Discover Together Biobank Projects: How Your Samples Contribute to Discovery

Discover Together Biobank plays a vital role in research at Cincinnati Children’s. Using samples from our biobank lets investigators save time in recruiting participants, and allows researchers to precisely look at specific diseases or medications to better understand disease mechanisms; diagnose, cure, or prevent diseases; discover new treatments; learn how people react to medications; and better appreciate why some people stay healthy. That’s why contributing your or your child’s samples to our biobank could have a lasting impact on other children’s lives.

Here are examples of how our Cincinnati Children’s researchers are using samples from Discover Together Biobank:

Akihiro Asai, MD, PhD, of Cincinnati Children's.

Principal Investigator: Akihiro Asai, MD, PhD
Disease: Liver Disease

We want to understand the molecular mechanism of genetic liver disease in humans. Therefore, we will study biologically transformed cells derived from patients’ blood cells.

 

 


 

Cincinnati Children's researchers are studying the connections between asthma and eczema.

Principal Investigators: Jocelyn M. Biagini Myers, PhD; Gurjit (Neeru) Khurana Hershey, MD, PhD
Diseases: Eczema; Asthma

The Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH) is the first U.S.-based eczema study cohort. Nearly 600 enrolled infants / toddlers with eczema complete annual study visits to allow physicians and scientists to follow the progression of eczema to the development of other allergic conditions including food allergy, allergic rhinitis and asthma. Parents complete questionnaires and allow their children to donate biological samples. This allows researchers to study the molecular and mechanistic pathways of underlying the “atopic march,” especially the development of allergic diseases in children with asthma.

 

 


 

Cincinnati Children's researchers are studying Wilms tumor.

Principal Investigator: James Geller, MD
Disease: Wilms Tumor / Nephroblastoma

Wilms tumor is a cancerous tumor that begins in kidney cells. We are researching different types of Wilms tumor – looking at both typical and biologically complex. We are separating the samples into individual cell nuclei and sequencing the RNA of each. This will allow us to determine how different the genetic expression is within each single nucleus; if there are differences between types; and how much difference is in each tumor. This will help us better determine treatments for Wilms tumor in children.

 

 


 

John Harley, MD, PhD, of Cincinnati Children's.

Principal Investigator: John Harley, MD, PhD
Disease: Multiple Diseases

Cincinnati Children’s Electronic MEdical Records and GEnomics (eMERGE) Phase III Return of Results is a research project that includes sequencing of biobank samples using a next-generation sequencing panel developed specifically for the project. That panel contains 109 genes and over 1,500 single nucleotide variants (SNVs). SNVs are changes to a part of the DNA, which may or may not indicate a disease or potential for disease.

We had approval from our Institutional Review Board (IRB) to recontact biobank participants if we found a change in a gene that could result in a disease in childhood. This project helps us better understand what changes to a person’s genome could result in a disease as well as the impact of returning genomic results to biobank participants.

 

 


 

Cincinnati Children's researchers are studying premature birth.

Principal Investigator: Taosheng Huang, MD, PhD
Disease: Premature Birth

The mitochondria are known as the “powerhouse of a cell.” They are located in the cytoplasm of a cell and found in most cells in the body. Their role is to produce energy and regulate metabolism. We are researching how the genome of mitochondria might play a role in premature birth. Once we understand this, we might be able to prevent preterm birth.

 

 


 

Kenneth Kaufman, PhD, of Cincinnati Children's. 

Principal Investigator: Kenneth Kaufman, PhD
Diseases: Many Types

Somatic mutations are changes in a person’s DNA that happen after birth. These changes can happen in any cell of the body, except for sperm and egg, so they cannot be passed on to children. We believe these changes in the DNA may lead to many types of diseases. We are looking for somatic mutations in biospecimens to determine if there is a way to measure them in the DNA, and if that knowledge could help develop treatments for a variety of diseases.

 

 


 

Paul Kingma, MD, PhD, of Cincinnati Children's.

