Evidence for a universal TPR binding domain onhsp90.

Prior to their hormone-dependent activation, steroid receptors are recovered in the cytosolic fraction of target cells in multimeric protein complexes containing both heat shock protein (hsp) and immunophilin chaperones. It is the goal of this thesis to examine in detail the interactions between hsp90 and immunophilins, and to show that these complexes are ubiquitously conserved in eukaryotes. All members of the immunophilin protein family have peptidyl-prolyl isomerase activity, and like hsp90, they are thought to play major roles in protein folding and trafficking in the cell. We have previously shown that FKBP52/hsp56, an immunophilin of the FK506-binding class, is bound directly to hsp90 in both the hsp (hsp90$\cdot$hsp70$\cdot$hsp56) heterocomplex that exists independent of receptors and the glucocorticoid receptor (GR) heterocomplex formed by this chaperone machinery. I show here that the 40 kDa cyclosporin A-binding immunophilin CyP-40 is also present in both the hsp and GR heterocomplexes. Both FKBP51/hsp56 and CyP-40 bind directly to hsp90 via their tetratricopeptide repeat (TPR) domains, and excess CyP-40 blocks FKBP52/hsp56 binding, suggesting that hsp90 may contain a common immunophilin binding site. Unlike other proteins recovered in steroid receptor heterocomplexes, the immunophilins are not required for receptor heterocomplex assembly. Since FKBP52/hsp56 has been implicated in targeted protein trafficking, I examined the hsp90 binding of four TPR-containing proteins all thought to be involved in protein movement. FKBP52/hsp56 and CyP-40 each contain 3 TPR domains and are weakly bound to hsp90. Mas70p, a mitochondrial membrane receptor with 7 TPR domains, and p50, a component of hsp90$\cdot$oncogenic protein kinase complexes, both bind very tightly to hsp90. Their binding is not blocked by the TPR domain segment of CyP-40, but the binding of all four proteins is blocked by bacterially-expressed p60, an hsp90-binding TPR protein required for GR-hsp90 complex assembly. The data are consistent with the notion that hsp90 has a region that acts as a general TPR domain acceptor. The thesis proposes a model for protein movement in which proteins that are chaperoned by hsp90 move as dynamic complexes to cellular sites of action with the TPR-containing protein targeting movement of the complexes.Ph.D.PharmacologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/105003/1/9624701.pdfDescription of 9624701.pdf : Restricted to UM users only

Plain language summary of safety and symptom improvement with vibegron in people with overactive bladder: results from the EMPOWUR study

What is this summary about? This is a plain language summary of an article originally published in the Journal of Urology. Overactive bladder (also called OAB) has been treated with the same type of medicine for more than 40 years. Vibegron is in a newer class of medicine for treating overactive bladder called beta-3 adrenergic receptor agonists. The EMPOWUR study was a phase 3 clinical trial that looked at whether vibegron was safe and improved symptoms in people with overactive bladder. Vibegron was approved by the US Food and Drug Administration (also called the FDA) based in part on the results of this study. What were the results? Participants of the EMPOWUR study who took vibegron showed an improvement in their overactive bladder symptoms. These symptoms include the number of urinations (peeing), the urgent need to urinate, and accidental urination (bladder leaks). After 12 weeks, participants who took vibegron had significantly greater improvements than participants who took placebo. What do the results mean? This study suggests that vibegron could safely improve symptoms in people with overactive bladder

Plain language summary: does treatment with vibegron result in improvements in overactive bladder (OAB) symptoms that are meaningful to people with OAB?

What is this summary about? This is a plain language summary of an article published in the journal Advances in Therapy. In 2020, the US Food and Drug Administration (also called the FDA) approved a medicine called vibegron to treat overactive bladder, also called OAB. The key results used to approve vibegron were from the EMPOWUR study. In the EMPOWUR study, participants who took vibegron had fewer urination episodes, urgency episodes, and bladder leaks each day than those who took a pill containing no medicine, called a placebo. At the end of the study, participants also rated how much their overactive bladder symptoms changed overall during EMPOWUR by responding to a survey. Many participants rated their overactive bladder symptoms as improved overall. This study asked if improvements in the number of urination episodes, urgency episodes, and bladder leaks caused by urgency were associated with feeling better overall. This study also looked at how many participants in the EMPOWUR study had improvements in the number of urination episodes, urgency episodes, and bladder leaks that were big enough to matter. A separate group of people with overactive bladder were asked about the magnitude of improvements that would be important to them. This group had not participated in the EMPOWUR study. What were the results? EMPOWUR participants who reported that taking medicine resulted in their overactive bladder symptoms getting better overall also generally reported fewer daily urinations, urgency episodes, and bladder leaks after treatment. Many had changes in their symptoms that were meaningful. Meaningful was defined for each symptom as: at least 15% fewer urinations, 50% fewer urgency episodes, and 75% fewer bladder leaks. Participants who received vibegron had meaningful reductions in the daily number of episodes of urination, urgency, and bladder leaks more often than those who received the placebo (pill with no active medicine). People with overactive bladder who did not participate in the study were interviewed and said that improvements to those symptoms, similar to those seen in the EMPOWUR study, would be important to them. What do the results mean? This study suggests that the results we measured in the EMPOWUR study may also reflect changes in overactive bladder symptoms that are big enough to be important to people with overactive bladder. Many participants who took vibegron in the EMPOWUR study felt that it helped to improve their individual overactive bladder symptoms. This may also help improve quality of life of participants