Seed Grants 2013

Mechanisms leading to osteoporosis in patients with lysosomal dysfunction due to genetic alterations in osteoblast and osteoclast glucocerebrosidase

Ricardo A. Feldman (UMB School of Medicine, Department of Microbiology and Immunology) and Norma W. Andrews (UMCP Department of Cell Biology and Molecular Genetics)

Gaucher disease (GD), the most frequent lipid storage disorder is caused by mutations in the glucocerebrosidase gene. Patients afflicted by GD develop severe osteoporosis, but the mechanisms involved are unknown. In order to find new therapies for GD and for osteoporosis in general, it is necessary to have a supply of patients' cells so we can develop the proper drug screening tools. Dr. Ricardo Feldman's laboratory is using a new stem cell technology to derive unlimited quantities of the cells responsible for bone formation (osteoblasts) and bone resorption (osteoclasts). This is done by reprogramming of cells obtained from skin biopsies of patients and healthy subjects, into osteoblasts and osteoclasts. We found that patient-derived osteoblast precursors have developmental and functional abnormalities that interfere with their maturation to fully functional bone-forming cells. In this project, we will use state-of-the-art reagents and technologies developed in Dr. Norma Andrews' laboratory to elucidate the mechanisms by which mutations in the glucocerebrosidase gene in bone-forming and bone-resorbing cells leads to bone fragility. Importantly, this system provides a novel platform to screen for drugs that can reverse osteoporosis in patients with GD. Successful new treatments for GD may be applicable to more common cases of osteoporosis as well.

A robotic grasping and vision (GraspVis) system for stroke rehabilitation

Kelly Westlake (UMB Department of Physical Therapy and Rehabilitation Science), Jaydev P. Desai (UMCP Department of Mechanical Engineering), and Cornelia Fermuller (UMCP, University of Maryland Institute for Advanced Computer Studies)

Stroke is the leading cause of long-term neurological disability and number one reason for seeking rehabilitative services in the US. Of the 2.5 million stroke survivors, impaired hand function is one of the most frequently persistent consequences of stroke. While the importance of rehabilitation to help restore hand function through adaptive neuromotor mechanisms is well recognized, most therapies aimed at specifically reversing motor impairments fall short. Key principles of motor learning and associated brain plasticity support repetitive, task-specific practice to reduce impairment and restore function. The challenge is to translate these principles to clinical practice and to transfer skills learned in the clinic to real world activities. To this end, we propose to develop a camera-assisted, portable, robotic exoskeleton with a custom-designed glove and active assisted hand flexion and extension capability (GraspVis) to assist and improve affected hand function in subjects with stroke. The unique training and assistive system proposed will modulate the amount of force needed for grasping based on the user force feedback and represents the first lightweight, portable device to allow multi-joint motion of the hand.

The role of early brain circuits in autism

Bruce K. Krueger (UMB School of Medicine) and Patrick O. Kanold (UMCP Department of Biology, College of Mathematics and Natural Sciences)

Autism is a neurodevelopmental disorder characterized by abnormal communication and social interactions as well as stereotyped, repetitive behaviors. Although the symptoms become evident in late infancy, considerable evidence suggests that errors in brain development during early pregnancy cause autism. During the first trimester, the first neurons of the cerebral cortex and hippocampus are generated and form primitive neural circuits that are transformed into the complex circuitry of the mature brain. Errors in these developmental processes are postulated to cause autism. The incidence of autism is 10-fold higher when the mother takes the anti-epileptic and mood-elevating drug, valproic acid (VPA), during early pregnancy. Similarly, when VPA is administered to pregnant mice, their offspring develop autistic-like symptoms; consequently, fetal VPA exposure is a widely-used animal model for the disorder. In our research, we will examine effects of VPA on the production, migration and survival of newly-generated neurons in the fetal mouse cortex and hippocampus (Krueger), as well as the formation and function of early cortical circuits comprising these neurons (Kanold). We will test the hypothesis that VPA-induced errors in the production of cortical neurons and their incorporation into functional neuronal circuits during fetal development cause autistic behavior. Our research will provide a clearer understanding of the causes of autism and may lead to improved strategies for its prevention.

Ambient air pollution and metabolic syndrome in the Lancaster County Amish

Braxton Mitchell (UMB School of Medicine, Epidemiology and Public Health) and Robin Puett (UMCP School of Public Health, Maryland Institute for Applied Environmental Health)

Though medical history and lifestyle are important risk factors for cardiometabolic diseases, it is also clear that environmental exposures, such as air pollution, also contribute to the development and exacerbation of cardiovascular and metabolic disease. The overall goal of this pilot project is to determine if the health effects of ambient air pollution are enhanced in the presence of known diabetes susceptibility gene variants. The study brings together investigators with expertise in air pollution exposure modeling, and environmental, cardiovascular and genetic epidemiology to assess the effects of air pollution on cardiovascular and metabolic risk factors among the Amish community in Lancaster County, PA.