Principal Investigator: Paul Kingma, MD, PhD
Disease: Tracheal Esophageal Defects

We are studying how abnormal connections between the esophagus and the respiratory tract develop. Patients with these abnormal connections require surgery to repair the defect, but it is unclear what future implications this may have. By studying how this disease occurs, we can better predict what other potential issues these patients may have in the future.

 

 


 

Q. Richard Lu, PhD, of Cincinnati Children's.

Principal Investigator: Q. Richard Lu, PhD
Diseases: Neurofibromatosis (NF); Malignant Peripheral Nerve Sheath Tumor (MPNST); Cancer

In NF and MPNST, Schwann cells − which are nerve cells that contribute to nerve regeneration − no longer behave like normal cells because of mutations that occur with the diseases. These cells can even transition into cancer cells. However, how that happens is largely a mystery. In addition, extra cells normally not present in healthy tissues, such as immune cells, are abundant in these tumors. All these cells interact with the tumor, just as the tumor can interact with these surrounding cells. This creates a highly dynamic ecosystem that is constantly changing to serve the needs of the tumor. Cancer behaviors including how a tumor grows, spreads, and resists drugs critically depend on how tumor cells talk among themselves and to the surrounding cells through a “signal sending-receiving” relationship.

Our research seeks to understand what signal is exchanged between individual cells within a tumor. We are using techniques called single-cell transcriptomics and epigenomics to allow us to detect global gene expression patterns of individual cells and what gene networks control these patterns. Single-cell data can tell us what cell populations are within a tumor and how they talk to one another to make the tumor grow bigger and deadlier. One way tumor cells become more powerful is to escape from surveillance by immune T cells, which act like “police” cells in the body. This research will allow us to develop drugs to make cancer cells more visible to the immune system. In addition, this will open new opportunities for finding out how tumor microenvironments may cause the transition of benign NF into MPNST and allow us to develop better tools to specifically attack the tumor.

 

 


 

Lori Luchtman-Jones, MD, of Cincinnati Children's.

Principal Investigator: Lori Luchtman-Jones, MD
Disease: Blood Vessel Diseases; Vascular Malformations

The Cancer and Blood Diseases Institute’s specialty Hemostasis and Thrombosis Laboratory is developing a new clinical test to assess levels of the protein Angiopoietin-2 (Ang-2) in blood. Knowledge of Ang-2 levels can assist physicians in both diagnosing and treating some problems with the abnormal growth of blood vessels and lymphatic tissue called vascular malformation syndromes.

We need to understand what normal values are for Ang-2 in boys and girls of various ages.

Previous work in a research lab allows us to decide that we need to look at three age ranges to generate normal range values: 0-4, 4.1-10.5, and 10.6-18 years.

 

 


 

Satish Madala, PhD, of Cincinnati Children's. 

Principal Investigator: Satish Madala, PhD
Disease: Asthma

We will use tissue samples from patients with asthma to explore the molecular mechanisms that cause structural changes in the airway − such as thickened walls or narrowed airways − known medically as airway remodeling.

 

 


 

Tesfaye Mersha, PhD, of Cincinnati Children's.

Principal Investigator: Tesfaye Mersha, PhD
Disease: Asthma

Our overall goal is to decipher the causes of childhood asthma, including the genetic and environmental exposure factors. We are doing this by looking at parts of the genome called single nucleotide polymorphisms (SNP) in biospecimens from patients with African-American ancestry. In addition, we are mapping out the interactions between ancestry and environmental exposures. The analysis of ancestry in the context of an environmental exposure framework has significant potential to efficiently uncover variants that affect asthma susceptibility. Finally, we are replicating the top SNPs in order to develop a genetic ancestry risk score (GARS) to predict asthma risk in a patient.

 

 


 

Cincinnati Children's researchers are studying cystic fibrosis.

