Research

Current Research

Mary Austin, MD, MPH

Assistant Professor
Pediatric Neurosurgery

Pediatric Melanoma and Other Rare Tumors in Children and Adolescents
The University of Texas MD Anderson Cancer Center provides a unique environment in which to study pediatric and adolescent patients with rare tumors that more often occur in the adult population. For example, there are approximately 300-400 new melanoma diagnoses in children and adolescents each year in the United States. It is unclear as to the etiology of melanoma in this patient population as sun exposure is likely not the only contributing factor especially in the younger patients. We are working closely with our colleagues in pediatric oncology and adult surgical oncology to establish a multidisciplinary team approach to the management of these patients. We are also prospectively enrolling patients in a data and tissue collection study and plan to use this information to identify key prognostic factors in the development of the disease
Identifying Disparities in Access to Care for Pediatric Cancer Patients
PI: Mary Austin
Mentor: Linda Elting, PhD
Although there are several reports of racial/ethnic disparity in pediatric cancer outcomes, there has been no investigation into the role geography and/or socioeconomic status (SES) plays. Certainly, we know that SES is linked to race/ethnicity but its actual impact on either stage of presentation or outcome is not understood or described. Texas is a geographically and socioeconomically diverse state. We are currently using data from the Texas Department of Health Services Hospital Discharge Data File and the Texas Cancer Registry to determine if geographic location and/or socioeconomic status impacts stage at diagnosis and/or overall survival in pediatric cancer patients in Texas. This work is supported by a training grant in association with the Comparative Effectiveness Research on Cancer in Texas (CERCIT) program.
Splenectomy for Congenital Hemolytic Anemia Consortium
Project PI: Henry E. Rice, MD, Duke University Medical Center
UT Site PI: Mary Austin
The consortium is a multi-institutional prospective study to evaluate patients undergoing splenectomy for congenital hemolytic anemia. The goal of this project is to clarify clinical outcomes in this patient population and enhance communication among sites and families to make better clinical decisions regarding these patients. The patients are enrolled on the study and data are entered into a central registry.

Supinder Bedi, PhD

Instructor of Pediatric Surgery

Division of General and Thoracic Pediatric Surgery

Charles S. Cox, MD

Children's Fund Distinguished Professor
Director of the Pediatric Trauma Program at Children's Memorial Hermann Hospital

Pediatric Traumatic Brain Injury
Traumatic brain injury (TBI) affects nearly 1.5 million patients each year in the U.S. with a cost of nearly 60 billion dollars associated with it. TBI results in long-term physical and cognitive deficits. TBI is a central nervous system (CNS) injury that disrupts the normal interactions between the immune system and CNS. A CNS injury can lead to the production of inflammatory mediators or the disruption of the homeostatic signals in the circuitry of the neural-immune interactions. Immune responses are governed by distant organs such as the spleen and thymus, which act as “bioreactors” when combined with progenitor cell therapy. One potential target of the “bioreactors” is microglia, the resident immune-response cells of the CNS. After injury, microglia (macrophages) differentiate into two different phenotypes. The early phase after injury is dominated by M1 microglia that are considered pro-inflammatory. They potentially release pro-inflammatory cytokines such as IL-1, IL-6 and TNFα. The other microglia (M2) is anti-inflammatory. It releases cytokines such as IL-4 and IL-10. The ratio of M1 vs M2 is potentially a critical factory in a prolonged inflammatory state. We are currently investigating the signaling mechanisms that govern this ratio and the subsequent consequences of the changes in the ratio of M1:M2 when combined with progenitor cell therapy. In addition, we are also examining the role of tissue (Electrospun) scaffolds as carriers for cells intended to treat TBI. Tissue scaffolds provide mechanical, geometric and chemical indicators that promote and modulate cell growth. Electrospinning is a relatively simple method of producing tissue scaffolds with geometries similar to those found in the extracellular matrix (ECM) of living tissue. The process of electrospinning involves the use of an electric field to extrude thin fibers that accumulate to create the scaffold. Electrospun scaffolds have been applied to many different areas of the body including blood vessels, bone, and nerve grafts, and can be used with either natural or synthetic biomaterials. We are attempting to use electrospun scaffolds as carriers for cells intended to treat traumatic brain injury (TBI). This requires studying the fabrication parameters that influences cell growth, and the potential for neuroprotection and neurogeneration following TBI.
Safety of Autologous Mesenchymal Stem Cell Therapy for Spinal Cord Injury in Children
This is a FDA approved pilot study, conducted at Children’s Memorial Hermann Hospital and sponsored in part by TIRR, to determine if bone marrow harvest and transplantation are safe in children with SCI. Ten children, ages 0-15 years of age who have suffered a SCI within 6 months to 4 years of study enrollment, will undergo bone marrow aspiration. Following cell processing, the children will then receive an Intravenous infusion of their cells. They will return at 30 days and 6 months post-procedure for follow-up to assess late functional outcome using pre-transplantation spinal cord function as the control.
Safety of Autologous Human Cord Blood as a Treatment for Traumatic Brain Injury in Children
This is a FDA approved pilot study, conducted at Children’s Memorial Hermann Hospital and sponsored in part by Cord Blood Registry (CBR), to determine if autologous hUCB transplantation for TBI is logistically feasible and safe. Ten children, ages 18 months -17 years who have suffered a severe to moderate TBI 6 months to 18 months prior and who have their own cord blood banked at CBR, will receive an intravenous infusion of their cord blood derived cells. Follow-up will occur at 6 months, 1 year and 2 years post-procedure to assess improvement using pre and post-TBI neuropsychological and imaging outcomes measures.

