Targeting Protease-Activated Receptors (PARs) to Overcome CNS Inflammation
Two serine proteases, kallikreins 1 and 6, are elevated in the serum of patients with progressive multiple sclerosis, as cited in Biological Chemistry, 2008 (Scarisbrick et al.). The lab's new studies demonstrate that KLK6 promotes immune cell survival, while KLK1 promotes immune cell proliferation. Both enzymes also cause progressive neuron injury that results in permanent neurological deficits, as cited in PLoS ONE, 2008 (Scarisbrick et al.). These secreted enzymes, and the receptors they activate, therefore represent new targets to alleviate symptoms in patients with multiple sclerosis.
Acute and more-sustained inflammatory responses are a key component of many neurological disorders, whether of autoimmune, viral, genetic, traumatic or idiopathic origin. Based on preliminary findings in Dr. Scarisbrick's lab, it is hypothesized that elevated levels of secreted serine proteases at sites of neuropathology promote aberrant activation of protease-activated receptors that in turn promote and sustain neuroinflammation, thereby directly or indirectly driving astrogliosis, demyelination and neurodegeneration.
This line of research has resulted in the following patents:
- US 7,754,216 Method of treating Multiple Sclerosis with Anti-K6 antibody
Inventors: Isobel Scarisbrick, Moses Rodriguez, Sachiko Blaber and Michael Blaber
- US 8,530,427 Methods for Modulating Resistance to Apoptosis using KLK6
Inventors: Isobel Scarisbrick
- US 2013/0315926 Methods and Materials for Modulating Resistance to Apoptosis
Inventors: Isobel Scarisbrick
In ongoing projects, the neuroinflammatory and neurodegenerative roles of protease-activated receptors and their mechanism of action are being dissected to determine therapeutic utility for neuroprotection, neural regeneration and restoration of function.