Texas Children’s awards pediatric pilot grants to 12 promising researchers

November 18, 2014

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Dr. Susan Blaney, executive vice chair of Research in the Department of Pediatrics, recently announced the winners of the 2014 Pediatric Pilot Awards Research Grant Program. Twelve research applications were chosen by review committee members to receive grant funding in the amount of up to $50,000 for their projects.

The purpose of the Pediatric Pilot Awards Research Grant Program is to provide initial start-up “seed funding” for research projects. This grant program provides opportunities for new or less established researchers as well as experienced researchers who desire to expand their area of research. The grant projects are awarded based upon their scientific merit and the potential to generate the initial data necessary for a successful grant application submission to the NIH or other external, peer-reviewed funding mechanisms.

The pilot award program is a collaborative effort between Texas Children’s Hospital and its academic partner, Baylor College of Medicine.

Congratulations to the following 2014 pilot grant awardees. Click on the name below to learn more about the research project being funded.

Ronald Bernardi, M.D., Ph.D.
Assistant Professor, Pediatrics – Hematology/Oncology
Combinatorial tyrosine kinase inhibition as a novel therapeutic strategy in PTPN12-deficient pediatric cancers

Jennifer Foster, M.D.
Instructor, Pediatrics – Hematology/Oncology
Pre-clinical evaluation of ML4924, a novel NEDD-8 activating enzyme inhibitor in pediatric malignancies

Andras Heczey, M.D.
Assistant Professor, Pediatrics – Hematology/Oncology
Glypican-3 specific T cells to cure pediatric liver disease

Marisa Hilliard, Ph.D.
Assistant Professor, Pediatrics – Psychology
Promoting resilience in youth with type 1 diabetes: Pilot of a strengths-based family intervention to improve diabetes outcomes

Jimmy Holder, M.D.
Assistant Professor, Pediatrics – Neurology
Identifying post-translational regulators of SHANK3 – toward developing targeted therapeutics for neuropsychiatric disorders in children

Dongfang Liu, Ph.D.
Assistant Professor, Pediatrics – Immunology, Allergy and Rheumatology
Super-resolution imaging of HIV-specific CTL immunological synapse

Silke Paust, Ph.D.
Assistant Professor, Pediatrics – Immunology, Allergy and Rheumatology
Pollen grains as trojan horses for child-friendly oral vaccination

Elaine Seto, M.D., Ph.D.
Assistant Professor, Pediatrics – Neurology and Development Neuroscience
Investigating the role of dopamine in neurocognitive function

Amy Sims, M.D.
Assistant Professor, Pediatrics – Cardiology
Clinical-Officer led screening for rheumatic heart disease in Malawi, Africa

Bernard Suter, M.D.
Assistant Professor, Pediatrics – Neurology and Development Neuroscience
In vivo analysis of motor cortex function in the MECP2 duplication mouse

Scott Wenderfer,M.D., Ph.D.
Assistant Professor, Pediatrics – Renal
Novel Auto-antibody Markers of Lupus Nephritis

Janice Zawaski, Ph.D.
Assistant Professor, Pediatrics – Hematology/Oncology
The role of bone marrow in glioma radiotherapy response

 

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Ronald Bernardi, M.D., Ph.D.
Assistant Professor – Hematology/Oncology
Combinatorial tyrosine kinase inhibition as a novel therapeutic strategy in PTPN12-deficient pediatric cancers

Some cancers are driven primarily by increased activity of a single proliferation signal. Frequently, this abnormal stimulatory signal comes from an overactive tyrosine kinase, a class of enzymes that regulate cellular proliferation by adding phosphate groups to substrate proteins.

In this setting, specific tyrosine kinase inhibitors can limit the progression of the disease and even cause tumor regression. The development of such agents has improved outcomes dramatically for some cancers. However, for the vast majority of pediatric malignancies, the situation is not so straightforward. Thus, current options for therapy for many pediatric cancer patients remain limited in that they either have serious side effects or are ineffective.