William I. Douglas, MD

Associate Professor
Chief of the Division of Pediatric Cardiovascular Surgery.

Medtronic – Contegra Pulmonary Valved Conduit for Humanitarian Use
The Contegra device is indicated for patients under the age of 18 for the correction or reconstruction of Right Ventricular Outflow Tract (RVOT) in the following congenital heart malformations: pulmonary stenosis, tetralogy of Fallot, truncus arteriosus, transposition with ventricular septal defect, and pulmonary artresia. In addition, the device is indicated for the replacement of previously implanted but dysfunctional pulmonary homografts or valved conduits.

Stephen Fletcher, DO

Associate Professor
Pediatric Neurosurgery

MEDTRONIC Neurologic Technologies, “Pediatric Clinical Study of the Durepair Dura Regeneration Matrix”, STUDY
Texas Comparative Neuro-oncology Program Research Project

Lillian S. Kao, MD, MS

Studies on Hyperglycemia in Surgical Infection.
The goal of this NIH-funded grant is to evaluate two different glycemic control regimens on biologic response and clinical outcome in patients with necrotizing soft tissue infections.
Checklists, Patient Safety, and Surgical Complications: Putting Innovation Into Practice
The goal of this study, funded by The University of Texas Clinical Safety and Effectiveness Grants Program, is to evaluate the effectiveness of operative checklists on compliance with evidence-based measures on two surgical services at a county hospital.
Factors Associated with Infectious Complications on ECMO
PI: Lally
This study is funded by the Extracorporeal Life Support Organization (ELSO). The goals of the study are to characterize infectious complications on ECMO, to determine the effect of infectious complications on mortality, and to survey ELSO centers on antibiotic prophylaxis measures for ECMO patients.
Using Wikis to Improve the Dissemination, Evaluation, and Application of Evidence-Based Medicine in Surgical Practice
Co-I: Tsao
This study is funded by The University of Texas Academy of Health Science Education Small Grants Program. The goal of the grant is to perform a pilot randomized trial of the effect of mandatory journal club wiki participation on surgical residents’ critical appraisal skills and skills in identifying and interpreting the evidence for surgical therapies.

Kevin P. Lally, MD

Chairman, Department of Pediatric Surgery
A.G. McNeese, Chair in Pediatric Surgery
Richard Andrassy Distinguished Professor

