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Developmental vascular biology
Understanding how blood vessels form — and what happens when that process goes awry — could lead us to better tools to help kids with vascular conditions such as hemangiomas and solid tumors.
What is developmental vascular biology research?
The developmental vascular biology program, led by Ramani Ramchandran, PhD, investigates the basic mechanisms of blood vessel formation in vertebrates and how those vessels contribute to diseases. Our researchers study developing zebrafish and mouse embryos to gain insights into vascular conditions associated with children, such as hemangiomas and solid tumors.
We study cells called angioblasts, which eventually differentiate into arteries or veins. The basic mechanisms of this process often are deregulated in disease, so better understanding vessel formation is critical to generating new treatments for conditions affected by deregulated vessel growth.
During development, blood vessels adapt to the specific needs of the organ they supply. For example, in the lungs, the vasculature becomes highly specialized to provide efficient gas-exchange by participating with alveoli. Development of lung alveoli requires complex interactions among blood vessels, other specialized cells and the extracellular matrix. Defects in any one of these elements will adversely affect alveolar development and can lead to conditions such as emphysema and infant bronchopulmonary dysplasia.
In addition to studying blood vessel formation, our researchers are also developing tools for performing drug screens using zebrafish embryos, which will identify targets and potential drug leads for treating pediatric vascular conditions.
Ramani Ramchandran, PhD, professor of pediatrics
Vice chair for Research, Department of Obstetrics and Gynecology (MCW)
Patrick J. and Margaret G. McMahon Professor in Obstetrics and Gynecology (MCW)
The Developmental Vascular Biology Program, under the directorship of Dr. Ramchandran, is home to graduate students, post-doctoral fellows, undergraduate students and faculty. Dr. Ramchandran began his research career at the Georgia Health Sciences University (formerly called Medical College of Georgia) in Dr. Dorothy Tuan's laboratory in 1992 where he studied the transcriptional mechanisms controlling hematopoiesis. He then joined Dr. Vikas Sukhatme's laboratory in 1997 as a post-doctoral fellow at Beth Israel Deaconess Medical Center, Harvard Medical School. In Dr. Sukhatme's laboratory he studied the role of basement membrane proteins in endothelial cell growth and the implications of this process for tumor growth. His work at Harvard primarily focused on understanding the mechanisms of angiogenesis, the growth of new blood vessels from pre-existing vessels, and how this process affects tumor growth. In 2002, he was recruited to the NIH on receipt of the National Cancer Institute Scholar Award, and established his first independent research program studying the developmental mechanisms of vascular biology. In 2007, he was recruited to the Children's Research Institute at the Medical College of Wisconsin where he currently serves on the faculty as a professor in the Department of Pediatrics. At CRI, Dr. Ramchandran made a serendipitous discovery that led to the identification of mutations in two genes sucrose non-fermenting related kinase-1 (snrk-1) and dual specific phosphatase-5 (dusp-5) in patients with vascular anomalies. Since then his research has focused on the role of these genes in both normal and abnormal vascular development process in disease. He has also established a robust drug discovery program that is geared towards identifying small molecules targeting critical gene products responsible for diseases affected by deregulated vascular growth.
I support the Developmental Vascular Biology Program in terms of its day-to-day academic activities, and manage most of the logistics associated with these activities for Dr. Ramchandran, post doctoral fellows and technicians in his lab. Some of my administrative duties include coordinating grant submissions in eBridge, travel arrangements and reimbursement, CVs, budgets, scheduling meetings and human resource matters. In addition, I order supplies, equipment and instruments for the lab as needed.
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Ramchandran labTamjid Chowdhury, PhD, Post-doctoral Fellow in Obstetrics and Gynecology
I have a long-standing interest in RNA biology, and more recently in long non-coding RNAs (lncRNAs) as it relates to vascular development. In 2010, our lab identified lncRNAs from the Tyrosine kinase containing Immunoglobulin and Epidermal growth factor homology-1(tie1) locus in zebrafish, humans and mice. These lncRNAs are transcribed in the opposite orientation to the protein coding transcript (mRNAs) that originate from the tie1 locus. Thus, they are referred to as tie1 anti-sense (tie1AS) lncRNAs. Our lab further showed that one of the three TIE1AS lncRNAs identified in humans and one of the two tie1AS lncRNAs identified in zebrafish can regulate tie1/TIE1 mRNA levels. My project is focused on identifying the mechanism used by the tie1AS/TIE1AS lncRNA to regulate tie1/TIE1 mRNA. In a recent publication, we showed that tie1AS interacts with a well-known RNA binding protein called Embryonic lethal and abnormal vision Drosophila-like1 (Elavl1). This interaction takes place only in the head at a very specific time. Disturbing the interaction between tie1AS and Elavl1 using several complementary approaches showed that the interaction between tie1AS and Elavl1 is responsible for downregulating tie1 mRNA levels in a temporal and spatial manner, and is consequential in terms of patterning the head vasculature. I am currently focused on characterizing the human TIE1AS interaction with Elavl1 ortholog HuR in human endothelial cells, and studying the functional relevance of this interaction.
Dr. Shahram Eisa-Beygi, PhD, Kelleigh Gustafson Research Fellow in Radiology
I am a developmental biologist with long-term interest in studying embryonic processes in zebrafish development, and utilizing zebrafish as a model for human disease. I am interested in identifying the mechanisms of neuro-vascular development, with focus on the etiology of cerebral aneurysms, hemorrhagic strokes as well as vascular malformations of the brain, such as arteriovenous malformations (AVMs) and cerebral cavernous malformations (CMMs). Specifically, I am interested in elucidating the mechanisms of nascent blood vessel remodeling in response to mechanical cues. A thorough understanding of neurovascular development may help us design diagnostic tools and even identify potential therapeutic targets for CNS vascular malformations that present with high risk of hemorrhage.
