Opioid Interactions – Development of Selective Mu-Delta Heterodimer Antagonists, Clinical Opioids at Non-Mu Pain Targets and Endogenous Biased Signaling . [Internet] [Doctoral dissertation]. University of Arizona; 2017. [cited 2019 Aug 24]. Available from: http://hdl.handle.net/10150/626669.

Council of Science Editors:

Olson KM. Atypical Opioid Interactions – Development of Selective Mu-Delta Heterodimer Antagonists, Clinical Opioids at Non-Mu Pain Targets and Endogenous Biased Signaling . [Doctoral Dissertation]. University of Arizona; 2017. Available from: http://hdl.handle.net/10150/626669

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