Bonnie Blazer-Yost
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Dr. Bonnie Blazer-Yost’s primary interest is in epithelial cell biology as it relates to ion transport. Recently she has been investigating treatments for polycystic kidney disease. These studies resulted from a serendipitous finding regarding the potential use of Pioglitazone, a commonly used diabetes drug, in polycystic kidney disease patients. This research has progressed from tissue culture, through preclinical animal models and is currently funded as an initial clinical trial in polycystic kidney disease patients.
Dr. Blazer-Yost and her team are also researching potential treatments for hydrocephalus or “water on the brain.” Hydrocephalus may develop as a consequence of trauma, infection, tumors, intracranial hemorrhage or as a result of a congenital birth defect. Elderly patients may suffer from a poorly understood and underdiagnosed form called “normal pressure hydrocephalus,” characterized by urinary incontinence, gait instability, and dementia. Post-traumatic hydrocephalus occurs as the result of traumatic brain injury. Regardless of the form, brain surgery is currently the only effective long-term treatment. Dr. Blazer-Yost and her collaborators recently obtained a three-year Department of Defense grant to conduct translational studies in animal models with a goal of developing a drug treatment for hydrocephalus.
Dr. Blazer-Yost’s work to treat polycystic kidney disease and hydrocephalus is another example of how IUPUI faculty are TRANSLATING RESEARCH INTO PRACTICE.
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Item Channels and Transporters in Astrocyte Volume Regulation in Health and Disease(Cell Physiol Biochem Press, 2022) Reed, Makenna M.; Blazer-Yost, Bonnie; Biology, School of ScienceAstrocytes are the second most abundant cell type in the central nervous system and serve various functions, many of which maintain homeostasis of the intracellular milieu in the face of constant change. In order to accomplish these important functions, astrocytes must regulate their cell volume. In astrocytes, cell volume regulation involves multiple channels and transporters, including AQP4, TRPV4, TRPM4, VRAC, Na+/K+ ATPase, NKCC1 and Kir4.1. AQP4 is a bidirectional water channel directly involved in astrocyte cell volume regulation. AQP4 also forms heteromultimeric complexes with other channels and transporters involved in cell volume regulation. TRPV4, a mechanosensitive channel in involved in osmotic regulation in various cell types, forms a complex with AQP4 to decrease cell volume in response to cell swelling. TRPM4 also forms a complex with AQP4 and SUR1 in response to injury resulting in cell swelling. Another complex forms between Na+/K+ ATPase, AQP4, and mGluR5 to regulate the perisynaptic space. NKCC1 is a co-transporter involved in cell volume increases either independently through cotransport of water or a functional interaction with AQPs. VRAC is implicated in regulatory volume decreases and may also functionally interact with AQP4. Although Kir4.1 colocalizes with AQP4, its role in cell volume regulation is debated. In diseases where fluid/electrolyte homeostasis is disturbed such as stroke, ischemic injury, inflammation, traumatic brain injury and hydrocephalus, cell volume regulation is challenged, sometimes past the point of recovery. Thus, a greater understanding of signaling pathways which regulate transport proteins as well as the functional and physical interactions that exist between transporters will provide a basis for the development of pharmaceutical targets to treat these prevalent and often devastating diseases.Item A randomized phase 1b cross-over study of the safety of low-dose pioglitazone for treatment of autosomal dominant polycystic kidney disease(Oxford University Press, 2021-07) Blazer-Yost, Bonnie L.; Bacallao, Robert L.; Erickson, Bradley J.; LaPradd, Michelle L.; Edwards, Marie E.; Sheth, Nehal; Swinney, Kim; Ponsler-Sipes, Kristen M.; Moorthi, Ranjani N.; Perkins, Susan M.; Torres, Vicente E.; Moe, Sharon M.; Biology, School of ScienceBackground: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenetic disorders in humans and is characterized by numerous fluid-filled cysts that grow slowly, resulting in end-stage renal disease in the majority of patients. Preclinical studies have indicated that treatment with low-dose thiazolidinediones, such as pioglitazone, decrease cyst growth in rodent models of PKD. Methods: This Phase 1b cross-over study compared the safety of treatment with a low dose (15 mg) of the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist pioglitazone or placebo in PKD patients, with each treatment given for 1 year. The study monitored known side effects of PPAR-γ agonist treatment, including fluid retention and edema. Liver enzymes