Mechanochemical Signal Transduction and Role of Mechanical forces:

Various Aspects and its Clinical Implications

SUCHI AGRAWAL11610001

MSc Biotechnology,II Yr

SEMINAR TERM PAPER

A few simple things that intrigued me into this aspect of

biology…….

Do animals know at a physiological level how much they weigh andif so, do they make homeostatic adjustments in response to changes in body weight?Theyshould of course!But how?

Ever wondered how the continuous pressure experienced by the cells when we sit on a computer and write for extended periods gets dissipated and filtered out…not causing any tissue deformation?

A and B.Shear forces acting directly on membrane proteins or tugging forces on cytoskeleton causes associated Stress activated ion channels to open up like a ‘GATED SPRING’.

C.Effect of tensional forces on a substrate displaces it from the enzyme’s active site.

D.Stretch on a folded polypeptide opens up embedded/hidden residues only to be exposed and bound by an appropriate entity.

E.Compression and Relaxation forces alter the length of an actin filament by addition of new subunits.

NANOSCALE EFFECTS

(Ingber E Donald,2006)

EVOLUTIONARY HISTORY:Bioluminescence;explanation for Glowing Seas suggested

How suspended Dinoflagellates and adherent endothelial cells show conserved signaling mechanism to Shear stress involving G proteins (the present hypothesis)?FUTURE DIRECTION.Feasibility of a designing a live imaging system by using this shear stress dependent Lucifease Bioluminescence.Study of Scintillon design necessary!

(http://www.sciencedaily.com/releases/2011/10/111019190823.htm)

1.Role of physico-chemical environment in lung physiology:Deeper insights into

improving Mechanical Ventilation

POSTNATAL LUNGS:

Lung aeration causes surface tension to form which greatly increases lung recoil leading to a

reduction in interstitial tissue and pleural pressures as well as lung expansion inspite of

presence of Surfactant!

(Hooper.B Stuart et al.2005)

Lung expansion induced lung growth and AEC proliferation

(Hooper.B Stuart et al. 2005)

1.Greater insights into ‘Chronic diseases of lung’ due to Mechanical Ventilation at premature birth.Improvement by additional substitution with innumerable growth factors made on mechanical stress.

2.Future direction for treatment of Emphysema:Stress induced extracellular matrix expression and balancing of metalloprotease production.

(http://www.cts.usc.edu/lungvolumereductionsurgery.html)

2.Single-molecule Force Spectroscopy Approach to Enzyme Catalysis:Helpful

for probing ECM molecules and exploring the complex

Mechanochemistry

Single-molecule force spectroscopy assay for the detection of single reduction events by the

enzyme Trx(Thioredoxin)‘Finger print‘ characteristic of folding pattern of protein.

(George Alegre et al.2010)

FUTURE DIRECTON in this aspect:

A.AFM/Optical tweezers approach used for probing single Extracellular Matrix molecules under defined stress condition and checking the

mechanochemistry.Age and disease dependent studies to answer questions related to increased senility of older cells!Eg:Collagen destabilisation with age

. B.Differential Fluoroscence labeling of various cell,cytoskeletal and

extracellular protein components with different fluorochromes and study their response on application of artificial stress using a Confocal

Microscope!

3.MECHANOCHEMICAL

TRANSDUCTION AS DEVELOPMENTAL REGULATORS with specific focus on

stem cell differentiation

EXISTENCE OF STEM CELL NICHES OR ‘MICROENVIRONMENT’ IS THE KEY EVIDENCE TO THE FACT THAT SURROUNDING

MECHANOPHYSICAL ENVIRONMENT DICTATES STEM CELL FATE TO A GREAT EXTENT!

Ectopic expression of ‘Twist’ due to applied forces on Drosophila leads to production of Beta-actinin.Failure of embryonic development, due to disruption of the dorsal-ventral axis.

Crosstalk between Wnt signaling and mechanical cues in skeletal patterning and embryogenesis.

(Kastanon Irinka,2001)

MATRIX PATTERNINGFUTURE DIRECTON:Study effect of mechanical stress on cell adhesion factors ‘in isolation from effect of interdependent soluble mitogens/chemical cues’

Motility factors cause protusions to develop from a cell from the corners of the matrix!

