Project title
TGF-beta 結合蛋白於心臟及腎臟纖維化的調節角色
Internal ID
MOST106-2311-B002-008
Principal Investigator
Start Date
August 1, 2017
End Date
July 31, 2018
Organizations
Partner Organizations
Ltbps Manipulate Heart and Kidney Fibrosis = TGF-beta 結合蛋白於心臟及腎臟纖維化的調節角色
Description
Extracellular matrix (ECM) and associated proteins form a complex network of numerous macromolecules, which performs abundant mechanical, chemical and biological functions. ECM molecules can interact with cells and with themselves as well as play an important role in the regulation of several processes, including TGFβ signaling pathways. Increased TGFβ levels and abnormal ECM networks have been found in patients with cardiomyopathy, diabetic nephropathy, cancer, lung fibrosis, rheumatoid arthritis and systemic sclerosis, in all cases correlating with disease severity. TGFβ pathway has been proved to be closely related to fibrosis in human tissues. TGFβs are secreted from cells as latent complexes, consisting of mature dimeric growth factor, latent associated protein (LAP) and latent TGFβ binding protein (LTBP). The latent complex needs subsequently to be activated and this complex is secreted in a specific and targeted manner. Dysregulation of TGFβ signaling results in the ECM defects, whereas LTBPs are crucial for activation of TGFβ. Extensive evidences have demonstrated that increased TGFβ is correlated with the progression of renal failure and cardiac failure. It will be interesting to understand the contribution from LTBPs to the release and activation of TGFβ in renal fibrosis and cardiac fibrosis. The major goal for this proposal is to investigate the biological functions of the latent transforming growth factor-beta-binding proteins (LTBPs) and identify their pathophysiological effects in renal fibrosis and cardiac dysfunction. We will start from to understand the role of LTBPs in TGFβ pathway in vitro and understand the functions of LTBPs in knockout and overexpression mice in order to investigate the crosstalk between renal and cardiac dysfunction in vivo. TGFβ is related to development of renal fibrosis and cardiac fibrosis. The cardiac and renal interaction is a crucial entity addressed for years. The interconnetion is an attractive platform to understand the molecular and clinical pathogenetic piplines. Patients with renal impairment have high prevalence of cardiac dysfunction, whereas patients with cardiac failure present renal failure frequently. Therefore, in this proposal, we are going to understand more about cardiorenal syndrome or renocardial syndrome by attempting to elucidate how LTBPs may mediate TGFβ releasing and activation in fibrotic tissues. In vitro, we will use pairwise knockdown experiments to study possible functional overlaps between LTBP family members. Mutant renal fibrosis and cardiomyocytes are used to study the molecular mechanisms of LTBP action in ECM assembly and growth factor signaling and TGFβ receptors. Moreover, in human, LTBP4 deficiency causes multiple systemic manifestation including pulmonary, gastrointestinal, cardiovascular and urinary abnormalities. Thus, ltbp4S-/- , ltbp4-/- and ltbp4 overexpression mice will be our relevant animal models to investigate the significance of LTBP4 in the pathophysiology of cardiac fibrosis and renal fibrosis. Mice with cardiorenal syndrome and renocardial syndrome are another useful tools to help us understand the interaction between heart and kidney in fibrosis models. To study thoroughly about LTBP4 from gene to protein levels will be helpful to develop the therapeutic reagents for several other systemic diseases with public health concerns, such as renal failure and cardiac failure.