Principal Investigator: Anjaparavand (AP) Naren, PhD
Disease: Cystic Fibrosis

We are isolating sweat ducts from human skin – and then ductal epithelial cells from that sweat duct. Epithelial cells are the cells that line the surfaces of the body. The cystic fibrosis transmembrane conductance regulator (CFTR) is the product of the gene mutated in patients with cystic fibrosis (CF). CFTR is a cAMP-regulated chloride channel localized primarily at the apical or luminal surfaces of epithelial cells lining the airway, gut, exocrine glands, sweat gland etc., where it is responsible for transepithelial salt and water transport. In general CFTR is thought to be secretory in nature (efflux of chloride across the plasma membrane); however in the sweat duct it is rather absorptive (chloride influx across the plasma membrane). We are testing the chloride channel function and gene expression and importantly macromolecular complex formation in these sweat duct cells to see if there are any significant changes in epithelia cells of the human lung epithelial cells, and ductal cells of the sweat duct. In addition, we would like to compare expression pattern of complex formation in non-CF and CF patients.

 

 


 

Cincinnati Children's researchers are studying liver diseases.

Principal Investigator: Bahram Namjou-Khales, MD
Disease: Liver Diseases

In last few years, I have been using Discover Together Biobank specimens for genetic studies of several complex diseases including non-alcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis (PSC), autoimmune hepatitis, obesity and lupus. In my recent publication for NAFLD, we identified new genetic associations and pathway for disease severity focusing on pediatrics. In addition, as part of NIH-funded eMERGE network efforts, we “capture sequenced” – in other words, looked at specific areas of the genomes for more than 100 highly penetrant disease-causing genes for different diseases and successfully returned important results and findings to the patient after validation. In addition, we are also developing various phenotype algorithms − or, formulas that show which genes or combinations might lead to specific diseases in people. We’re doing this using natural language processing (computer program that can “read” language) to capture true cases and controls for different diseases under study in order to perform genetic analyses.

 

 


 

Carlos Prada, MD, of Cincinnati Children's.

Principal Investigator: Carlos Prada, MD
Diseases: RASopathies, including Cardiofaciocutaneous Syndrome; Costello Syndrome; Neurofibromatosis Type 1; Noonan Syndrome

The focus of this study is to learn more about a group of genetic conditions called RASopathies, including Noonan syndrome, neurofibromatosis type 1, cardiofaciocutaneous syndrome and Costello syndrome. Each syndrome in this group of disorders has unique features, but there are many overlapping characteristics including facial features, heart defects, skin abnormalities, thinking / learning delays, and a predisposition to cancer. Individually, each of these syndromes are rare. Together, they are one of the most common groups of genetic conditions in the world. Currently, there is no cure or treatment for the underlying cause of the disease. RASopathies are treated by addressing the manifestations of disease as they appear, while also monitoring for progression of symptoms. Better understanding this group of conditions will improve diagnosis and treatment of people with a RASopathy. We are collecting and storing samples from patients with suspected or diagnosed RASopathies. Once obtained, blood and/or tissue samples are processed for research on these diseases, including metabolic and genetic studies.

 

 


 

Lisa Privette Vinnedge, PhD, of Cincinnati Children's. 

Principal Investigator: Lisa Privette Vinnedge, PhD
Disease: Cancer

We found that certain types of cancers use what is medically known as autophagy – the body’s way to get rid of damaged cells to create new, healthier cells. Some cancers, it seems, use this method to get rid of toxic proteins they produce. Inhibiting this process can kill these types of cancer with minimal effect on normal cells. Therefore, we are trying to find ways to stop this process, thereby, preventing cancer growth.

 

 


 

Laura Ramsey, PhD, of Cincinnati Children's.

Principal Investigator: Laura Ramsey, PhD
Disease: Depression & Anxiety (Treatment of); Pharmacogenetics

There are a few genes that influence a patient’s response to antidepressants. We know that two of these genes are involved in the metabolism of the antidepressants, and three are involved in the way the drugs exert their effects within an individual.

We are studying those genes’ association with the dose, response, and side effects of various antidepressants.

Disease: Inflammatory Bowel Disease

We are testing whether there are genetic variants that influence nausea in pediatric patients with inflammatory bowel disease who are treated with the medication methotrexate.

