MIOARA MANOLE, MD, FAAP AND ALBERTO VAZQUEZ, PHD

Optogenetic Targeting of Cerebral Pericytes and Smooth Muscle Cells to Ameliorate Capillary Stasis

Dr. Mioara Manole, MD, FAAP from the Department of Pediatrics and Pharmacy and Therapeutics and her co-investigators (Alberto Vazquez, PhD from the Department of Radiology and Dennis Simon, MD from the Department of Critical Care Medicine) are studying abnormal contractions of vascular contractile cells, pericytes and smooth muscle cells after successful resuscitation from cardiac arrest. These cells limit blood flow to the recovering brain and may worsen neurological outcome. They have now proposed to improve blood flow and metabolism in the brain after cardiac arrest using a specific strategy that induces relaxation of vascular cells in specific areas of the brain.

The team will generate mice that express light-sensitive channels in the pericytes and smooth muscle cells. Upon stimulation with light, relaxation is induced in these vascular contractile cells. If relaxing the perivascular cells proves to be successful in restoring normal brain perfusion metabolism, microvascular-specific therapies can be developed to improve neurological function after brain injury.

Award: $40,000 - 12 months

JERRY VOCKLEY, MD, PHD AND EDUARDO VIEIRA NETO, MD, PHD

Mitochondrial Trifunctional Protein Deficiency: Mitochondrial Bioenergetics, Cardiolipin, and Novel Therapeutic Targets

Dr. Eduardo Vieira Neto, MD, PhD from the Department of Pediatrics, Jerry Vockley, MD, PhD, FACMG from the Department of Pediatrics and their co-investigators (Hülya Bayır, MD from the Department of Pediatrics, Department of Critical Care Medicine, and Department of Environmental and Occupational Health; and Valerian Kağan, PhD, DSc from the Department of Environmental and Occupational Health as well as the Department of Pharmacology and Chemical Biology, the Department of Radiation Oncology, and the Department of Chemistry) are exploring the mitochondrial trifunctional protein (TFP) deficiency as an inherited disorder caused by a block in fatty acid oxidation (FAO); the process by which stored fats are utilized for energy production during times of physiologic stress such as fasting, exercise, and intercurrent illnesses. Affected children can have a devastating disease including cardiomyopathy, hypoglycemia, and hyperammonemia with early mortality, or a chronic course with recurrent rhabdomyolysis, peripheral neuropathy, retinal degeneration as well as continued risk for cardiomyopathy. In addition to its role in FAO, TFP catalyzes a step in the synthesis of cardiolipin (CL), a lipid unique and critical to the inner mitochondrial membrane structure.

Award: $40,000 - 12 months

STEPHEN P. EMERY, MD AND STEPHANIE GREENE, MD

Ventriculoamniotic Shunting for Fetal Aqueductal Stenosis (VASFAS)

Dr. Stephen P. Emery, MD from the Department of Obstetrics, Gynecology, and Reproductive Sciences and his co-investigators (Stephanie Greene, MD from the Department of Neurological Surgery and Youngjae Chun, PhD from the Department of Industrial Engineering) are investigating fetal aqueductal stenosis (FAS) as it produces noncommunicating hydrocephalus (increased cerebrospinal fluid, or CSF) and increased intracranial pressure on the developing fetal brain resulting in permanent neurologic injury in survivors. Current management is neonatal shunting and management of neurologic sequelae. They hypothesize that in-utero shunting of excess CSF will prevent neurologic damage, resulting in normal fetal brain development, thereby preventing lifelong adverse neurologic outcomes. They have developed a novel ventriculo-amniotic shunt and are testing it in a large animal model (fetal sheep), where they have demonstrated proof-of- concept. Funding from CNI will enable them to prepare a Humanitarian Use Device application for the FDA.

Award: $40,000 - 12 months

ANTONY MICHEALRAJ, PHD AND IAN F. POLLACK, MD, FACS, FAAP

Elucidating Genetic and Therapeutic Vulnerabilities of Lethal Pediatric Ependymomas

Dr. Antony Michealraj, PhD and Ian F. Pollack, MD, FACS, FAAP from the Department of Neurological Surgery are examining supratentorial ependymoma as one of the lethal pediatric cancers which does not have an effective therapeutic option. Up to 40% of children with this Ependymoma succumb to their disease, and survivors are often left disabled because of toxicity from the tumor and treatment. They have made reasonable progress on identifying the abnormal gene elements that could potentially drive this lethal tumor. However, they are still far behind in understanding the molecular network which makes children vulnerable to this tumor. Unraveling this network is very important for novel therapeutic interventions.

Award: $40,000 - 12 months

Udai Pandey, PhD and Deepa Rajan, MD

“Identification of modifiers in GEMIN5 related neurodevelopmental disorders"

Dr. Rajan and her co-investigators (Dr. Udai Pandey, PhD from the Department of Pediatrics and Dr. Sukhleen Kour, PhD from the Department of Pediatrics) identified a new disease caused by novel genetic variants in the GEMIN5 gene. She is working on describing the disease spectrum and molecular consequences of this new neurogenetic syndrome. Neither the clinical disease nor the variants have been reported in published literature or publicly available databases. Gemin5 is a highly conserved, multifunctional RNA-binding protein involved in regulating multiple aspects of cellular function including assembly of Spinal Motor Neuron (SMN) protein complex. Elucidating the presence and role of modifiers, understanding the underlying molecular mechanisms will help us evaluate potential therapeutic targets. Completion of this project would help delineate a new neurogenetic disease, add to the landscape of genetic ataxic disorders and potentially identify novel treatment options for this disease.