and risk of hypoglycemia were assessed throughout the study. As a secondary objective, the efficacy of low-dose pioglitazone was followed using a primary assessment of total kidney volume (TKV), blood pressure (BP) and kidney function. Results: Eighteen patients were randomized and 15 completed both arms. Compared with placebo, allocation to pioglitazone resulted in a significant decrease in total body water as assessed by bioimpedance analysis {mean difference 0.16 Ω [95% confidence interval (CI) 0.24-2.96], P = 0.024} and no differences in episodes of heart failure, clinical edema or change in echocardiography. Allocation to pioglitazone led to no difference in the percent change in TKV of -3.5% (95% CI -8.4-1.4, P = 0.14), diastolic BP and microalbumin:creatinine ratio. Conclusions: In this small pilot trial in people with ADPKD but without diabetes, pioglitazone 15 mg was found to be as safe as placebo. Larger and longer-term randomized trials powered to assess effects on TKV are needed.Item Hydrocephalus: A Comprehensive Analysis and Considerations for Treatment(Springer, 2022) Hochstetler, Alejandra; Raskin, Jeffrey; Blazer-Yost, Bonnie L.; Biology, School of ScienceHydrocephalus is a serious condition that affects patients of all ages, resulting from a multitude of causes. While the etiologies of hydrocephalus are numerous, many of the acute and chronic symptoms of the condition are shared. These symptoms include disorientation and pain (headaches), cognitive and developmental changes, vision and sleep disturbances, and gait abnormalities. This collective group of symptoms combined with the effectiveness of CSF diversion as a surgical intervention for many types of the condition suggest that the various etiologies may share common cellular and molecular dysfunctions. The incidence rate of pediatric hydrocephalus is approximately 0.1–0.6% of live births, making it as common as Down syndrome in infants. Diagnosis and treatment of various forms of adult hydrocephalus remain understudied and underreported. Surgical interventions to treat hydrocephalus, though lifesaving, have a high incidence of failure. Previously tested pharmacotherapies for the treatment of hydrocephalus have resulted in net zero or negative outcomes for patients potentially due to the lack of understanding of the cellular and molecular mechanisms that contribute to the development of hydrocephalus. Very few well-validated drug targets have been proposed for therapy; most of these have been within the last 5 years. Within the last 50 years, there have been only incremental improvements in surgical treatments for hydrocephalus, and there has been little progress made towards prevention or cure. This demonstrates the need to develop nonsurgical interventions for the treatment of hydrocephalus regardless of etiology. The development of new treatment paradigms relies heavily on investment in researching the common molecular mechanisms that contribute to all of the forms of hydrocephalus, and requires the concerted support of patient advocacy organizations, government- and private-funded research, biotechnology and pharmaceutical companies, the medical device industry, and the vast network of healthcare professionals.Item Cytokine and inflammatory mediator effects on TRPV4 function in choroid plexus epithelial cells(American Physiological Society, 2019-11) Simpson, Stefanie; Preston, Daniel; Schwerk, Christian; Schroten, Horst; Blazer-Yost, Bonnie; Biology, School of ScienceThe choroid plexus (CP), composed of capillaries surrounded by a barrier epithelium, is the main producer of cerebrospinal fluid (CSF). The CP epithelium regulates the transport of ions and water between the blood and the ventricles, contributing to CSF production and composition. Several studies suggest a connection between the cation channel transient receptor potential vanilloid-4 (TRPV4) and transepithelial ion movement. TRPV4 is a nonselective, calcium-permeable cation channel present in CP epithelia reported to be activated by cytokines and inflammatory mediators. Utilizing the PCP-R (porcine choroid plexus-Riems) cell line, we investigated the effects of various cytokines and inflammatory mediators on TRPV4-mediated activity. Select proinflammatory cytokines (TNF-α, IL-1β, TGF-β1) had inhibitory effects on TRPV4-stimulated transepithelial ion flux and permeability changes, whereas anti-inflammatory cytokines (IL-10, IL-4, and IL-6) had none. Quantitative mRNA analysis showed that these cytokines had no effect on TRPV4 transcription levels. Inhibition of the transcription factor NF-κB, involved in the production and regulation of several inflammatory cytokines, inhibited TRPV4-mediated activity, suggesting a link between TRPV4 and cytokine production. Contrary to published studies, the proinflammatory mediator arachidonic acid (AA) had