We propose an approach that may broaden the use of tyrosine kinase inhibitors. Tyrosine phosphatases are a class of proteins that normally function to counteract the activity of tyrosine kinases. As tyrosine phosphatases typically have several substrates, loss of a tyrosine phosphatase may aberrantly activate multiple tyrosine kinases, which can act in concert to promote tumor progression.

We previously identified PTPN12 as a tyrosine phosphatase that is frequently deficient in breast cancer, leading to the activation of a number of tyrosine kinases. Combinatorial inhibition of these activated tyrosine kinases reduced proliferation of PTN12-deficient models that are resistant to single agents. We also have preliminary evidence that diminished PTPN12 expression correlates with poor prognosis in pediatric cancers. In this pilot project, we aim to more thoroughly assess the spectrum of loss of PTPN12 in pediatric cancers and to assess the functional role of PTPN12 and identify the tyrosine kinases that it regulates in this setting. Further, we plan to test the combined inhibition of PTPN12 regulated tyrosine kinases for the ability to inhibit the growth of pediatric cancers that have diminished PTPN12.

Our results will be critical for designing clinical trials of drug combinations that are tailored to the genetic alterations and susceptibilities of each individual tumor.

Jennifer Foster, M.D.
Instructor – Hematology/Oncology
Pre-clinical evaluation of ML4924, a novel NEDD-8 activating enzyme inhibitor in pediatric malignancies

Neuroblastoma is a devastating form of cancer that develops from immature nerve cells. Only half of children diagnosed with high-risk neuroblastoma survive beyond childhood. New treatments are needed to improve their survival.

In our proposed study, we will examine a novel chemotherapeutic agent, MLN4924. MLN4924 kills neuroblastoma cells differently than standard chemotherapy. The traditional way to kill neuroblastoma tumor cells has been to attack their DNA. However, in this proposal, we will test another mechanism which involves killing neuroblastoma cells by preventing protein breakdown. Blocking protein breakdown with a new drug, MLN4924, will result in “proteotoxic stress” that can kill the cancer cells following standard chemotherapy, improving our ability to kill tumor cells.

MLN4924 is currently undergoing testing in adults with various forms of cancer and has yielded promising results. Adults with relapsed or difficult to cure cancer treated with MLN4924 experience improved survival with minimal side effects. Our goal is to improve clinical outcomes in neuroblastoma by adding MLN4924 to standard chemotherapy regimens. Our preliminary data shows that MLN4924 is effective at killing neuroblastoma cells.

This research will provide the pre-clinical data necessary to successfully incorporate MLN4924 into pediatric clinical trials and is being conducted in conjunction with a proposed Phase 1 clinical trial run by the National Cancer Institute (NCI)-sponsored Children’s Oncology Group (COG). In this proposal we will determine 1) with what chemotherapies MLN4924 works best in conjunction to kill neuroblastoma cells and 2) how neuroblastoma cells are dying after treatment with MLN4924. This information is crucial in optimally designing future clinical trials for patients with neuroblastoma which will combine MLN4924 with standard anti-cancer agents. The addition of novel anti-cancer drugs, such as MLN4924, to the treatment regimen of children with neuroblastoma is crucial in improving their survival.

Andras Heczey, M.D.
Assistant Professor – Hematology/Oncology
Glypican-3 specific T cells to cure pediatric liver disease

Hepatoblastoma and hepatocellular carcinoma are the most common forms of liver cancer in children. Despite severe side effects, current medical therapies have limited effectiveness in patients whose tumors cannot be surgically removed completely.

In our study, we propose to collect and genetically modify special immune cells from the blood to destroy liver cancer cells in the laboratory. Our long-term goal is to develop a new immunotherapy method by genetically engineering the patient’s own immune system to eliminate liver cancer without the toxicity of current therapies.

Marisa Hilliard, Ph.D.
Assistant Professor of Pediatrics – Psychology
Promoting resilience in youth with type 1 diabetes: Pilot of a strengths-based family intervention to improve diabetes outcomes

Type 1 diabetes is a common chronic condition characterized by the body’s inability to produce insulin due to the autoimmune destruction of the beta cells in the pancreas.

The daily management requirements of type 1 diabetes are complex and demanding. Adolescence is a particularly difficult period as teens begin to assume responsibility for their own diabetes management and worsening glycemic control is common during this time.