Necrotizing Enterocolitis Surgical Trial (NEST)
The NEST trial is a multi-center NIH-sponsored study through the Neonatal Research Network. This randomized, controlled trial is designed to determine the neurological status of patients at 18-22 months as the primary outcome after initial laparotomy or intraperitoneal drainage for infants (<1000 grams at birth) with NEC. In addition, the study also evaluates several secondary outcomes including surgical outcomes, nutritional status, grown and development, and biologic tissue studies. Infants are centrally randomized to immediate laparotomy or initial peritoneal drain. Pediatric surgeons have the option of a preference arm for those neonates thought to be only laparotomy candidates. The NEST trial is the largest neonatal surgical trial ever sponsored by the NIH.
Molecular Studies of Tracheal/Esophageal Anomalies and VACTERL (Vertebral, Anal, Cardiac, Tracheal, Esophageal, Renal and Limbs) Association
This study is created to provide a DNA and tissue bank repository devoted to the study of tracheal/esophageal anomalies and VACTERL association. Blood samples from children with tracheal/esophageal anomalies and/or VACTERL association and their parents will be collected and stored and later used to perform molecular studies to characterize the gene defects for these disorders. These samples will then be used to perform linkage studies and other molecular testing that will ultimately help in the identification of the gene responsible for these anomalies.
Molecular Studies in Congenital Diaphragmatic Hernias
Blood samples collected on children with Congenital Diaphragmatic Hernia (CDH) and their parents are collected at Children’s Memorial Hermann and Texas Children’s Hospital to be housed in a DNA and tissue bank repository devoted to the study of CDH. Material collected in these repositories is stored and used to perform molecular studies to identify and characterize chromosomal regions and specific genes that cause CDH. These samples are also used to perform linkage studies and other molecular testing that will ultimately help in the identification of the affected gene/genes.
Advancing Clinical Research in Pediatric Surgery: An Observational Study of Infants with Congenital Diaphragmatic Hernia
This is an international registry dedicated to the study of CDH, designed to prospectively review the outcome of all children with congenital diaphragmatic hernia.
Collection of Neuroblastoma Tissue, Bone Marrowand Blood Samples for Laboratory Correlates
Co-PI:Hayes-Jordan
Tumor samples are collected from one hundred children, ages 0-18 years, at MD Anderson Cancer Center and Children’s Memorial Hermann Hospital to establish the potential efficacy of EGF pathway inhibitors in the treatment of children with recurrent neuroblastoma, and provide further justification for their use in Phase I trials.

Yong Li, MD, PhD

Associate Professor
Children's Program in Regenerative Medicine

Children’s Regenerative Medicine
The project will use various cell sources combined with bioengineering scaffolds to build functional tissues for repair of pediatric defects, such as children’s diaphragmatic hernia
Dedifferentiation and Stem Cell Populations
The project aims to enlarge the stem cell pool without genetic modification as a cell source for regenerative medicine.
Adult Embryonic Potential Stem Cells and Application
Obtain natural embryonic potential stem cells from adult tissue for utilization in tissue engineering and regenerative medicine.
Fibrosis and Prevention Studies
Investigate the mechanism behind the fibrosis process after injuries and diseases, and seek methods for prevention of fibrous scar tissue formation

Michael Lypka, MD, DMD

Associate Professor
Pediatric Plastic and Craniofacial Surgery

Mandibular Distraction
Pierre Robin Sequence is the triad of micrognathia, glossoptosis, and airway obstruction. It has many treatment options. Mandibular distraction is a newer method of treatment that has been found to be very effective in selected cases. The effect of this treatment has not been investigated long term. It is the goal to follow patients over a long period to determine if any deleterious effects exist.

Stacey Moore-Olufemi, MD

Assistant Professor
Division of General and Thoracic Pediatric Surgery

Clinical Research

Gastroschisis: A Prospective Cohort Outcome Study
This is a prospective study to examine the outcomes of all children with gastroschisis at Children’s’ Memorial Hermann Hospital. Specific outcomes that will be evaluated will include length of stay, time until feedings are tolerated, need for additional surgery, and development of complications such as NEC or central line infections.
Creation of Multicenter Database and Analysis of Outcomes in Neonatal Abdominal Wall Defects
This is a multi-center institutional retrospective study to examine the outcomes of children with abdominal wall defects.
STEP Registry
This is a prospective study to examine the outcomes of children with intestinal failure undergoing a Serial Transverse Enteroplasty (STEP) procedure.
Evaluation of Children's Memorial Hermann Hospital Intestinal Failure Program
This is a prospective study to examine the outcomes of all children with intestinal failure at Children’s’ Memorial Hermann Hospital. Specific outcomes that will be evaluated will include length of stay, effect of multidisciplinary management, liver disease, central line care and nutritional strategies.