Award: $35,000 - 12 months

Bing Wang, MD, PhD and Hoda Abdel-Hamid, MD, FAAN

"From Bench to Bed –Test One-step Gene Therapy Technology in Human DMD Cells"

Dr. Wang, MD, PhD from the Department of Orthopedic Surgery and Dr. Abdel-Hamid, MD, FAAN from the Department of Pediatrics stated that "gene therapy is a potential treatment for Duchenne muscular dystrophy (DMD) mice by reducing the inflammation. Because of inflammation, the ongoing gene therapy phase II clinical trials using different versions of the micro-dystrophin gene delivered by recombinant adeno-associated viral (rAAV) vector were recently not successful as expected. Based on our pervious findings observed in DMD murine models, we propose a one-step gene therapy technology to assess the synergistic effect of dystrophin gene replacement combined with anti-inflammatory adjunct in muscle cells isolated from DMD patients. In addition to providing the benefit of therapeutic gene replacement, it would simultaneously improve downstream pathology, providing a novel strategy to optimize DMD gene therapy.

Award: $35,000 - 12 months

Ian Pollack, MD and Sameer Agnihotri, PhD

"The role of QPRT and NAD metabolism in glioma treatment resistance"

Dr. Pollack, MD and Dr. Agnihotri, PhD from the Department of Neurological Surgery proposed that their studies “will provide new insights into the role of mediators of NAD+ biosynthesis and energy metabolism in the treatment-resistance of pediatric malignant gliomas, the most commonly fatal brain tumors of childhood, incorporating our unique resource of treatment-naïve and treatment-resistant glioma models. Our observations, using agents currently in clinical trials, will define the underlying causes of pre-existing and acquired resistance, which has to date been an intractable problem for children with these tumors. Our preliminary data, approach and the rigor of our previous studies support a hypothesis that treatment-resistant cells demonstrate exquisite dependence on mediators of NAD+ synthesis, such as quinolinic acid phosphoribosyltransferase (QPRT), a rate-limiting enzyme for the NAD+ biosynthetic process. NAD+-mediated pathways, in turn, drive enzymes that are critical for glucose metabolism, that appear to confer tumor cells with a survival advantage. This work seeks to identify targets for therapeutic intervention that can be exploited to improve the chances for cure in children with malignant glioma and may have applicability to other tumor types.”

Award: $35,000 - 12 months

Mioara Manole, MD; Alberto Vazquez, PhD; & Dennis Simon, MD

“Elucidating the Role of Vascular Contractile Cells in Capillary Stasis after Cardiac Arrest”

There are more than 500,000 cases of cardiac arrest in the US yearly. While timely resuscitation is often effective at restoring cardiac function, many survivors develop hypoxic ischemic encephalopathy-the single factor preventing normal neurological recovery after cardiac arrest. After resuscitation from cardiac arrest, contraction of perivascular cells (pericytes and smooth muscle cells) limit blood flow to the recovering brain and may worsen neurological outcome. Dr. Manole and her research team (Dr. Alberto L. Vazquez, PhD from the Department of Radiology and Dr. Dennis Simon, MD from the Department of Critical Care Medicine) propose to examine the role of contractile perivascular cells in blood flow disturbances and to determine if an intervention that relaxes the contractile perivascular cells of the microcirculation restores normal cerebral perfusion and improves functional outcome after cardiac arrest. If relaxing the perivascular cells proves to be successful in restoring normal brain perfusion and improves neurological outcome, microvascular-specific therapies can be developed to improve neurological outcome after brain injury.

Award: $35,000 - 12 months

Deepa Rajan, MD; Udai Pandey, PhD; & Sukhleen Kour, PhD

“Identification of Modifiers in GEMIN5 Related Neurodevelopmental Disorders”

Dr. Rajan and her co-investigators (Dr. Udai Pandey, PhD from the Department of Pediatrics and Dr. Sukhleen Kour, PhD from the Department of Pediatrics) identified a new disease caused by novel genetic variants in the GEMIN5 gene. She is working on describing the disease spectrum and molecular consequences of this new neurogenetic syndrome. Neither the clinical disease nor the variants have been reported in published literature or publicly available databases. Gemin5 is a highly conserved, multifunctional RNA-binding protein involved in regulating multiple aspects of cellular function including assembly of Spinal Motor Neuron (SMN) protein complex. Elucidating the presence and role of modifiers, understanding the underlying molecular mechanisms will help us evaluate potential therapeutic targets. Completion of this project would help delineate a new neurogenetic disease, add to the landscape of genetic ataxic disorders and potentially identify novel treatment options for this disease.

Award: $35,000 - 12 months

Kate Kernan, MD; Dennis Simon, MD; Deepa Rajan, MD; & Kavita Thakkar, MD

“Whole Genome Sequencing to Identify Inborn Errors of Immunity in Critically Ill Children with Idiopathic Acute Encephalitis”

Encephalitis is abnormal brain inflammation that can cause altered level of consciousness, headaches, and seizures in addition to other short and long-term neurologic morbidities in children. However, the reasons why some children are susceptible to encephalitis is poorly understood. This research lead by Dr. Kernan and her co-investigators (Dr. Dennis Simon, MD from the Department of Critical Care Medicine, Dr. Deepa Rajan, MD from the Department Pediatric Neurology, and Dr. Kavita Thakkar, MD from the Department of Pediatric Neurology) aims to use whole genome sequencing to understand how children with encephalitis differ in genes that contribute to central nervous system development and function, the immune system or the interaction between these two systems. Understanding these differences may offer insight into the pathogenesis of pediatric encephalitis and the molecular pathways affected, thus providing insights that in the future may lead to targeted intervention.

Award: $35,000 - 12 months