Lead Inventors:
Martin Chalfie, Ph.D.,
Thomas Benzing, Ph.D.
Prohibitin Homology (PHB) Domain Proteins Potential in Regulating Nervous System Activity
Prohibitin homology (PHB) domain proteins are membrane proteins that regulate a variety of biological activities, such as osmotic homeostasis, mechanosensation, and cell signaling. In addition, it has been shown that they participate in protein complexes involved in various important human diseases, including nephropathy, hypertension, Alzheimer's, immunological disorders. Recent studies reveal that PHB-domain proteins bind and recruit sterols to influence the activity of associated proteins in membrane protein supercomplexs. However, little is known about the role of lipid binding for the regulation of ion channels, which control the flow of ions across the membrane in all cells. Thus, understanding the mechanism by which PHB-domain proteins regulate ion-channel activity represents a worthwhile endeavor. Finding compounds that modulate the interaction between PHB domains that are associated with ion channels and sterols hold promise for identifying new drugs capable of regulating channel activities, e.g., for regulating nervous system activity.
Modulating PHB Domain Protein Activity for Diagnosing Neurodegenerative Disorders
This technology shows that many PHB-domain proteins can regulate various cellular activities by directly interacting with cholesterol and related compounds. It is based on the finding that cholesterol binding proteins, Podocin and MEC-2, can regulate the activity of ion channels to which these PHB-domain proteins associate by binding cholesterol: DEG/ENaC channels for MEC-2 and TRPC channels for Podocin. This technology provides methods for modulating the activity of a PHB domain protein. It also includes methods for identifying compounds, which can bind to and/or modulate activity of PHB-domain polypeptide such as Podocin or MEC2.
Applications:
This technology is useful in identifying PHB-domain protein modulators for preparing therapeutic compositions for diagnosing or treating PHB-domain proteins related symptoms, especially neurodegenerative disorders. It offers:
• Potential way of modifying membrane protein function
• Possible route to a mechanism for controlling nerve cell production of the A-beta peptide from the Amyloid Precursor Protein (APP), which is a potential cause of Alzheimer's disease
• Regulation of kidney function by sterols
• Potential control of red blood cell lysis
• Mutation screening in cholesterol binding portions of PHB-domain proteins
Advantages:
• A novel mechanism regulating activity of PHB-domain proteins, which are involved in a variety of human diseases. Identified compounds might be used in treating multiple diseases at the same time
• New and convenient methods to identify subjects having a disorder related to a PHB domain protein and predict whether such subjects will respond to treatment with a lipid-interfering compound
Patent Status: Patent Pending (US20090175845) ~ see link below.
Licensing Status: Available for Licensing and Sponsored Research Support
Publications:
Huber TB, et al. (2006) Podocin and MEC-2 bind cholesterol to regulate the activity of associated ion channels. Proc Natl Acad Sci USA 103:17079-17086