 

 


 

Michael Rosen, MD, of Cincinnati Children's. 

Principal Investigator: Michael Rosen, MD, MSCI
Disease: Ulcerative Colitis; Inflammatory Bowel Disease; Pharmacogenetics

Infliximab is a medicine given to patients with ulcerative colitis (UC) or inflammatory bowel disease-unspecified (IBD-U). In our research, we are learning about how quickly the body gets rid of infliximab in children with colitis. We are also learning how to tell which children will benefit from taking infliximab. This study may help us to find better ways to treat children with UC or IBD-U.

 

 


 

Cincinnati Children's researchers are studying kidney diseases.

Principal Investigator: Meredith Schuh, MD
Disease: Congenital Nephrotic Syndrome; Kidney Disease

Congenital nephrotic syndrome is a rare condition which presents early in life that causes protein to be lost in the urine and can lead to swelling, infections, blood clots and kidney failure. Many genes are now known to cause congenital nephrotic syndrome, though there are likely many more that are yet undiscovered. Based on genetic testing, we will use kidney tissue and special staining to look at whether certain proteins involved in metabolism are present in the cells involved in nephrotic syndrome.

Disease: Kidney Disease

We are studying how a mutation or variant in the gene LRP2 leads to kidney disease and the loss of protein in the urine. We will use kidney tissue and special staining to look at whether certain proteins are absent based on this genetic mutation.

 

 


 

Pranavkumar Shivakumar, PhD, of Cincinnati Children's.

Principal Investigator: Pranavkumar Shivakumar, PhD
Disease: Biliary Atresia

Biliary atresia is a severe form of liver disease affecting newborn children. Although several mechanisms have been looked at to discover its cause, none has translated into a treatment. We are analyzing liver tissues from patients with biliary atresia for a protein BCL6, a marker of B cells, and comparing those to control tissue, to identify treatments.

 

 


 

Cincinnati Children's researchers are studying diseases of the trachea.

Principal Investigator: Debora Sinner, PhD
Diseases: Tracheomalacia and Complete Tracheal Ring (Windpipe Defects)

Birth defects affecting the respiratory tract are prevalent, in particular those concerning the upper airways. These defects include tracheomalacia, in which the walls of the trachea (windpipe) lack rigidity because of the absence of cartilage. On the other hand, the complete tracheal ring pathology is characterized by an excess of rigidity and significant narrowing of the pipe. Currently, there are no effective treatments for these diseases that affect normal breathing. We study the formation of the respiratory tract, specifically the airways that include the trachea. Our goal is to identify genes that are required for cartilage and muscle formation in the trachea and bronchi. Using fixed tissue, we will determine the expression of genes that contribute to the development of the large airway.

 

 


 

Ying Sun, PhD, of Cincinnati Children's.

Principal Investigator: Ying Sun, PhD
Disease: Gaucher Disease

We are examining nervous system and brain tissue to understand more about Gaucher disease.

Gaucher disease is a genetic disease in a category of metabolic diseases known as lysosomal storage disorders, which causes a buildup of glycolipids in cells.

Available treatment lacks effectiveness for the highly lethal central nervous system form of the disease.

We are researching the mechanisms of the disease to find new drug targets to treat patients with neuronopathic form Gaucher disease.

 

 


 

Takanori Takebe, MD, of Cincinnati Children's.

Principal Investigator: Takanori Takebe, MD
Disease: Cancer (Neuroendocrine Tumor)

We are replicating a patient’s tumor with cells in a dish to study the personalized disease mechanism of the patient’s intractable neuroendocrine tumors. Our plans are that in the future we will develop a new treatment for these types of cancers.

Disease: Liver Diseases

We are studying liver diseases using hepato-biliary-pancreatic organoids (HBPO) derived from human induced pluripotent stem cells (iPSC). The HBPOs consist of the liver, bile duct and pancreas. They can model diseases in a dish, and we are trying to discover new medications to cure patients with complex liver / bile duct diseases.