Translational Research

Gene Expression & Methylation Profiling in Pediatric Intestinal Failure
This is a retrospective study to examine the patterns of genes expressed in the intestine of children with intestinal failure undergoing surgical procedures at Children’s’ Memorial Hermann Hospital. This study will attempt to identify the differential expression of genes in normal versus diseased intestine, so a potential animal model can be developed to evaluate mechanisms contributing to intestinal failure/short gut syndrome.
Genetic Determinants of Gastroschisis-Related Intestinal Dysfunction: Developmental Intestinal Smooth Muscle Phenotypic Plasticity
This is a prospective study to examine the functional genomics of the intestinal smooth muscle in gastroschisis infants.

Basic Research

Molecular Pathophysiology of Gastroschisis-Related Intestinal Dysfunction (GRID)
This a basic science project using a combination of animal models and cell culture to examine the physiological, functional, biomechanical and molecular mechanisms of GRID.

Scott Olson, PhD

Assistant Professor
Program in Regenerative Medicine

Mesenchymal stem cells in cellular therapies to immunomodulate and restore homeostasis
Mesenchymal stem cells (MSCs) have been used in a large number of clinical trials to treat a wide variety of diseases and injuries with some success. When viewed as a whole, MSC have been most efficacious when used in a situation where there is a secondary or chronic injury associated with prolonged or exaggerated inflammation, perhaps due to their impressive ability to control the activation of the immune system systemically and in local microenvironments. We hypothesize that as we better understand the mechanisms by which MSC can exert their effects, we can begin to rethink and redesign cellular therapies to amplify their efficacy while increasing their safety.
Comparing MSC preparations
As part of our global effort to identify the best candidate for cellular therapies, we are working with a number of similar but different MSC and MSC-like cells derived from different tissues and even commercial sources. Our group has been designing and executing a number of assays designed to explore what biomarkers or in vitro assays we might be able to use to predict therapeutic efficiency in paired in vivo studies in collaboration with Drs. Triolo and Cox. These studies are initially focusing upon efficacy in models of Traumatic Brain Injury, but will expand later into other diseases and injuries with significant inflammatory elements.
MSC-effector cell interactions
Additionally, we are focusing upon MSC interactions with specific immune cell populations derived from both circulating peripheral blood mononuclear cells and leukocytes that reside in the spleen. We are particularly interested in the ability of MSC to influence monocyte and macrophage phenotype, and the resulting change in their secretome that may blunt inflammation or even restore system-wide homeostasis.
Mixed cell preparations as a therapeutic
A large part of the therapeutic value of MSC therapies relies upon the interactions that MSC have with the host immune system. To this end, we aim to augment the efficacy of MSC by introducing them directly to effector cells ex vivo and then shielding the resulting cells from immune recognition that may lead to rejection. In this manner, we hypothesize that we can create a systemic-style response inside an implantable construct that can be placed in the vulnerable microenvironment using a selectively permeable, non-toxic scaffold.

David Sandberg, MD

Associate Professor and Chief
Division of Pediatric Neurosurgery

Research Interests and Medical Missions
Dr. Sandberg's major research interests focus on novel means of delivering therapeutic agents into the brain for the treatment of childhood brain tumors. He has developed translational research models in piglets and primates and is currently initiating a Phase I clinical trial based upon these research efforts. He has been principal investigator of studies funded by the Woman's Cancer Association of the University of Miami, Miami Children's Hospital Foundation and the Emily Dorfman Foundation, and has served on medical missions to Guatemala, Honduras, Peru, Uganda and Haiti. He is a member of the Board of Directors of the Foundation for International Education in Neurological Surgery (FIENS).

Nitin Tandon, MD

Associate Professor in the Department of Pediatric Surgery
Associate Professor, The Vivian L. Smith Department of Neurosurgery

Brain mapping with functional MRI, electrical stimulation and diffusion tractography
Intra-cranial electrophysiology

Fabio Triolo, PhD

Assistant Professor

Director, cGMP Facilities
Program in Regenerative Medicine

Research Interests and Medical Missions
Dr. Triolo, an expert in clinical cell therapy manufacturing for regenerative medicine applications, directs the Judith R. Hoffberger Cellular Therapeutics Laboratory and the Evelyn H. Griffin Stem Cell Therapeutics Research Laboratory within the Program of Regenerative Medicine. The Hoffberger laboratory is focused on translating, scaling-up, validating and supporting IND applications (CMC section) of promising new therapeutic technologies developed by scientists and physicians at a preclinical level into clinical-grade processes that can be used to manufacture cell-based and/or tissue engineered products for clinical applications. The Griffin Laboratory is an FDA-registered facility where tissues and organs are processed to produce cells for clinical applications in compliance with current Good Manufacturing Practice (cGMP).

