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.
Kathy Thorpe, administrative assistant
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 serve as an Evacuation Marshall, and am in the process of earning my CERT and CRP certifications.
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Michelle Bordas, research technologist
I am interested in all aspects of animal care and research. My role in the lab is to maintain our mice colony. I maintain the colony in accordance with the guidelines and regulations for animal care use in research. Through my effort and those of other lab members, we are able to complete many valuable research projects while upholding the standards of best possible animal care. Together we are committed to the humane and appropriate use of animals for research.
Stephanie Cossette, PhD, post-doctoral fellow
My research focuses understanding the role of sucrose non-fermenting related kinase 1 (SNRK1) during embryonic development. SNRK1 is involved in the metabolism-sensing pathway and is regulated by liver kinase B1 (LKB1), which is a tumor suppressor that is also associated with the Peutz-Jeghers syndrome. By using the mammalian system to systematically remove SNRK1 from various types of tissue/organ populations, I will be able to investigate the specific role of SRNK1 in development as well as investigate the developmental relationship between SNRK1 and LKB1.
Sreenivas Kilari, PhD, post-doctoral fellow
At present, I have two research interests based on my current projects. In the first project, I am focusing on the VEGFR-2/KDR signaling as modified by ECSCR (Endothelial Cell Specific Chemotaxis Receptor) during vascular development. In a second project, I am examining ephrin-B2 signaling partners in endothelial cells.
Shabnam Pooya, PhD, post-doctoral fellow
My research in the Developmental Vascular Biology program includes two major gene products that participate in vascular development. SNRK, a serine threonine kinase is a cytoplasmic signaling protein that is necessary for maintaining normal cell growth in highly metabolic tissues. Etv2, an ets-related transcription factor is a master regulator of transcriptional program leading to vascular morphogenesis. SNRK is known to communicate with LKB1. Bases on my previous experience with LKB1, I am working on vascular patterning problems associated with SNRK and LKB1 in murine models. In terms of Etv2, our lab has previously published Etv2’s fascinating role in the transcriptional network, mediating developmental plasticity of endothelial progenitor cells during embryonic development in zebrafish. In this project, I am studying Etv2’s role in ES cell differentiation into endothelial cells.
Tamjid Chowdhury, PhD, post-doctoral fellow
Our lab had previously identified a long non-coding RNA anti-sense (AS) to tie-1 mRNA in zebrafish embryo. This long non-coding RNA, known as tie-1 AS, is conserved in human and mouse, and is implicated in human disease. We have also shown that tie-1 AS specifically regulates the expression of tie-1 mRNA. However, the exact mechanism of this regulation and the tie-1AS RNA function is unknown. Using molecular and developmental biology approaches, I am characterizing the function(s) and molecular mechanism(s) underlying the tie-1 AS RNA regulation of tie-1 during embryonic vascular development.
Chris Koceja, technician
My research entails combining two different transgenic approaches to over-express oncogenes in sympathetic neurons of the zebrafish nervous system, while utilizing the GAL4/UAS system.
Raman Kutty, graduate student
I work on refining and adding to our understanding of vascular growth and development. Specifically, my graduate work focuses achieving better understandings of the etiological mechanisms of vascular tumors such as hemangiomas. Currently, I am developing in vitro techniques and animal models to better understand the role of dual specific phosphatase-5 (dusp-5), particularly its role in endothelial cell signaling. Concurrently, I am using these advancements to aid in the development of small molecule targets of dusp-5, for use in the treatment of hemangiomas. As an MD/PhD candidate, translational efforts such as these are at the heart of my medical education and will ultimately serve as the cornerstone for my professional career.
Michael Lepley, MS, research associate
Therapeutic treatments for vascular diseases require a multifaceted approach in translational medicine. My research goals in the lab have adopted this mentality as I am primarily focused on drug discovery and differentiation of vascular cells from human pluripotent stem cell sources. For the former, I am investigating small molecule inhibitors of specific phosphatases known to be involved in cancers and vascular malformations. For the latter, I am developing methods to efficiently and effectively differentiate endothelial cells in vitro to study specific gene expression during development and potential roles in vascular diseases. Investigation of these two areas of research will hopefully provide promise of future clinical therapies.
Noah Leigh, MS, research associate
My research interests are focused on drug discovery related to the process of angiogenesis. Currently I am working on the characterization of a novel gene DU644441 that I worked on for my Masters thesis. My goal is to determine the cell type the gene is expressed in during embryonic development in zebrafish and to confirm this gene is a matrix metalloproteinase (MMP) by conducting MMP assays using expressed protein.
Keguo Li, PhD, research scientist
My research interest lies in understanding the significance of intergenic transcripts. Specifically, I am interested in the roles of the transcripts in the flanking regions of Dll4 locus. We use quantitative visualizing technology with single molecular sensitivity to track such transcripts during vascular development. Gain- and loss-of-function studies are utilized to probe the impact of the transcripts on angiogenesis. Another intriguing field to me is the positional cloning of subtelomeric genes.
Jaladhi Nayak, research associate
My research involves the study of lymphatic malformations such as generalized lymphatic anomaly (GLA) and Gorham-Stout syndrome (GSS), which later lead to abnormal bone resorption. Currently, I am focusing on characterizing the effects of cell-cell communication between lymphatic endothelial cells and osteoclasts and its potential role in GLA and GSS pathogenesis. I am also currently working on protein expression and purification of a crucial protein involved in vascular development.
Emily Gronseth, graduate student
My research focuses on cancer metastasis, in particular the metastasis of medulloblastoma to extraneural locations. For my graduate work, I am specifically interested in the interaction between medulloblastoma tumors and astrocytes. Astrocytes are dynamic glial cells that comprise the majority of a medulloblastoma tumor microenvironment. I am currently working to determine the underlying mechanism(s) that cause astrocytes to induce medulloblastoma tumor cell invasion using in vitro techniques and an in vivo zebrafish xenotransplant model.
Ling Wang, MD, PhD, instructor
My research interest is to understand the pathogenesis of cardiovascular disease and cancer, and applying this knowledge to treatment in the clinic. Currently, I am focused on elucidating the fundamental vasculogenesis mechanisms using a variety of cell culture, zebrafish and mouse models, and to explore the contribution of the vasculogenic process to tumor growth.
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Erin Bishop, MD, assistant professor
The goal of my research is to determine the role ovarian cancer spheroids play in ovarian cancer metastasis and resistance to treatment. I am specifically focusing on the interactions between spheroids and the mesothelium by characterizing adhesion protein expression and function as well as the ability of spheroids to form tumors and respond to chemotherapy in vivo. A second project I am involved in describes the role of SNRK1 in ovarian cancer. As a gynecologic oncologist I take care of gynecologic oncology patients and plan to continue to combine my basic science experience and my clinical knowledge to work towards developing better treatments for gynecologic cancers.