Blazer-Yost Laboratory

Bonnie Blazer-Yost, Ph.D.

Bonnie Blazer-Yost is a Professor in the Department of Biology at IUPUI with joint appointments in the Department of Integrative and Cellular Physiology and the Department of Anatomy and Cell Biology in the Indiana University School of Medicine.

The main focus of her laboratory is the physiology and pathophysiology of barrier epithelial cells. Our group studies how various hormones and other effectors regulate transepithelial ion transport in renal, airway and brain cells.

The major projects in the laboratory are directed toward understanding and treating diseases such as polycystic kidney disease, hypertension, metabolic syndrome and hydrocephalus.

Research projects

TRPV4 and Hydrocephalus

One of the major projects in the Blazer-Yost laboratory is the study of a pressure- and osmotic-sensitive cation channel known as TRPV4. An unexpected observation has led to the discovery that TRPV4 antagonists relieve hydrocephalus, or "water on the brain" in a rat model of pediatric hydrocephalus. Hydrocephalus is a devastating disease which affects nearly 1 in 1000 births, and has medical costs over $1 billion per year.

The accumulating cerebrospinal fluid results in increased hydrostatic pressure causing pain and neuronal destruction and can ultimately cause permanent damage or death. Currently, there are no drugs to treat this disease, with the only viable treatment being surgical intervention. The standard of care is the placement of cerebral shunts to drain the excess fluid, however this approach often results in a less than optimal outcome. Shunt failures due to blockage, infection, and other causes are as high as 50% even in major medical centers which specialize in these procedures.

Two chemically distinct forms of TRPV4 antagonists have been shown to be effective in decreasing the hydrocephalus in the rat model. The laboratory members are currently studying the mechanism of action of these compounds using tissue culture and preclinical animal models.

Interdisciplinary Hydrocephalus Team

The successful funding of a Department of Defense Congressionally Directed Medical Research Program (CDMRP) Grant allowed the Blazer-Yost laboratory to join an interdisciplinary team of scientists and medical professionals who are all working together to develop a treatment for hydrocephalus.

Karl Balsara and Jeffrey Raskin, both neurosurgeons, keep the basic scientists focused on the importance of translational aspects of the studies and provide advice on small animal surgical techniques. They are also helping obtain human CSF samples for comparative studies with the animal models.

Paul Territo, Scott Persohn and Mandy Bedwell from the Department of Radiological Sciences developed and apply MRI techniques that are necessary to follow disease development in rodent models. Charles Goodlett is a behavioral psychologist from the Psychology Department who leads the "behavioral team" of graduate and undergraduate students who are exploring the differences in learning and development between the normal and hydrocephalic animals and then researching the brain changes that underlie these differences.

Nick Berbari, a faculty member in the Biology Department, is an expert in ciliopathies and also in animal models. He and his laboratory members are integral to the animal, genotyping and biochemical studies on the rodent models. Teri Belecky-Adams, a faculty member in the Biology Department, is an expert in ocular development and diseases and is piloting studies to use the rat model to study the vision problems in hydrocephalic patients. Together we are all working toward the goal of finding a pharmaceutical to treat hydrocephalus and support the Hydrocephalus Association in their goal for "No More BS". The BS is brain surgeries.

Renal Ion Transport and Polycystic Kidney Disease

Another of the ongoing projects is a study of potential drugs to treat autosomal dominant polycystic kidney disease (ADPKD). This is a genetic disease that affects over 1 in 1,000 people. The cystic kidneys grow slowly throughout the patient's life, causing pressure and pain and eventually in middle to old age result in renal failure in over half the patients.

At the time of renal failure, the kidneys can be the size of footballs causing pain and distention of the abdomen. There are no FDA-approved drugs to treat ADPKD and the only thing that can be done for the patients is to aspirate the largest of the cysts to relieve that pain and dialyze or transplant the patients when their kidneys fail.

Due to a serendipitous observation that insulin sensitizing agents of the PPARg class of compounds have the unexpected effect of inhibiting the synthesis of the CFTR Chloride channel in cultured renal cells, the investigators have examined the potential for these agents to inhibit cyst growth in animal models of PKD. The positive results in pre-clinical models suggest that FDA-approved PPARg agonists such as pioglitazone and rosiglitazone may be effective agents for long-term therapy in PKD patients.

This research is the culmination of a bench to bedside series of experiments that may result in a new treatment for ADPKD. The clinical trial using pioglitazone to treat ADPKD has been funded by the FDA under their Orphan Diseases Program and the Polycystic Kidney Disease Foundation. The clinical trial initiated at the Indiana University School of Medicine in 2016. Other, more preliminary studies to explore new and innovative therapies for the treatment of late-stage PKD are ongoing.

FDA-Orphan Products Drug Development FD-R-004826-01-A2

Active 9/1/15-8/31/19

  • Title: Phase I Study of Low Dose Pioglitazone for the Treatment of Autosomal Dominant Polycystic Kidney Disease
  • Corresponding PI - S. Moe, M.D; Co-PI - B. Blazer-Yost
  • Goal: Conduct a clinical trial in PKD patients

PKD Grant - Supplemental Grant

Active 9/1/15-8/31/19

  • Title: Over-encapsulated pioglitazone and placebo for FDA-sponsored clinical trial
  • PI: B. Blazer-Yost
  • Goal: PKD Foundation support of FDA clinical trial (FD-004826-01-A2) by paying for the over-encapsulated drug and placebo. This cost was more than allowed by the clinical trials grant

Congressionally Directed Medical Research Program Grant Department of Defense (CDMRP)

Active 07/01/17-06/30/20

  • Title: Development of Pharmacotherapies for the Treatment of Hydrocephalus
  • PI: B. Blazer-Yost
  • Goal: Preclinical testing of potential treatments for hydrocephalus

Pilot Research Grant Mayfield Education and Research Foundation

Active 03/01/18 - 08/30/19

  • PI: B. Blazer-Yost
  • Title: Development of Pharmacotherapy for the Treatment of Hydrocephalus
  • Goal: Pilot studies of preclinical testing of SGK1 inhibitors for the treatment of hydrocephalus

Indiana University Collaborative Research Grant

Active 07/01/18 - 06/30/19

  • Title: Advanced Ultrasound Imaging of the Brain in Neonatal Hydrocephalus Using a Rat Hydrocephalus Model
  • Corresponding PI: Monica Forbes-Amrhein; Co-PIs Bonnie Blazer-Yost, Jeffrey Raskin, Mark Holland and Rupa Radhakrishnan
  • Goal: Test new ultrasound techniques in a rodent model of hydrocephalus with a view to developing bed-side imaging techniques in neonatal humans with hydrocephalus