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The Manton Center Associates are physicians and scientists at Boston Children's Hospital who receive funding through The Center's Innovation Fund, Fellowships Program or other related source, or who have close ties to The Center's activities because of research projects with goals of particular relevance to the mission of The Manton Center.

Fernando Camargo, PhD
Stem cell therapy for rare liver metabolic disorders
A subset of rare congenital metabolic liver diseases is amenable to treatment by the replacement of faulty liver cells. While cellular transplants have been attempted in patients, these have failed because the donor cells did nor persist or were immune rejected. Additionally, it is very difficult to find a donor liver from which to isolate cells for transplantation. We propose a new strategy to grow large numbers of liver progenitor cells from a patient so that these could be genetically corrected in the petri dish and reintroduced back into the same patient. These type of personalized stem cell therapy has the potential to produce long-lasting cures for these disorders.

Carla Kim, PhD
Investigating the tissue origin of LAM
Lymphangioleiomyomatosis (LAM) is a rare, chronic disease almost exclusively affecting females. LAM results from the growth and accumulation of abnormal cells in the lung, which ultimately leads to severe lung destruction. Lung transplantation is currently the only therapeutic option for advanced LAM disease. Although LAM is thought to originate from outside the lung, the specific tissue of origin is unknown. We compared LAM gene expression patterns to a comprehensive collection of 369 other tissue types representing normal or diseased states of virtually all tissues of the body. This analysis demonstrated that LAM is closely related to normal and cancerous tissues of the uterus. We propose to directly test the possible uterine origin of LAM by further examining whether additional LAM lesions exhibit gene expression patterns and functional properties of uterine tissues. We will also work to model the disease in mice by inducing a LAM-specific mutation directly within the uterus. By conducting a comprehensive set of experiments from determination of the cellular origins of the disease to testing the hypothesis in animals, we will be able to understand what is causing the disease. Our proposed studies will not only clarify the origins of LAM, but will aid in the development of novel therapeutic avenues for this orphan disease.

Chiara Manzini, PhD
Gene identification in rare genetic disorders disrupting cell-extracellular matrix interactions
The goal of this proposal is to study the genetics of rare disorders affecting the interactions between cells and the extracellular matrix (ECM), the meshwork of proteins and sugars surrounding cells and tissues. The ECM is an important regulator of cellular differentiation and organogenesis, and defects in its structure often affect a multitude of systems in the body. Brain, eyes and muscle in particular rely heavily on the ECM for differentiation and are frequently concurrently affected with different levels of severity. Because these disorders are extremely genetically and clinically heterogeneous, determining guidelines for genetic testing and identifying the multiple undiscovered disease genes has been very challenging. We will use state-of-the-art sequencing technologies to sequence every gene in the genome of each affected individual to bypass this heterogeneity and explore each family/subject individually. We will then use the zebrafish as an animal model to explore the functional effects of the genetic variants we identified to determine whether such changes replicate the phenotypes observed in the patients. This work will likely yield multiple new candidate genes responsible for disorders of cell-ECM interaction, help determine the relative contribution to each gene to ease the establishment of guidelines for genetic testing and provide new insight into the mechanisms responsible for brain, eye and muscle development.

Patrick Smits, PhD
Delineating protein trafficking pathways using heritable disorders of bone and cartilage
Dr. Smits' research interests focus on an understudied question in the skeletal field: how do chondrocytes and osteoblasts deal with the high demand for production and secretion of proteins needed to maintain a functional extracellular matrix? This is an important question to ask, because its answer would help to clarify the properties of bone and cartilage. The long-term goal of Dr. Smits' research is to identify the mechanisms and pathways involved in intracellular trafficking of matrix proteins by chondrocytes and osteoblasts during skeletal development, homeostasis and disease. He receives his PhD from University of Antwerp, Belgium and trained with Dr. B. de Crombrugghe and Dr. V. Lefebvre, two leaders in the skeletal field.

Jing Chen, PhD
Regulation of Retinal Angiogenesis by Wnt Signaling
A common fundamental problem in three related blinding orphan eye diseases, familial exudative vitreoretinopathy (FEVR), Norrie disease and Coats' disease, is a lack of blood vessel growth in the retina. This poor vascularization causes low tissue oxygen in the retina which then stimulates subsequent abnormal and sight-threatening vessel proliferation. Current ablation surgery is only partially effective in suppressing pathologic vessel growth to prevent vision loss in these diseases. A more refined approach promoting normal vascularization rather than inhibiting all vessels depends on a better understanding of the inter-related pathways involved in these diseases which share a common phenotype. Norrie disease, FEVR, and Coats' disease all have in common abnormalities of Wnt signaling pathways, a pathway fundamentally important for embryonic development. Since mutations involve Wnt receptor Frizzled4, co-receptor LRP-5 and Wnt ligand Norrin has been associated with all of these orphan diseases in human, studies in Wnt signaling is likely to lead us to the mechanism of poor retinal vascular growth and design of potential therapies to selectively promote normal vessel growth and inhibit pathological neovessels.

Hanna T Gazda, MD, PhD
Genetics and Biology of Ribosomes in Diamond-Blackfan Anemia
Diamond-Blackfan anemia (DBA) is the first human disease known to be caused by mutations in ribosomal protein (RP) genes. Ribosomal protein genes provide the information for our body to produce ribosomal proteins. There are 79 ribosomal proteins, which together with ribosomal RNA form ribosomes. There are seven RP genes reported to be mutated in ~ 42% of DBA patients. Recently, we have completed screening by sequencing of the all 79 RP genes (excluding one gene, RPS4Y, located on chromosome Y) and have obtained evidence for mutations in four additional RP genes in ~10% of DBA patients. This brings the total number of RP genes mutated in ~52% of patients with DBA to 11.

Mustafa Sahin, MD, PhD
Dr. Sahin received his MD and PhD in neurobiology at the Yale University School of Medicine. He completed an internship at Children's Hospital of Philadelphia and residencies at both Children's Hospital of Philadelphia and Boston Children's Hospital. He has received numerous awards, including a Mentored Clinical Scientist Development Award, a William Randolph Hearst Fund Award, and a Spinal Muscular Atrophy Foundation Young Investigator Award and the 2005 Young Investigator Award from the Child Neurology Society. Currently, Dr. Sahin studies Tuberous sclerosis (TSC), a multisystem disorder which can cause seizures and other neurological problems, and spinal muscular atrophy (SMA), a progressive muscle weakness disorder caused by the degeneration of the anterior horn cells in the spinal cord.

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