extracellular matrix
DESCRIPTION
By, Raghu Ambekar BioE 506 Photonics Research of Bio/nano Environments Department of Electrical & Computer Engineering University of Illinois Urbana Champaign 04/19/10 Extracellular matrix proteinases Extracellular matrix proteins Fibril assembly and collagen diseases Collagen Classification 04/19/10TRANSCRIPT
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EXTRACELLULAR MATRIX PROTEINS AND
PROTEINASES
By,Raghu
AmbekarPhotonics Research of Bio/nano Environments
Department of Electrical & Computer EngineeringUniversity of Illinois Urbana - Champaign
BioE 506
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Outline
Extracellular matrix proteins
Collagen
Classification
Fibril assembly and collagen diseases
Extracellular matrix proteinases
Role of MMP in metastasis
Modification of tumor collagen for therapeutics
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Extracellular matrix (ECM)
Surrounds cell Provides mechanical support Controls the flow of nutrients and signals to the cells Consists of
Fibrous: collagen, elastin, fibronectin, laminin Non-fibrous: Proteoglycans and polysaccharides
http://kentsimmons.uwinnipeg.ca/cm1504
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Collagen
Collagen : most abundant protein found in the human body. About 1/3rd of the total proteins. Found abundantly in tendon, cartilage, bone and skin Functions:
cell migration cell adhesion molecular filtration tissue repair
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Structure of collagen
It has a triple-helix structure containing three α-polypeptide chains arranged in right-handed supercoil Glycine, proline, hydroxyproline 1.5 nm diameter At least 28 different collagens found The three α-chains could be same (collagen II) or different (collagen I)
Collagen molecule
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Classification of collagen
No interruptions in triple helix Regular arrangement results in characteristic “D” period of 67 nm Diameter : 50-500 nm Example : Types I, II, III, V, XI
1. Fibril-forming collagens
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Classification of collagen
Forms network in basement (Collagen IV) and Descemet’s membrane (Collagen VIII) Molecular filtration Example : Types IV, VIII, X
2. Network-forming collagens
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Classification of collagen
Short collagens with interruptions Linked to collagen II and carries a GAG chain Found at the surface of fibril-forming collagens Example : Types IX, XII, XIV
3. Fibril-associated collagens with interrupted triple helices (FACITs)
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Classification of collagen
Provides functional integrity by connecting epithelium to stroma Example : Type VII
4. Anchoring collagens
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Classification of collagen
Form structural links with cells Example : Type VI Collagen VI crosslink into tetramers that assemble into long molecular chains (microfibrils) and have beaded repeat of 105 nm
5. Beaded-filament-forming collagens
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Type I Fibril assembly
Chain recognition sequence
Fibril assembly is determined by chain recognition sequence in C-propeptide
Fish scale
Bone osteon
Tendon
Skin
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Diseases associated with collagen
Diseases caused by mutations
Subtypes of osteogenesis imperfecta (collagen I)
Ehlers-Danlos syndrome (collagen I and V)
Alport syndrome (collagen IV)
Certain arterial aneurysms (collagen III)
Ullrich muscular dystrophy (collagen VI)
Certain chondrodysplasias (collagen IX and XI)
Kniest dysplasia (collagen II)
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Role of MMP in metastasis
Metastasis
Metastasis Spread of cancer from a primary tumor to distant sites of the body A defining feature of cancer
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Role of MMP in metastasis Understanding the molecular mechanisms of metastasis is crucial for the design of therapeutics Extracellular matrix metalloproteinases (MMP) associated with metastasis MMPs are capable of digesting ECM and basement membrane under physiologic conditions
Collagenases degrade fibrillar collagen Stromelysins degrade proteoglycans and glycoproteins Gelatinases degrade nonfibrillar and denatured collagens
At tumor sites, experiments have found Increased number of MMPs Increased levels of MMPs Reduced levels of TIMPs (Tissue inhibitors of metalloproteinases)
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Role of MMP in metastasis Major role of MMPs was to facilitate the breakdown of physical barriers, thus promoting invasion, intravasation, extravasation and migration MMPs targeted for antimetastasis therapies
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Role of MMP in metastasis
Clinical trials of inhibiting MMPs to cure cancer have failed
Metastasis is a complicated process
MMPs contribute to every stage in tumor progression at both
primary and metastatic sites
Specific MMPs play a role in each stage of metastasis
MMP 13, 14 – invasion
MMP 9– angiogenesis
Understand the role of the MMPs in each cancer setting
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Modification of collagen for therapeutics
Structure and content of collagen governs the delivery of therapeutic molecules in tumors
Penetration of therapeutic molecules improved by developing agents that modify ECM and increase diffusion
Detect tumor collagen noninvasively to quantify collagen content and estimate drug delivery characteristics
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Modification of collagen for therapeuticsUses Second-harmonic generation (SHG) for imaging only collagen fibers
Conditions :
Non-centrosymmetric (collagen, microtubules)
Lasers (high intensity)
Advantages :
No staining
3D imaging
No photobleaching
SAMPLE
Red Wavelength=800 nm
SHG: BlueWavelength=400 nm
Collagen stained red and imaged by fluorescence
microscopy
Collagen imaged by SHG microscopy
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Modification of collagen for therapeutics
SHG intensity collected from live imaging of collagen fibers provides an good estimate of diffusion coefficient in tumors
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Modification of collagen for therapeutics
Chronic relaxin treatment degrades tumor matrix and improve macromolecular diffusion in tumors
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