Complex issues that make diabetes even more challenging to manage for adolescents include family disagreements about diabetes, depression, and “diabetes burnout.” Family factors that help teens and families manage diabetes more easily include being good problem-solvers, ongoing parent support, and coping with diabetes challenges in an optimistic way.

Psychologists and physicians have developed intervention programs to promote good diabetes outcomes and most have focused on minimizing the impact of diabetes challenges. However, there are fewer programs designed to promote good diabetes outcomes by building on teens’ and families’ existing strengths.

Thus, the purpose of this study is to pilot test an intervention program that will recognize specific actions teens with diabetes and their families do well for their diabetes management (such as talking to friends about diabetes and asking parents for help when needed) in order to strengthen those positive diabetes behaviors.

As part of the intervention, teens and their parents will complete a web-survey before attending two routine visits with their diabetes care provider. The web-survey will include a questionnaire about positive diabetes behaviors and one about how often the teen and family complete various diabetes management tasks (such as checking blood glucose values or giving insulin). At the diabetes clinic visits, the diabetes care provider will receive a print-out of the family’s “Diabetes Strengths Profile” and will be trained to talk with the teen and family about their strengths and successes with diabetes management during the clinical encounter, rather than focusing on what is not going well.

We hope this strengths-based family approach will help patients and families feel more satisfied with diabetes care, feel less burdened by diabetes management demands, and feel empowered to use more positive diabetes behaviors. Ultimately, we expect these improvements will translate to better quality of life and better glycemic control for adolescents with type 1 diabetes.

Jimmy Holder, M.D.
Neurology & Development Neuroscience
Identifying post-translational regulators of SHANK3 – toward developing targeted therapeutics for neuropsychiatric disorders I children

Autism is a common neurodevelopmental disorder affecting more than one in 100 children. Currently, there are no effective therapies to treat the primary symptoms of autism which include abnormal language development, socialization and restricted interests. This is largely due to our incomplete understanding of the neurobiological basis of autism.

Mutations of a gene called SHANK3 are one of the more common genetic causes of autism. In addition to the core symptoms of autism, children with mutations in SHANK3 have moderate to severe intellectual disability and often intractable epilepsy.

Through this pilot award, we will attempt to identify regulators of SHANK3 protein stability. Identifying these regulators will serve as therapeutic entry points for treating the symptoms of autism due to mutations in SHANK3 as well as potentially providing insight into the neurobiological of autism.

Dongfang Liu, Ph.D.
Assistant Professor – Immunology, Allergy and Rheumatology
Super-resolution imaging of HIV-specific CTL immunological synapse

How do some patients infected with HIV control virus levels in their blood to an undetected level without HIV medications? Why do HIV medications require a life-long commitment for patients? Can we control the virus to an undetected level without lifetime treatment?

My study will use multiple innovative, super-resolution imaging approaches in live, single cells – at the single-molecule level – to answer these critical questions and explain how one population of white blood cells fights HIV during chronic infection.

HIV is a virus that attacks the immune system in our bodies. HIV is different from other viruses because the body’s immune system never fully gets rid of it. Over time, HIV destroys the body’s ability to fight infection and disease. When that occurs, HIV infection can lead to Acquired Immune Deficiency Syndrome, or AIDS.

Cytotoxic T lymphocytes (CTLs) is one type of white blood cell that recognizes and kills HIV-infected cells in the body. However, the CTLs fail to function normally and do not prevent progression of disease in most people during chronic HIV infection. The mechanism responsible for CTLs dysfunction remains unclear.

A major gap in our current knowledge of CTLs dysfunction is the lack of understanding of the CTLs-virally infected target cell interface called immunological synapses (IS). Formation of a functional interface is required for effective CTLs responses to occur, which is essential for eradicating HIV.

HIV medications inhibit HIV but do not eradicate HIV. The virus rebounds after cessation of HIV medications. Neither eradication of the virus nor restoration of effective CTLs function can be achieved by HIV medications. Therefore, it is crucial to understand the interface between CTLs and virally infected target cells during HIV infection and to train CTLs in the body to fight HIV. Traditional biochemical and cell biological approaches do not reveal the critical spatiotemporal parameters of intracellular signal transduction cascades and dynamics of interface between CTLs and HIV-infected target cells.