A new Vision towards driving Human Stem Cell Differentiation:Implication for Translational

Medicine and hESC Therapy

Signal transduction pathways like Wnt and Hedgehog (Hh) in the PRIMARY CILIA are crucial for embryological development and tissue differentiation.The existence of primary cilia and the localization of signaling components in undifferentiated hESCs establishes a mechanistic basis for the regulation of hESC differentiation.Picture:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2265400/figure/fig1/

4.IMPLICATIONS IN MEDICINE

AND MECHNODISEASES:Getting into

the physical basis of

diseases…

Tumour FormationEven alterations in vasculature development due to altered ECM architecture around blood vessels leads to Metastasis

Acupuncture,massage to set right a lower back pain,application of

‘Traction forces’ to reset the displaced muscle and bone configurations are common

clinical practices

Breast impant surgeries are becoming so common nowadays…Would be exciting to realise how the surrounding tissue adjusts to allow an external entity to create space for itself in such a compact,uniformly structured matrix!

Mutation or deletion of the polycystin genes that encode mechanosensitive ion channels that mediate urine flow sensation in kidney epithelium leads to the development of Polycystic kidney disease

Acute Cell contractility is a common feature of many diseases Botulinum A (Botox) D is being tested as a

treatment for a wide range of ailments,including stroke paralysis, migraine

headaches,facialtics,stuttering,lower back pain…

(Nauli M. Saurya et al. 2006)

FUTURE PERSPECTIVEGenetic cause of disease isn’t the only important criteria to treat or relieve symptoms and reduce morbidity.Most cases of patents coming to clinics are a result of altered tissue mechanics and structure.

Study of the relation between structure and function at the molecular scale in living cells and tissues leading to the development of entirely new biomaterials and microdevices for repair and replacement of injured tissues;’BIOMIMETICS’

To advance patient care in the twenty first century, reintegrate mechanics into our understanding of the molecular basis of disease by treating mechanochemical signal transducers as a therapeutic target!

• Ingber E Donald. Mechanobiology and diseases of Mechanotransduction, Annuals of Medicine, (2003)Taylor and Francis. ISSN 0785-3790

• Mingyao Liu and Martin Post. Invited Review:Mechanochemical Signal transduction in the

fetal lung, Journal of applied physiology, (2000)American Physiological Society • Stuart B. Hooper and Meg J. Wallace. Role of the physiochemical environment in lung

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• Jorge Alegre-Cebollada,Raul Perez-Jimenez, Pallav Kosuri and Julio M. Fernandez. Single-molecule Force Spectroscopy Approach to Enzyme Catalysis,J Biol Chem. 2010 June 18; 285(25): 18961–18966

• Donald E. Ingber. Cellular mechanotransduction: putting all the pieces together again, The FASEB

Journal,Vol 20 no. 7 811-827 • Surya M. Nauli, Sandro Rossetti, Robert J. Kolb, Francis J. Alenghat, Mark B. Consugar, Peter C. Harris†

et al. Loss of Polycystin-1 in Human Cyst-Lining Epithelia Leads to Ciliary Dysfunction, Journal of the American Science of Nephrology April 2006 Vol 17 no. 4 1015-1025

• Bioluminescence: Explanation for Glowing Seas Suggested:ScienceDaily (Oct. 20, 2011) • Molecular Mechanochemistry: An Emerging Discipline At The Nexus Of Biology And Physics, Back to

Eurek Alert, Public release date: 18-Feb-1998 • Marden JH, Fescemyer HW, Saastamoinen M, MacFarland SP, Vera JC, Frilander MJ, Hanski I. Weight

and nutrition affect pre-mRNA splicing of a muscle gene associated with performance, energetics and life history, J Exp Biol. 2008 Dec;211(Pt 23):3653-60.

• Gudi SR,Clark CB,Frangos JA. Fluid flow rapidly activates G proteins in human endothelial cells.

Involvement of G proteins in mechanochemical signal transduction, Circ Res 1996 Oct;79(4):834-9 • Alexander Eekhoff Navid Bonakdar. Glomerular podocytes: A study of mechanical properties and

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THANK YOU!