Touch-free manipulation of live cancer cells to observe their tumor-formation and drug response behavior

Stuart Martin (UMB School of Medicine, Greenebaum NCI Cancer Center) and Benjamin Shapiro (UMCP Fischell Department of Bioengineering)

Cancer spreads when cells detach from a primary tumor, enter the blood stream, circulate, and then reattach in distant locations in the body to form new tumors. The process by which circulating tumor cells grab blood vessel walls, crawl out, and form new tumors is thought to involve micro-tentacles. Till now, it has been difficult to study micro-tentacles -- cells are usually placed on a microscope slide for imaging, and doing so makes the microtentacles retract. In this project, the school of engineering is teaming up with the medical school to study microtentacles on cancer cells using a novel technology. Instead of putting cells on slides, live cells are kept in place for imaging by flow control -- whenever a cell starts to drift out of view, the media surrounding the cell is flowed in the opposite direction to keep the cell in view, and under observation. This feedback control will be used to monitor single cells, and to observe their micro-tentacles as cells grasp surfaces, each other, with and without the presence of cancer drugs. The end goal is to understand which drugs can be used to combat microtentacles, and thus the ability of cancers to spread throughout the body.

Development of a novel animal model for human preeclampsia

Loren Thompson (UMB School of Medicine, Departments of Obstetrics, Gynecology & Reproductive Sciences and Physiology) and Bhanu Telugu (UMCP Department of Animal Science)

Preeclampsia (PE) is a pregnancy-specific syndrome characterized by high maternal blood pressure, protein spillage into the urine, and in severe cases leading to maternal and infant illness or death. A primary cause is inadequate invasion of placenta-derived trophoblast cells into the uterine wall and arteries during placental development. Oxygen (O2) tension plays a critical role in the maturation and migration of trophoblast cells, however the role of O2 in the development of pregnancy disorders including PE is poorly understood. This study aims at developing the pregnant guinea pig (GP) as an animal model of PE and to understand the role of O2 in the mechanisms of trophoblast migration and invasion. GPs were chosen because; unlike other rodent models, GPs exhibit placental morphology and degree of placental invasion similar to that of humans. Pregnant GPs will be exposed to either normoxia or hypoxia (varying severity and duration) during gestational ages critical for placental development. Trophoblast cell migration and invasion will be measured using a Matrigel™ invasion chamber and a dual-cell (trophoblast-endothelial cell) culture assay, respectively. Cardiovascular parameters and placental pathology of the GP will be assessed for characteristics of the preeclamptic syndrome. This study will provide a unique opportunity for understanding the role of hypoxia-sensitive pathways in O2-regulated trophoblast invasion. By targeting causal mechanisms, this may identify new predictive biomarkers and/or advance therapeutic approaches, currently limited to delivery or risk of premature birth.

Maternal-infant immunization for protection against B. Pertussis

Marcela Pasetti (UMB School of Medicine, Center for Vaccine Development, Department of Pediatrics) and Xiaoping Zhu (UMCP Department of Veterinary Medicine)

Whole cell and acellular vaccines have been used prophylactically to prevent Bordetella pertussis infection (or whooping cough) through childhood vaccination. The acellular pertussis vaccine, introduced as a safer alternative to the reactogenic whole cell vaccine, has been part of the routine pediatric immunization schedule as a component of the Diphtheria-Tetanus vaccine (DTaP) for over two decades. Despite widespread vaccination, the disease has emerged in recent years, affecting primarily young infants who have not yet completed their vaccination series. In a collaborative study, Dr. Marcela F. Pasetti and Dr. Xiaoping Zhu from University of Maryland Baltimore and College Park, will investigate the mucosal immune responses induced by B. pertussis vaccines, their contribution to protection and the immunological mechanisms involved, using a mouse model of neonatal/maternal immunization. They will examine the role of mucosal IgG in vaccinated infants and the protection afforded by vaccine-induced maternal IgG antibodies transferred to the newborns through the placenta and milk, testing the hypothesis of IgG transport through the Fc neonatal receptor (FcRn). Understanding the mechanisms and immunological effectors involved in protection against B. pertussis will inform the development of new vaccine candidates. The knowledge generated could be also applicable to other pediatric infections that affect infants during the first year of life.