The mechanical properties of developing and mature organ systems are primarily determined by the deposition of fibrillar collagens in the extracellular matrix. It follows that structural defects in these macromolecules cause dominantly inherited conditions that adversely affect the integrity of bodily organs. In addition to their supportive function, collagens also play a dynamic role in a number of developmental programs and physiological processes, such as tissue remodeling and wound healing. Deregulated collagen biosynthesis is the hallmark of several pathological conditions, including fibrotic, inflammatory and arthritic diseases. It is the long-term goal of this application to elucidate the mechanisms underlying collagen pathophysiology. Toward this end, two major research themes are proposed. The first will explore the phenotypic consequences of collagen mutations in human conditions and in transgenic mice. The second will decipher the molecular circuitries that require collagen biosynthesis. Specifically, we will characterize type II collagen mutations in chondrodysplastic patients to confirm and extend the genetic and clinical understanding of this collagenopathy. We will utilize the transgenic mouse model to establish the function and pathogenesis of minor fibrillar collagen types. We will employ transfection experiments and DNA:protein binding assays to identify cis-acting regulatory elements that control the expression of collagen genes. Finally, we will clone the genes encoding the trans-acting factors that regulate collagen expression. The thrust of this work is to achieve a better understanding of connective tissue pathology as it relates to the function and biosynthesis of fibrillar collagen types.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR038648-06
Application #
3158680
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
1989-07-01
Project End
1996-06-30
Budget Start
1991-08-01
Budget End
1992-06-30
Support Year
6
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10029
Su, Jianmin; Gorse, Karen; Ramirez, Francesco et al. (2010) Collagen XIX is expressed by interneurons and contributes to the formation of hippocampal synapses. J Comp Neurol 518:229-53
Matsuo, Noritaka; Tanaka, Shizuko; Yoshioka, Hidekatsu et al. (2008) Collagen XXIV (Col24a1) gene expression is a specific marker of osteoblast differentiation and bone formation. Connect Tissue Res 49:68-75
Tanaka, Shizuko; Ramirez, Francesco (2007) The first intron of the human alpha2(I) collagen gene (COL1A2) contains a novel interferon-gamma responsive element. Matrix Biol 26:185-9
Kajimura, Daisuke; Dragomir, Cecilia; Ramirez, Francesco et al. (2007) Identification of genes regulated by transcription factor KLF7 in differentiating olfactory sensory neurons. Gene 388:34-42
Ramirez, Francesco; Tanaka, Shizuko; Bou-Gharios, George (2006) Transcriptional regulation of the human alpha2(I) collagen gene (COL1A2), an informative model system to study fibrotic diseases. Matrix Biol 25:365-72
Matsuo, Noritaka; Tanaka, Shizuko; Gordon, Marion K et al. (2006) CREB-AP1 protein complexes regulate transcription of the collagen XXIV gene (Col24a1) in osteoblasts. J Biol Chem 281:5445-52
Smaldone, Silvia; Ramirez, Francesco (2006) Multiple pathways regulate intracellular shuttling of MoKA, a co-activator of transcription factor KLF7. Nucleic Acids Res 34:5060-8
Laub, Friedrich; Dragomir, Cecilia; Ramirez, Francesco (2006) Mice without transcription factor KLF7 provide new insight into olfactory bulb development. Brain Res 1103:108-13
Svegliati-Baroni, Gianluca; Inagaki, Yutaka; Rincon-Sanchez, Ana-Rosa et al. (2005) Early response of alpha2(I) collagen to acetaldehyde in human hepatic stellate cells is TGF-beta independent. Hepatology 42:343-52
Laub, Friedrich; Lei, Lei; Sumiyoshi, Hideaki et al. (2005) Transcription factor KLF7 is important for neuronal morphogenesis in selected regions of the nervous system. Mol Cell Biol 25:5699-711

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