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Molecular mechanisms of LTBP4-related cutis laxa

Su, Chi-Ting (2014) Molecular mechanisms of LTBP4-related cutis laxa. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Structural proteins of the extracellular matrix (ECM) and associated proteins build up a complex network that is abundant in the human body. In addition to serving key biomechanical roles, ECM proteins play an important role in storage, presentation and contextualization of growth factors, including transforming growth factor-β (TGFβ). This work focused on investigating the biomechanical consequences of and molecular disease mechanisms leading to cutis laxa (CL), a rare inherited disorder characterized by loose skin and frequently associated with systemic involvement, including aortic aneurysms, pulmonary artery disease, and emphysema.
A DermaLab suction cup device was used to evaluate the mechanical properties of the skin in CL patients. The results showed significant reduction of elastic and viscoelastic moduli (VE). VE appeared to be a reliable measurement of biomechanical aging of the skin and also offered a predictive value in distinguishing cases from controls.
To study molecular disease mechanisms in CL, control and LTBP4-mutant human dermal fibroblasts were used to investigate TGFβ activity and signaling. In LTBP4-mutant cells, despite elevated extracellular TGFß activity, downstream signaling molecules of the TGFß pathway were markedly suppressed. TGFß receptors (TGFBR1 and TGFBR2) were reduced at the protein, but not at the RNA level. Treatment with exogenous TGFβ1 led to a further decrease in downstream signaling and receptor abundance. Upon treatment with TGFBR1 kinase inhibitor, endocytosis inhibitors or a lysosomal inhibitor, the levels of TGFBR1 and TGFBR2 were normalized. Antisense mophorlino oligonucleotide-mediated knockdown of LTBP4 reduced TGFβ receptor abundance and signaling in normal cells and supplementation of recombinant LTBP4 enhanced these measures in mutant cells. I conclude that, in the absence of LTBP4, TGFBR1 and TGFBR2 are internalized and degraded by lysosomes in a ligand-dependent and receptor kinase activity-dependent manner. Thus, LTBP4 is a key molecule required for the stabilization of the TGFβ receptor complex.
Increased TGFβ levels have been found in patients with cardiomyopathy, diabetic nephropathy, cancer, and lung fibrosis, in all cases correlating with disease severity. The discovery of a new mechanism for TGFβ receptor regulation will be helpful in developing novel therapeutic reagents for systemic diseases of major public health impact.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Su, Chi-Tingchs145@pitt.eduCHS145
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairUrban, Zsolturbanz@pitt.eduURBANZ
Committee MemberWeeks, Daniel E.weeks@pitt.eduWEEKS0000-0001-9410-7228
Committee MemberWang, Yadongyaw20@pitt.eduYAW20
Committee MemberPadiath, Quasarqpadiath@pitt.eduQPADIATH
Date: 27 June 2014
Date Type: Publication
Defense Date: 9 April 2014
Approval Date: 27 June 2014
Submission Date: 4 April 2014
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 175
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Date Deposited: 27 Jun 2014 20:30
Last Modified: 30 Jun 2022 16:18


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