Stem Cell and Regenerative Medicine Applications in Neurological Injury
Despite dramatic advancements in medical and surgical care, effective clinical therapies for neurological injury are limited. The past decade’s rapid advancement in stem cell biology and neurology has generated a growing body of literature supporting the use of various progenitor cell types to treat acute neurological injuries. In this context, we are actively involved in several research endeavors of the Program of Regenerative Medicine. These include the development of innovative human adult and fetal cell-based therapies to improve neurological conditions, such as anoxic brain injury at birth, cerebral palsy, traumatic brain injury and stroke, all of which are still unmet medical needs that have not been able to be satisfied by conventional healthcare therapies.

• Amniotic Fluid Derived MSCs for Neurological Injury (In collaboration with Drs. Charles Cox and Scott Olson). We have developed a xeno-free method to isolate, expand and cryopreserve clinical-grade human amniotic fluid-derived mesenchymal stromal cells (hAFMSCs) in compliance with cGMP and we are investigating their potential use to treat neurological injury associated with prenatally diagnosed congenital heart disease of infants. This fetal tissue engineering approach is currently being tested in a pre-clinical model with the ultimate goal of using the 15-20 week window between amniotic fluid harvest and birth, to isolate and expand hAFMSCs to treat the affected infant on a predetermined date just prior to, or after birth.

• Development of an Efficient and Safe Cryopreservation Method for the Storage of Clinical-Grade Wharton’s jelly (in collaboration with Dr. Charles Cox). This project aims at investigating the cryopreservation of human MSC-containing Wharton’s jelly for its use in regenerative medicine applications, using xeno-free and serum-free conditions.

• Treatment of Severe Adult Traumatic Brain Injury Using Autologous Bone Marrow Mononuclear Cells (in collaboration with Dr. Charles Cox). This Phase I dose-escalation study is aimed at evaluating the safety of acute, intravenous, autologous bone marrow-derived mononuclear cells to treat severe Traumatic Brain Injury in adults.

• Phase II Trial of Pediatric Autologous Bone Marrow Mononuclear Cells for Severe Traumatic Brain Injury (in collaboration with Dr. Charles Cox). Following the first acute, autologous cell therapy treatment Phase I study for traumatic brain injury in children, successfully completed within the Program of Regenerative Medicine, this study is aimed at evaluating whether bone marrow-derived cells preserve injured brain tissue after traumatic injury in children, and if so, whether such preservation is associated with improvement in functional and cognitive outcomes.

• Autologous Cell Therapies for Cerebral Palsy-Chronic (in collaboration with Dr. Charles Cox and Cord Blood Registry). This is a randomized, blinded, placebo-controlled, cross-over Phase II study designed to compare the effects of autologous bone marrow-derived versus autologous umbilical cord blood-derived mononuclear cells on pediatric patients with cerebral palsy, a group of brain pathologies that result from in utero or perinatal injury to the developing brain, often through stroke, hypoxic insult or hemorrhage and which produce chronic motor disability in children.

• Double-Blind, Randomized, Placebo-Controlled Phase 2 Safety and Efficacy Trial of MultiStem in Adults With Ischemic Stroke (In collaboration with Dr. Sean Savitz and Athersys, Inc.). This study is aimed at evaluating the safety and potential effectiveness of the adult stem cell investigational product, MultiStem, in adults who have suffered an ischemic stroke.

