Project title
間質蛋白質fibrillin/LTBP於腎臟衰竭及心臟衰竭的調控
Internal ID
MOST109-2311-B002-006
Principal Investigator
Start Date
August 1, 2020
End Date
July 31, 2021
Organizations
Partner Organizations
Molecular Mechanisms of Fibrillin/Ltbp Superfamily in Renal Fibrosis and Cardiorenal Sydrome = 間質蛋白質fibrillin/LTBP於腎臟衰竭及心臟衰竭的調控
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 to be related to fibrosis in human tissues. Dysregulation of TGFβ signaling results in the ECM defects, whereas LTBPs are crucial for activation of TGFβ and associated FBNs have been proved to stabilize the structure of ECM structure. 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 and associated FBNs to the release and activation of TGFβ in cardiorenal and renocardial syndrome. The major goal for this proposal is to investigate the biological functions of the latent transforming growth factor-beta-binding proteins (LTBPs) and FBNs and identify their pathophysiological effects in renal fibrosis and cardiac dysfunction. Our preliminary data suggested up-regulation of renal LTBP4 in CKD patients. We will start from to understand the role of LTBPs in TGFβ pathway in vitro and understand the functions of LTBP4 in knockout mice and conditional knock out mice in order to investigate the crosstalk between renal and cardiac dysfunction in vivo. Human induced pluripotent stem cell-derived cardiomyocytes provide a fantastic platform to understand the impact of LTBP4 on cardiomyocytes. In addition, the interaction between kidney and hear is an attractive entity 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, 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, human proximal tubules will served as a nice a start because of up-regulated LTBP4 expression had been noted in peri-proximal tubule areas. We will create mutant renal proximal tubules and cardiomyocytes to study the molecular mechanisms of LTBP action and associated Fibulins 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-/- mice is the relevant animal model to investigate the significance of LTBP4 in the pathophysiology of cardiac fibrosis and renal fibrosis. Moreover, to avoid the perinatal lethality seen in systemic ltbp4-null mice, cardiac-specific and renal-specific ltbp4 conditional knockout mice will be bred. Mice with cardiorenal syndrome and renocardial syndrome are other useful tools to help us understand the interaction between heart and kidney in fibrosis models.To study thoroughly about LTBP4 and fibulins 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.