inhibitory rather than stimulatory effects on TRPV4-mediated responses. However, inhibition of AA metabolism also caused inhibitory effects on TRPV4, suggesting a complex interaction of AA and its metabolites in the regulation of TRPV4 activity. Together these data imply that TRPV4 activity is involved in the inflammatory response; it is negatively affected by proinflammatory mediators. Furthermore, arachidonic acid metabolites, but not arachidonic acid itself, are positive regulators of TRPV4.Item TRPV4 antagonists ameliorate ventriculomegaly in a rat model of hydrocephalus(American Society for Clinical Investigation, 2020-09-17) Hochstetler, Alexandra E.; Smith, Hillary M.; Preston, Daniel C.; Reed, Makenna M.; Territo, Paul R.; Shim, Joon W.; Fulkerson, Daniel; Blazer-Yost, Bonnie L.; Biology, School of ScienceHydrocephalus is a serious condition that impacts patients of all ages. The standards of care are surgical options to divert, or inhibit production of, cerebrospinal fluid; to date, there are no effective pharmaceutical treatments, to our knowledge. The causes vary widely, but one commonality of this condition is aberrations in salt and fluid balance. We have used a genetic model of hydrocephalus to show that ventriculomegaly can be alleviated by inhibition of the transient receptor potential vanilloid 4, a channel that is activated by changes in osmotic balance, temperature, pressure and inflammatory mediators. The TRPV4 antagonists do not appear to have adverse effects on the overall health of the WT or hydrocephalic animals.Item Activation of TRPV4 stimulates transepithelial ion flux in a porcine choroid plexus cell line(American Journal of Physiology, 2018-09-01) Preston, Daniel; Simpson, Stefanie; Halm, Dan; Hochstetler, Alexandra; Schwerk, Christian; Schroten, Horst; Blazer-Yost, Bonnie L.; Biology, School of ScienceThe choroid plexus (CP) epithelium plays a major role in the production of cerebrospinal fluid (CSF). A polarized cell line, the porcine CP-Riems (PCP-R) line, which exhibits many of the characteristics of the native epithelium, was used to study the effect of activation of the transient receptor potential vanilloid 4 (TRPV4) cation channel found in the PCP-R cells as well as in the native epithelium. Ussing-style electrophysiological experiments showed that activation of TRPV4 with a specific agonist, GSK1016790A, resulted in an immediate increase in both transepithelial ion flux and conductance. These changes were inhibited by either of two distinct antagonists, HC067047 or RN1734. The change in conductance was reversible and did not involve disruption of epithelial junctional complexes. Activation of TRPV4 results in Ca2+ influx, therefore, we examined whether the electrophysiological changes were the result of secondary activation of Ca2+-sensitive channels. PCP-R cells contain two Ca2+-activated K+ channels, the small conductance 2 (SK2) and the intermediate conductance (IK) channels. Based on inhibitor studies, the former is not involved in the TRPV4-mediated electrophysiological changes whereas one of the three isoforms of the IK channel (KCNN4c) may play a role in the apical secretion of K+. Blocking the activity of this IK isoform with TRAM34 inhibited the TRPV4-mediated change in net transepithelial ion flux and the increased conductance. These studies implicate TRPV4 as a hub protein in the control of CSF production through stimulation by multiple effectors resulting in transepithelial ion and subsequent water movement.Item Hydrocephalus in a rat model of Meckel Gruber syndrome with a TMEM67 mutation(Springer Nature, 2019-01-31) Shim, Joon W.; Territo, Paul R.; Simpson, Stefanie; Watson, John C.; Jiang, Lei; Riley, Amanda A.; McCarthy, Brian; Persohn, Scott; Fulkerson, Daniel; Blazer-Yost, Bonnie L.; Biology, School of ScienceTransmembrane protein 67 (TMEM67) is mutated in Meckel Gruber Syndrome type 3 (MKS3) resulting in a pleiotropic phenotype with hydrocephalus and renal cystic disease in both humans and rodent models. The precise pathogenic mechanisms remain undetermined. Herein it is reported for the first time that a point mutation of TMEM67 leads to a gene dose-dependent hydrocephalic phenotype in the Wistar polycystic kidney (Wpk) rat. Animals with TMEM67 heterozygous mutations manifest slowly progressing hydrocephalus, observed during the postnatal period and continuing into adulthood. These animals have no overt renal phenotype. The TMEM67 homozygous mutant rats have severe ventriculomegaly as well as severe polycystic kidney disease and die during the neonatal period. Protein localization in choroid plexus epithelial cells indicates that aquaporin 1 and claudin-1 both remain normally polarized in all genotypes. The choroid plexus epithelial cells may have selectively enhanced permeability as evidenced by increased Na+, K+ and Cl- in the cerebrospinal fluid of the severely hydrocephalic animals. Collectively, these results suggest that TMEM67 is required for the regulation of choroid plexus epithelial cell fluid and electrolyte homeostasis. The Wpk rat model, orthologous to human MKS3, provides a unique platform to study the development of both severe and mild hydrocephalus.Item The normal increase in insulin after a meal may be required to prevent postprandial renal sodium and volume losses(American Physiological Society, 2017-06-01) Irsik, Debra L.; Blazer-Yost, Bonnie L.; Staruschenko, Alexander; Brands, Michael W.; Biology, School of ScienceDespite the effects of insulinopenia in type 1 diabetes and evidence that insulin stimulates multiple renal sodium transporters, it is not known whether normal variation in plasma insulin regulates sodium homeostasis physiologically. This study tested whether the normal postprandial increase in plasma insulin significantly attenuates renal sodium and volume losses. Rats were instrumented with chronic artery and vein catheters, housed in metabolic cages, and connected to hydraulic swivels. Measurements of urine volume and sodium excretion (UNaV) over 24 h and the 4-h postprandial period were made in control (C) rats and insulin-clamped (IC) rats in which the postprandial increase in insulin was prevented. Twenty-four-hour urine volume (36 ± 3 vs. 15 ± 2 ml/day) and UNaV (3.0 ± 0.2 vs. 2.5 ± 0.2 mmol/day) were greater in the IC compared with C rats, respectively. Four hours after rats were given a gel meal, blood glucose and urine volume were greater in IC rats, but UNaV decreased. To simulate a meal while controlling blood glucose, C and IC rats received a glucose bolus that yielded peak increases in blood glucose that were not different between groups. Urine volume (9.7 ± 0.7 vs. 6.0 ± 0.8 ml/4 h) and UNaV (0.50 ± 0.08 vs. 0.20 ± 0.06 mmol/4 h) were greater in the IC vs. C rats, respectively, over the 4-h test. These data demonstrate that the normal increase in circulating insulin in response to hyperglycemia may be required to prevent excessive renal sodium and volume losses and suggest that insulin may be a physiological regulator of sodium balance.Item Lysophosphatidic acid is a modulator of cyst growth in autosomal dominant polycystic kidney disease., Lysophosphatidic Acid is a Modulator of Cyst Growth in Autosomal Dominant Polycystic Kidney Disease(2011) Blazer-Yost, Bonnie; Blacklock, B. J.; Flaig, S.; Bacallao, R. L.; Gattone, V. H.Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the slow growth of multiple fluid-filled cysts predominately in the kidney tubules and liver bile ducts. Elucidation of mechanisms that control cyst growth will provide the basis for rational therapeutic intervention. We used electrophysiological methods to identify lysophosphatidic acid (LPA) as a component of cyst fluid and serum that stimulates secretory Cl- transport in the epithelial cell type that lines renal cysts. LPA effects are manifested through receptors located on the basolateral membrane of the epithelial cells resulting in stimulation of channel activity in the apical membrane. Concentrations of LPA measured in human ADPKD cyst fluid and in normal serum are sufficient to maximally stimulate ion transport. Thus, cyst fluid seepage and/or leakage of vascular LPA into the interstitial space are capable of stimulating epithelial cell secretion resulting in cyst enlargement. These observations are particularly relevant to the rapid decline in renal function in late-stage disease and to the "third hit" hypothesis that renal injury exacerbates cyst growth.Item Pioglitazone Attenuates Cystic Burden in the PCK Rodent Model of Polycystic Kidney Disease(2010) Blazer-Yost, Bonnie; Haydon, Julie; Eggleston-Gulyas, Tracy; Chen, Jey-Hsin; Wang, Xiaofang; Gattone, Vincent; Torres, Vicente E.Polycystic kidney disease (PKD) is a genetic disorder characterized by growth of fluid-filled cysts predominately in kidney tubules and liver bile ducts. Currently, the clinical management of PKD is limited to cyst aspiration, surgical resection or organ transplantation. Based on an observation that PPARγ agonists such as pioglitazone and rosiglitazone decrease mRNA levels of a Cl(-) transport protein, CFTR (cystic fibrosis transmembrane conductance regulator), and the Cl(-) secretory response to vasopressin in cultured renal cells, it is hypothesized that PPARγ agonists will inhibit cyst growth. The current studies show that a 7- or 14-week pioglitazone feeding regimen inhibits renal and hepatic bile duct cyst growth in the PCK rat, a rodent model orthologous to human PKD. These studies provide proof of concept for the mechanism of action of the PPARγ agonists and suggest that this class of drugs may be effective in controlling both renal and hepatic cyst growth and fibrosis in PKD.