KuoJen Tsao, MD

Associate Professor
Division of General and Thoracic Pediatric Surgery

Errors and Adverse events in the setting of the Neonatal Surgery performed in the Neonatal Intensive Care Unit
Operations and procedures are commonly performed in the NICU. However, this is often performed in suboptimal conditions. Errors, adverse events, and good catches in this operative environement is unknown. This NIH-funded observational study will determine the types and incidence of errors and adverse events associated with neonatal surgery performed in the neonatal intensive care unit.
Operative team compliance with Preoperative Checklist and Antibiotic Administration: A quality Improvement Project & Assessment of the Implementation of a Pediatric Surgical Preoperative Checklist
Peri-operative checklists are mandated by many hospitals based on the reduction in morbidity and mortality seen with utilization of the World Health Organization’s (WHO) “Surgical Safety Checklist.” Although an adapted peri-operative checklist was implemented within our hospital system without formal system-wide training, compliance with the checklist is reported to be 100%. However the clinical practice is not consistent with the reported compliance.
Recognition of the deficiency in the current checklist process has developed into a hospital-wide initiative to develop a pediatric-specific, meaningful checklist that incorporates and addresses key issues in caring for pediatric surgical patients. This prospective observational study, evaluates the completion of the 12 pre-incision components of the WHO surgical checklist during the 6 month post-implementation period.
Analysis of Compliance with SCIP-Based Antibiotic Prophylaxis.
The Surgical Care Improvement Project (SCIP) recommends appropriate spectrum and timing of antibiotic prophylaxis to prevent surgical site infections (SSIs). However, emerging data has demonstrated that despite increased compliance, SSIs are not decreasing. Furthermore, there is an all-or-none phenomenon associated with SCIP infection guidelines. Despite the routine administration of antibiotic prophylaxis in pediatric surgical operations, adherence with appropriate evidence-based practice may not occur in every case. This observational study is designed to evaluate the adherence and compliance of SCIP-based surgical antibiotic prophylaxis.
Hospital Quality Reporting Does Not Accurately Measure Hospital Quality.
Surgical site infections (SSI) are utilized as a measure of hospital quality. Typically, hospital infection control programs assign surgical wound classification (SWC) based on data from the medical record. This SWC is frequently recorded by the operating room support staff and may not be confirmed by the operative surgeon. The hospital assigned SWC is used to risk-stratify operations for the likelihood of SSI development. The purpose of this study was to assess the accuracy of hospital-documented compared to surgeon-based SWC in pediatric appendectomies, considered to be the correct classification in a multi-center study.
Timing of Inguinal Hernia Repair in Premature Infants: A Randomized Trial
The impact of the timing of inguinal hernia (IH) repair on the overall incidence of adverse events in premature infants who have an IH diagnosed while in the neonatal intensive care unit (NICU) is unknown. Due to the lack of evidence related to the impact of timing of this surgical treatment, we aim to complete a pilot multi-center randomized clinical trial (RCT) with a limited enrollment period to assess the feasibility of a subsequent definitive trial. This study evaluates the impact of the timing of inguinal hernia repair on the overall incidence of adverse events in premature infants who have an inguinal hernia diagnosed while in the Neonatal Intensive Care Unit.
Improvements in patient safety culture in a pediatric perioperative environment requires a multi-faceted approach
Given increased healthcare costs and concerns about patient safety, the Institute of Medicine (IOM) issued two landmark reports that explained to the healthcare community the importance of examining the role of organizational factors on healthcare quality and patient safety outcomes (HQPSO). To Err is Human focused on the importance of patient safety culture and Crossing the Quality Chasm discussed ways in which organizations can best support and engage employees to provide safe and high-quality care. The IOM argued that these organizational factors should be important in predicting HQPSO in healthcare settings because these factors are vital in predicting outcomes in other high-risk industries (i.e., aviation, nuclear power). The first of these organizational factors - patient safety culture - refers to “the product of individual and group values, attitudes, perceptions, competencies, and patterns of behavior that determine the commitment to, and the style and proficiency of, an organization's health and safety management.”1

The safety culture concept, exhibited by high reliability organizations (HROs) and adopted by healthcare, minimizes adverse events in complex and hazardous setting. To improve a sustainable patient safety culture, we instituted a multi-faceted safety program, patterned after HROs and designed specifically for the pediatric perioperative environment (micro-system). This study evaluates the impact of this program on safety culture in a pediatric perioperative environment.