 

 


 

Susan Thompson, PhD, of Cincinnati Children's.

Principal Investigator: Susan Thompson, PhD
Disease: Juvenile Idiopathic Arthritis

Arthritis in children most commonly begins before 6 years of age, often seeming to appear out of the blue. Seasonal variation in onset and other clues have long suggested that the disease is triggered by viral infection, but there are so many different viruses that this hypothesis has been difficult to test.

In this pilot study, we are using a next-generation DNA sequencing-based method, called VirScan, to evaluate past exposure to more than 200 viruses in 50 young children with a new-onset diagnosis of arthritis living in Cincinnati, and then comparing them to a similar number of healthy children from Cincinnati matched for age and gender.

We predict that we will find important differences in the types and number of viral infections that these children have experienced, potentially pointing the way to new options for treatment and even prevention of juvenile idiopathic arthritis. In the future, we may search for viral exposures and their relationship to other autoimmune diseases.

 

 


 

Brian Turpin, DO, of Cincinnati Children's.

Principal Investigator: Brian Turpin, DO
Disease: Sarcomas

Radiopharamaceutical therapies are radioactive medicines used in the diagnosis and treatment of some cancers. These medicines work by targeting specific proteins within a tumor to inhibit that tumor’s growth. One of those proteins, somatostatin receptor type 2 (encoded by the SSTR2 gene), represents a possible target for currently available medications.

It is well known that some types of tumors express SSTR2, and are, therefore, candidates for a radiopharmaceutical therapy known as peptide receptor-mediated radiotherapy (PRRT). However, there is very little known about SSTR2 expression in sarcomas, and our research could change that.

Given the radiosensitivity of pediatric and young adult sarcomas and the availability of the FDA-approved drug Lutathera − an SSTR2 targeting PRRT − we want our research to increase knowledge about the frequency of SSTR2 expression in sarcomas – and, therefore, produce a potential new treatment option for patients.

 

 


 

Alexander (Sander) A. Vinks, PhD, PharmD, of Cincinnati Children's.

Principal Investigator: Alexander (Sander) A. Vinks, PhD, PharmD, FCP
Disease: Immunosuppressive Medications; Pharmacogenetics / Genomics; Precision Dosing

Currently, immunosuppressant drug dosing for pediatric transplant patients follow considerably basic protocols, despite that these patients differ widely across numerous pharmacologically important factors, which include age, genetics, physiology, patency of immune response and disease progression. There is an unmet need for individualization and precision dosing of immunosuppressant drugs (and likely for most appropriate medication choice as well) in these populations with the goal of maximizing treatment efficacy (reduced incidence of rejection) while minimizing harmful off-target effects. Towards this end, we are developing a novel virtual patient platform which incorporates the most up-to-date and relevant scientific information on the aforementioned factors, in order to more accurately predict the pharmacokinetic (what the body does to the drug) and pharmacodynamic (what the drug does to the body) characteristics of pediatric transplant patients. This platform will be able to predict drug concentrations and calculate appropriate dosages for real patients and may eventually provide guidance on the optimal choice of the most optimal therapeutic regimens as well.

 

 


 

Katherine Yutzey, PhD, of Cincinnati Children's.

Principal Investigator: Katherine Yutzey, PhD
Disease: Congenital Heart Disease

It is widely known that small mammals can repair and regenerate their hearts in the week after birth. This occurs because the heart muscle cells divide and produce new cells. However, it is not known if this occurs in human hearts. We are assessing heart muscle cell turnover in the human heart from very young ages up to early adulthood to gain insights into the potential for cardiac repair in infants with congenital heart disease.

Disease: Heart Valve Disease

Heart valve disease is a significant cause of morbidity in the United States, but there are currently no pharmacologic-based treatments for this condition. We are examining molecular and cellular mechanisms that contribute to progression of congenital myxomatous valve disease, including in Marfan syndrome. Congenitally malformed valves also are predisposed to disease in adults, often necessitating surgical replacement. Our goal is to develop new therapies to prevent or stop the progression of heart valve disease.

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