Clinical Sciences

Molecular Mechanisms of Temporomandibular Joint Disorders by Use of Genetic and Nongenetic Mouse Models

Funder(s): The Eleanor and Miles Shore 50th Anniversary Fellowship Program for Scholars in Medicine

The objective of this research study focuses on the pathogenesis of temporomandibular joint disorders (TMJD) that affect millions of people around the world. Dr. Xu has identified two mutant mouse models for TMJD and established a surgically induced mouse TMJD model by partial discectomy. Dr. Xu has been investigating risk factors that are responsible for trauma-induced TMJD by use of these mouse models. Results from these studies will provide information for...

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Molecular Mechanisms of Choroidal Neovascularization and Vascular Homeostasis

Funder(s): NIH/NEI

Choroidal neovascularization (CNV) in age-related macular degeneration (AMD) is one of the leading causes of blindness worldwide. Our long-term goal is to elucidate the molecular mechanisms that regulate choroidal vascular development, choroidal vascular homeostasis in the adult, and CNV. Understanding these mechanisms is likely to provide the basis for a more targeted therapeutic approach in patients with neovascular AMD.

Recent experimental and clinical data have provided strong evidence for a pathogenetic role of VEGF signaling in...

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Molecular and Cellular Mechanisms of Vascular Anomalies

Funder(s): NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases

This program project (P01) aims to elucidate pathogenetic mechanisms of human vascular anomalies, to generate mouse models and identify therapeutic targets. These common vascular disorders belong to the group of childhood conditions popularly known as vascular birthmarks. One in about 100 children born have a vascular birthmark, and although significant progress has been made in identifying the genetic basis for many of the more rare forms of these anomalies, they are...

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Innovative Mouse Model to Study Parathyroids and an Application to Human Disease

Funder(s): NIH/National Institute of Diabetes and Digestive and Kidney Diseases

Parathyroid glands produce parathyroid hormone (PTH), one of the most important regulators of calcium and phosphate homeostasis, and of bone metabolism. FGF23, secreted from bone, is another crucial regulator of phosphate homeostasis. Recent data have suggested a bone-parathyroid axis in which FGF23 and PTH regulate each other; however, the existing data are contradictory and require clarification. Progress in understanding the molecular regulation of parathyroid cells is very slow...

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In Vivo Interactions of Fgf-23, Klotho, and Vitamin D

Funder(s): NIH/National Institute of Diabetes and Digestive and Kidney Diseases

Recent studies have shown crucial roles of fibroblast growth factor-23 (FGF-23) and klotho in regulating calcium and phosphate homeostasis. FGF-23 is an important in vivo regulator of phosphate homeostasis, while klotho is involved in regulating calcium homeostasis by interacting with the epithelial calcium channel transient receptor potential-vanilloid-5 (TRPV5). Interestingly, Fgf-23- and klotho-ablated (kl/kl, klotho-/-) mice have very similar physical, biochemical, and...

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Collagen gene structure and expression

Funder(s): NIH/NIAMS

The long-term goals of this project are to gain insights into mechanisms by which extracellular matrix components contribute to assembly, maintenance and function of vascular and epithelial tissues. The work is focused on a component of basement membranes, the specialized structures that separate epithelial and endothelial cells from underlying connective tissues. This component, collagen XVIII, interacts with other basement membrane constituents and receptors on adjacent cells via one of its domains, endostatin. In humans, recessive...

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BMP-3 signaling in the formation and regulation of bone

Funder(s): NIH/NIAMS

Although research on the bone morphogenetic proteins (BMPs) has expanded exponentially over the past decade, we actually know very little about the physiological roles that individual BMPs play in the skeleton. Our decision to focus this proposal on role the BMP3 in bone is based on several important findings. First, although BMP3 is the most abundant BMP in bone, accounting for 65% of the total BMP protein stored in bone matrix, little is known about its biology. A second reason for our interest in BMP3 are recent reports that correlate...

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BMP-2 regulation of bone homeostatis

Funder(s): NIH/NIAMS

Bone morphogenetic proteins (BMPs) were identified as potent bone forming agents based on their ability to induce de novo bone formation in adult animals and this unique feature of BMP activity has led to use of BMPs as therapeutic agents in bone repair. It has also generated intense interest in defining the role endogenous BMPs play in the skeleton. Removal of individual osteogenic BMPs (BMPs 2, 4, 5, 6, 7) during embryonic development shows that loss of any individual BMP can be compensated for by the other BMPs present. Mice in which...

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Biogenesis of extracellular matrix

Funder(s): NIH/NIAMS

The long-term goal of these studies is to understand the cellular and molecular mechanisms that control bone development and homeostasis. During the past funding period, significant progress has been made in identifying the multiple roles of vascular endothelial growth factor (VEGF) in skeletal development. These roles include serving as chemotactic factor for vascular invasion into cartilage models of future bones, serving as survival factor for chondrocytes in hypoxic regions, promoting matrix production by osteoblasts and chondrocytes...

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Regulation of Xenopus Embryonic Development by TGFbeta

Investigators: Maja Edenius, PhD, research fellow; Chang-Yeol Yeo, PhD, research fellow
Funder(s): NIH/National Institute of Child Health and Human Development

Our long-term goal is to understand how members of the TGFa superfamily act to exert a wide range of cell-type specific actions during development. Our current focus is on the role of TGFa ligands and their primary signal transducers, the Smads, in two sets of developmental events: 1) the regulation of migration of cell populations that establish the craniofacial skeleton and the...

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Multigenic Dissection of Nonsyndromic Oral Clefts

Funder(s): NIH/National Institute of Dental and Craniofacial Research

Cleft lip and/or cleft palate are among the most common birth defects and have serious physical, psychological, and financial consequences for those affected. Nevertheless, little is known about the causes of these anomalies because clefts are the result of genetic and environmental risk factors, rather than a single factor. This research has the potential to make a unique contribution to our understanding of clefts, as it employs novel analytical approaches that allow the simultaneous...

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Development of a New Family of Small Molecule Therapeutics for the Treatment of Chronic Inflammation

Investigators: Maja Edenius, PhD, Research Fellow
Funder(s): Harvard University Technology Development Accelerator Fund

Drs. Whitman and Keller are working as co-principal investigators in collaboration with Anjana Rao, of the Immune Disease Institute at Children’s Hospital Boston. They are developing a new family of small molecule therapeutics for the treatment of chronic inflammatory conditions and autoimmune diseases. 

Established by the Office of the Provost and Office of Technology Development, the Accelerator Fund is...

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Clinical and Radiographic Evaluation of Titanium-Zirconium Narrow-Diameter Dental Implants

Investigators: Goran Benic, DMD, research fellow; Muiz Mokti, DMD, implant resident
Funder(s): ITI Foundation

This multicenter, prospective, controlled, randomized clinical study will compare the outcomes of titanium-zirconium narrow-diameter implants and titanium regular-diameter implants. One study-implant per patient will be placed and restored with a single crown. Outcome parameters will be intraoperative time for the implant bed preparation, dimensions of the residual buccal bone and of the osseous defects immediately after the...

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From Adhesion to Bone Resorption: The Role of Dynamin in Osteoclasts

Funder(s): NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases

Bone resorption is performed by the mature osteoclast. To resorb bone, osteoclasts require both the presence of dynamic actin adhesion structures in the sealing zone (podosomes) and very efficient endocytosis in the ruffled-border domain. Data generated in our laboratory within the last five years has clearly established that two signaling enzyme activities are directly involved in the regulation of both bone resorption and actin dynamics in the osteoclast. On the one hand, we have shown...

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