My study will use high-resolution imaging at the single-molecule level to address important questions about CTLs and HIV-infected target cell’s interface. They include dynamics of interface formation (how CTLs recognize a virally infected target cell) and the critical factors determining the outcome of interface. By looking at the interface between CTLs and target cells using high-resolution imaging at the single-molecule level, we will determine the mechanism of CTLs dysfunction during chronic HIV infection. This knowledge will provide an excellent framework for designing specific protein inhibitors or antagonists to restore CTLs functions during chronic HIV infection.

Silke Paust, Ph.D.
Assistant Professor – Immunology, Allery and Rheumatology
Pollen grains as trojan horses for child-friendly oral vaccination

With the absence of a preventive or therapeutic HIV vaccine, 2.7 million new HIV infections occur annually, and over 34 million people are infected worldwide. As differences in infection levels are most pronounced among young people aged 15-24 years, a preventive HIV vaccine will need to be administered to children.

We propose to evaluate an inexpensive, child-friendly, self-administrable HIV vaccine for simple translation to the clinics. My collaborator at Texas Tech University, Dr. Gill, has developed a vaccine formulation based on pollen grains, which are cleaned to remove their allergenic compounds and refilled by vacuum with HIV protein antigens and vaccine adjuvants. Pollen-based formulations are administered orally (they are eaten), thus offering the advantages of a painless, needle-free, child-friendly, easy vaccination approach.

This pilot project is to assess the effectiveness of this novel HIV vaccine when it is administered orally to mice that have been given a human immune system. By vaccination and HIV challenge of this animal model, we can assess the quality of the human immune response upon HIV pollen vaccination and assess whether this vaccine formulation protects against HIV infection.

If successful, this project will aid in the development of an inexpensive, easy-to-transport and administer HIV vaccine that is suitable for adults and children.

Elaine Seto, M.D., Ph.D.
Assistant Professor – Neurology and Development Neuroscience
Investigating the role of dopamine in neurocognitive function

Cells of the nervous system, known as nerve cells or neurons, function through the regulated release of chemical messengers known as neurotransmitters. The human brain utilizes many different neurotransmitters to relay information from neurons to downstream cells. One neurotransmitter that has garnered significant attention is dopamine. During adulthood, misregulation of dopamine is thought to underlie the movement abnormalities seen in patients with Parkinson’s disease.

Interestingly, dopamine can be detected early in fetal brain development and misregulation in the developing brain may likely contribute to neuropsychiatric conditions such as attention deficit hyperactivity disorder (ADHD).

In a screen for modifiers of dopamine in fruit flies, we have isolated genes implicated in several neurodevelopmental conditions such as autism and intellectual disability. By altering these genes specifically in dopamine-expressing neurons, we can determine how these genes affect dopamine transmission and if these changes result in altered cognition.

My study will provide further insight into the role dopamine plays in pediatric neurocognitive disorders. This work may also lead to novel therapeutic options since medications that modulate dopamine transmission are already being utilized for other medical diagnoses.

Amy Sims, M.D.
Assistant Professor – Cardiology
Clinical-Officer Led Screening for Rheumatic Heart Disease in Malawi, Africa

While almost eradicated in the U.S., rheumatic heart disease (RHD) is the leading cause of cardiac morbidity and death among children in impoverished nations around the world, like Malawi, Africa.

RHD is a chronic heart condition caused by acute rheumatic fever which can result in severe heart valve damage. Secondary prevention consists of monthly penicillin injections for RHD patients, which prevents progression of heart valve disease. The 2012 guidelines issued by the World Heart Federation provides consensus for RHD diagnosis by echocardiography. RHD screening programs that use echocardiography to produce images of the heart’s valves and chambers are sensitive to detecting early signs of the disease. Early detection and effective secondary prevention dramatically reduces morbidity and mortality.

We conducted a study last year which was the first to establish the prevalence of RHD in Malawi. Our preliminarily findings suggest that Malawi may have one of the highest prevalences of RHD in the world. Thus, expanding the capacity to screen for RHD and enroll affected children in secondary prophylaxis programs can drastically reduce the sequaelae of this disease.