Karen L. Uray, PhD

Assistant Professor
Division of General and Thoracic Pediatric Surgery

Mechanism of resuscitation-induced ileus: disregulation of MLC phosphorylation.
Intestinal edema development in trauma patients causes decreased intestinal motility, a significant complication leading to delayed enteral feeds, increased septic complications, prolonged hospital stays and a major economic burden. Intestinal edema dramatically impairs intestinal contractility via decreased smooth muscle myosin light chain (MLC) phosphorylation. Preliminary data suggest that while MLCK is unchanged, MLC phosphatase activity is increased in edematous intestinal smooth muscle. Understanding the mechanism by which edema alters the regulation of MLC phosphatase activity is essential in understanding how edema causes intestinal contractile dysfunction in trauma patients. The objective of this study is to understand the molecular mechanisms by which edema alters the regulation of MLC phosphatase. The central hypothesis is that intestinal edema inhibits MLC phosphorylation by abrogating the constitutive inhibition of MLC phosphatase.
Role of NF-kappaB in edema-induced intestinal dysfunction.
Preliminary data suggest that edema induces decreased inhibition of MLC phosphatase resulting in decreased MLC phosphorylation. NF-kappaB activity is significantly upregulated with edema formation and inhibition of NF-κB attenuates edema-induced decreases in MLC phosphorylation and consequently, preserves contractile activity in edematous intestine. We hypothesize that NF-κB activation induces decreased MYPT1 phosphorylation in edematous intestinal smooth muscle. We propose in our model, supported by preliminary data, that in the edematous intestinal smooth muscle, NF-κB induces increased Rnd1 expression which inhibits Rho kinase mediated (inhibitory) phosphorylation of MYPT1 resulting in more MLC phosphatase activity and, thus, decreased MLC phosphorylation.

Pamela Wenzel, PhD

Assistant Professor
Regenerative Medicine

In an effort to identify new ways of improving cellular therapies available for the treatment of pediatric hematopoietic disorders, injuries, and cancers, we pursue two major research areas in the lab. Each are designed to define the role of biomechanical force as a regulator of cellular potential and function, and emphasize the impact of frictional force (shear stress) and stretching (circumferential strain) on genetic programs that determine stem cell specification and self-renewal: (1) in the embryonic blood system and from embryonic stem cells; (2) in adult cells, including mesenchymal stem cells, endothelial cells, cancer cells, and other types of progenitor cells present in the hematopoietic and vascular niches.

Induction of Hematopoiesis
In the developing embryo, initiation of the heartbeat causes blood to circulate through the vasculature and subjects vessel walls to hemodynamic forces, including friction, pressure, and stretching. Recently, we have found that the frictional force (shear stress) created by fluid flow is a powerful, and even necessary, signal for emergence of hematopoietic stem cells and progenitors during embryonic development.
Our current research is designed to address how biomechanical force activates the hematopoietic program and how we might use this information in the laboratory to expand improved sources of hematopoietic cells that can be used for patients in the clinic. A number of candidate genetic and biochemical pathways are currently under investigation as key players mediating this signaling cascade, and we employ various approaches to evaluate their role in blood development, including biomechanics, microfluidics, pharmacology, embryonic stem cell modeling, mouse genetics, and transplantation assays.
Stromal Biology and Regenerative Medicine
Biomechanical force is present throughout the body and impacts a wide array of tissues and cell types. We now know that blood development is intimately linked to the physical forces present in the hematopoietic niche, but these are not the only types of cells sensitive to the unique signaling cascades of mechanical stress. Endothelial cells that line blood vessels are renowned for their sensitivity to fluid shear stress within the vasculature and adapt to changes in blood flow by modification of morphology, gene expression programs, and release of paracrine and endocrine signaling molecules that impact progression of cardiovascular disease and inflammation.
Shear stress also modulates behavioral response of mesenchymal stem cells and other cells of the stroma, and the intensity of mechanical stimulation is known to impact cell cycle (proliferation), anti-apoptotic signaling (survival), and differentiation (fate decisions) of these cells. Our research aims to evaluate the effects of biomechanical force on a number of biological processes, including innate immune response, inflammatory signaling, cellular adhesion, and metastasis. Experiments are designed to utilize culture-based assays, cellular phenotyping, and mesenchymal stem cell-based therapy models of stroke and traumatic brain injury as readouts of response to mechanical stimuli.
Scientific Approaches
Projects rely upon in vitro methodologies for the exposure of stem cells to shear stress and cyclic strain, and we pair this approach with in vivo functional analyses in animal models of blood development and neurological injury. Experiments often require a combination of classical cell and molecular biology techniques, fluorescence activated cell sorting, chemical and mechanical engineering, small molecule screens, large-scale gene expression analysis, and modeling in animal subjects.
More on Wenzel lab studies