Renhao Li Lab:Research

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(Developing novel reagents for better diagnostics and therapy)
(Developing novel tools for better diagnostics and therapy)
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==Developing novel tools for better diagnostics and therapy==
==Developing novel tools for better diagnostics and therapy==
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1. Specific inhibitors of GPIba shedding
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1. Specific inhibitors of GPIbα shedding
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The biological significance of ectodomain shedding is often linked with the transmembrane receptor undergoing shedding. Thus it is desirable to
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The biological significance of ectodomain shedding is often linked with the transmembrane receptor undergoing shedding. Thus it is desirable to achieve specific inhibition of shedding of the target receptor and not that of any other receptors. We are exploring the method of achieving
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 +
 
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2. Automated epitope mapping of anti-FVIII antibodies
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The biological significance of ectodomain shedding is often linked with the transmembrane receptor undergoing shedding. Thus it is desirable to achieve specific inhibition of shedding of the target receptor and not that of any other receptors. We are exploring the method of achieving
 +
 
 +
3. To be updated

Revision as of 22:26, 13 June 2013

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Regulation of Ectodomain Shedding

Ectodomain shedding is a process in which an integral membrane protein is proteolytically cleaved and its extracellular domain released from the cell. It affects many membrane proteins including growth factor precursors, amyloid precursor proteins, cytokines, cell adhesion receptors, and proteoglycans. Excessive shedding activity often leads to diseases such as cancer, arthritis and neurodegenerative diseases. We are interested in elucidating the molecular mechanisms underlying regulation of ectodomain shedding by intracellular events including protein interactions with the cytoplasmic domain of shedding substrates. The following questions drive our current studies:

  1. How does a mutation in the cytoplasmic domain of a shedding substrate protein modulate its shedding that happens on the other side of the plasma membrane? There have been reports of such cytoplasmic mutations in many membrane receptors. These mutations appear to be free of any links to modulation of sheddase activities. We are focusing on a few mutations in the cytoplasmic domain of L-selectin that appear to render L-selectin resistance to PMA-induced shedding.
  2. Why does sometimes the same membrane receptor have different shedding behaviors in closely related cell lines? Presumably the answer lies in the small but critical difference between the cell lines. Then what is the difference that causes the different shedding activity?

In parallel, we aim to, based on what we have learned of the regulation mechanisms, devise ways to inhibit and modulate shedding of membrane protein substrates, particularly those with significant implications in human diseases.


Structure and Regulation of Platelet GPIb-IX-V Complex

The glycoprotein (GP)Ib-IX-V complex (a.k.a. CD42) is one of the major hubs on the platelet surface for its aggregation and activation. Malfunction or lack of the GPIb-IX-V complex in platelets results in severe bleeding disorders, and it plays a critical role in a number of cardiovascular diseases including myocardial infarction and stroke. The interaction between the glycoprotein (GP)Ib-IX-V complex on the platelet surface and von Willebrand factor (VWF) that marks the injury site in the artery is widely considered as the first step for hemostasis. Upon binding to VWF, the GPIb-IX-V complex transduces into the platelet an activating signal, leading eventually to platelet aggregation and thrombus formation. The GPIb-IX-V complex consists of nine subunits of four kinds: GPIbα, GPIbβ, GPIX and GPV. Our current focus is to delineate the 3-dimensional organization of the complex, that is, how these subunits evolve, interact with one another and assemble into the functional receptor complex. The insights on the overall organization of the GPIb-IX-V complex will help us understand how it mediates signals of VWF-binding across the plasma membrane to activate the platelet, and how the binding activity of this complex is regulated by intracellular signals.


Developing novel tools for better diagnostics and therapy

1. Specific inhibitors of GPIbα shedding

The biological significance of ectodomain shedding is often linked with the transmembrane receptor undergoing shedding. Thus it is desirable to achieve specific inhibition of shedding of the target receptor and not that of any other receptors. We are exploring the method of achieving


2. Automated epitope mapping of anti-FVIII antibodies

The biological significance of ectodomain shedding is often linked with the transmembrane receptor undergoing shedding. Thus it is desirable to achieve specific inhibition of shedding of the target receptor and not that of any other receptors. We are exploring the method of achieving

3. To be updated

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