Karthikeyan Thirugnanam, PhD, Postdoctoral Fellow in Pediatrics
I am a biochemist who is interested in studying in signal transduction networks in cellular systems. One of the major focus in the laboratory is to understand the role of endothelial serine threonine protein kinase called sucrose nonfermenting related kinase (SNRK), a member of the AMP-activated protein kinase (AMPK) family. I work with team members to investigate the influence of SNRK in the cardiovascular system. I am particularly interested in investigating the association of SNRK with redox stress. I hypothesize that SNRK’s role in the overall metabolism of cardiovascular system will help realize its potential as a therapeutic target for conditions associated with the cardiovascular system. In addition, I work closely with other team members to explore the role of non-coding RNAs in vascular biology, especially the lncRNA in delta-like 4 (DLL4) locus.
Ankan Gupta, PhD, Postdoctoral Fellow in Pediatrics
I am an immunologist by training, and have a long-standing interest in investigating the role of immune system in various process including vascular development. Our lab previously reported identification of a mutation in dual specificity phosphatase 5 (DUSP5) in patients with vascular anomalies. Recently, we showed that during acute viral infection, DUSP5 is essential for survival of T cells. My current research is focused on understanding the role of DUSP5 as a regulator of inflammation. In addition to dephosphorylating nuclear pERK; DUSP5 is also reported to have non-canonical activities like promoting cytoplasmic phosphorylation of ERK and regulating NFκβ. My research focuses on targeting DUSP5 therapeutically, to control autoimmunity as well as chronic infection in experimental animal models. I also work with team members to investigate the role of non-coding RNA in the delta-like 4 locus (DLL4) and its implication in vascular biology.
Jeremy Larson, MS, Research Associate I in Pediatrics
I am a developmental molecular toxicologist by training and have extensive experience in zebrafish research in the context of gene-environment interactions. The objective of my research is to exploit molecular and imaging techniques to define the role of a sucrose non-fermenting related kinase (SNRK) in vascular development using embryonic zebrafish. Overall, my goal is to apply my zebrafish expertise toward the development of SNRK as a target for conditions afflicting children. I also provide support in the zebrafish facilities in the Children’s Research Institute and MACC Fund Research Center, and collaboratively with others in the program in achieving their research goals.
Shubhangi Prabhudesai, PhD, Lab Manager
I am a neurobiologist by training, and recently identified a role for cystathionine-beta-synthase (cbsb) enzyme, an enzyme critical for hydrogen sulfide synthesis in zebrafish embryonic development. Using several approaches, we published a recent paper that showed cbsb is critical for axis development in zebrafish embryo. In addition to research, I bring an interdisciplinary set of skills to the program, which includes zebrafish research and knowledge of neurosciences to the program. I also manage the program’s day-to-day needs and supervise our zebrafish-facilities in Children’s Research Institute and MACC Fund Research Center. Finally, I collaborate with investigators both outside of MCW, and with program personnel on projects that are critical to the mission of the Developmental Vascular Biology program.
Emily Gronseth, graduate student
I am a graduate student in training, and focused on studying pediatric brain tumors, specifically medulloblastoma. My research thesis project focuses on metastasis of medulloblastoma to extraneural locations. Based on past publications in the lab, which showed astrocyte glial cells are responsible for breast cancer metastasis, we hypothesized that medulloblastoma tumor cells will be influenced by astrocytes. For my graduate work, I am working on the interaction between medulloblastoma tumors and astrocytes. I am currently investigating the underlying mechanism(s) that cause astrocytes to induce medulloblastoma tumor cell invasion using in vitro techniques and an in vivo zebrafish xenotransplant model.
Erin Bishop, MD, assistant professor
I am a physician-scientist in-training in the Department of OBGYN and work closely with Dr. Ramchandran on investigating the underlying mechanisms influencing ovarian cancer metastasis. Our lab focuses on a serine threonine protein kinase called sucrose nonfermenting related kinase (SNRK), and its role in development and disease. The goal of my research is to investigate the role of SNRK in ovarian cancer metastasis. In a recent publication, we showed that SNRK is differentially expressed in primary vs. metastatic ovarian cancer sites. Thus, we hypothesize that SNRK has specific functions that are distinct at the primary versus metastatic tumor sites, and this function is dependent on SNRK’s influence on the surrounding tumor microenvironment. As a gynecologic oncologist, I take care of patients who have gynecologic malignancies including ovarian cancer, and plan to continue to combine my basic science experience and my clinical knowledge to work towards developing better treatments for gynecologic cancers.
Andrew D. Spearman, MD, Instructor of Pediatrics
As a pediatric cardiologist, and physician-scientist in training, I am interested in using the tools of molecular biology to better understand the pathophysiology and sequelae of congenital heart disease (CHD). Specifically, my current research focuses on the development of pulmonary arteriovenous malformations (PAVMs) in children with complex CHD who undergo a bidirectional Glenn surgical palliation. We are characterizing the molecular and phenotypic effects of the un-identified “hepatic factor” on pulmonary endothelial cells. Based on recent publications in the lab, we have identified a role for a serine threonine protein kinase called sucrose nonfermenting related kinase (SNRK) in dilated cardiomyopathy. Therefore, based on my cardiovascular biology interest, as a second project, I am investigating the underlying mechanisms controlled by SNRK in stress-induced cardiomyopathy condition.
Page updated 7/27/2018