With 0.19 physicians per 1000 people in Malawi and no in-country pediatric cardiologist, it is not feasible for RHD screening to be led by physicians. Task-shifting to Clinical Officer (CO)-led RHD screening is a more sustainable option. Computer-based modules describing screening for RHD aimed at non-physicians have been developed and validated.

This pilot award project aims to train nine Malawian CO’s in echocardiographic screening for RHD. After didactic and computer-based training, each CO will accompany a pediatric cardiologist to a local Malawian school and learn to screen for RHD first hand. We expect to screen over 1000 children for RHD. Each CO will be evaluated in their ability to screen for RHD.

This study will be a step towards eradicating RHD, the leading cause of cardiac death in children worldwide.

Bernard Suter, M.D.
Assistant Professor, Neurology and Development Neuroscience
In vivo analysis of motor cortex function in the MECP2 duplication mouse

Boys born with higher levels of a specific gene called MECP2 have autism spectrum disorder. Common symptoms include severe verbal and communication problems, as well as impaired motor function Specifically, their ability to walk is perturbed and over time becomes unstable. To date, we don’t know how the control of gait is disturbed in these individuals. In the mouse model of this disease, the way the mice walk worsens over time.

My study will examine part of the mouse brain that controls movements and gait called the primary motor cortex. Our brain works by the electrical firing signals of its principal cells, the neurons. In the primary motor cortex of MeCP2-duplication mice, I look at many neurons at the same time and observe what pattern of firing they exhibit during walking and running, and compare this to the patterns observed in normal mice.
By understanding how control of gait is disrupted, we can identify methods to modify and improve gait in humans with autism spectrum disorders.

Scott Wenderfer,M.D., Ph.D.
Assistant Professor – Renal
Novel Auto-antibody Markers of Lupus Nephritis

This project will assess a novel diagnostic tool for monitoring kidney involvement in children with systemic lupus erythematosus (SLE), a chronic inflammatory condition that occurs when the body’s immune system attacks tissues and organs.

Kidney involvement in SLE often drives the therapy decisions due to its enormous impact on patient outcomes and kidney function. To date, there are no reliable non-invasive diagnostic or prognostic markers for kidney involvement in these patients. Prior research by the applicant, assessing auto-antibodies against basement membrane material, found that severe kidney disease commonly develops in children with SLE, which can change the concentration in their bloodover time, and can discriminate between subsets of SLE patients.

In this study, the ability of this novel biomarker from blood to predict kidney involvement will be tested using a collection of subjects enrolled in the Midwest Pediatric Nephrology Consortium (MWPNC), a group of over 40 pediatric centers including Baylor College of Medicine. We will correlate findings with results of the more invasive kidney biopsy test. We will also explore relationships between anti-basement membrane antibodies and current clinical measures of kidney involvement in SLE.

The results will guide the applicant’s development of future studies to examine the value of this novel diagnostic tool among pediatric lupus patients and ultimately translate these findings to clinical practice.

Janice Zawaski, Ph.D.
Assistant Professor – Hematology/Oncology
The role of bone marrow in glioma radiotherapy response

Bone marrow derived cells (BMDCs) contribute to tumor growth and are associated with a worse clinical prognosis. Upon tumor initiation, the exact pathway/mechanism by which these BMDCs are recruited, migrate, and retained in the tumor are not well understood. However, low tumor oxygenation, as a result of radiotherapy, increases the influx of BMDCs.

The goal of this research is to create and characterize a mouse brain tumor model in which the bone marrow is fluorescent (GFP+) to study the contribution of BMDCs to tumor growth. As a result of the bone marrow being fluorescent it allows us to measure the magnitude and kinetics of the influx of BMDCs into the tumor pre- and post-radiotherapy using imaging techniques (microscopy, fluorescence imaging). In addition, translational imaging (PET and MRI) techniques, similar to clinical imaging currently performed on patients, will be used to study the effect of tumor oxygenation on the recruitment of BMDCs into the tumor pre- and post-radiotherapy.