Grant: $46,952 - National Institutes of Health - Jul. 14, 2009
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Award Description: PUBLIC HEALTH RELEVANCE: HPK1 is a molecule that control the activity of anti-cancer cells known as 'T cells'. Take away HPK1 from T cells will enable T cells to fight cancer more effectively. In this proposal, we described a series of experiments that may shed light as to how HPK1 is accomplishing this task.
Project Description: Proper functioning of the immune system requires elaborate network of negative regulatory mechanisms to modulate the strength of activation signal or to disengage the immune response after successful completion of a defense mounted against pathogens. One of the recent additions to this negative regulatory network is hematopoietic progenitor kinase 1 (HPK1), a member of the KHS subfamily of Ste20 serine/threonine kinases. In this proposal, we will evaluate the two know properties of HPK1 - its ability to negatively regulate TCR signaling pathway and its ability to induce apoptosis. Targeted disruption of HPK1 locus result in enhanced anti-cancer immunity, but it could not implicate which of these two HPK1-regulated functions contribute to this phenotype. We will determine whether the role of HPK1 as a kinase serves the primary function of inhibiting T cell activation, and upon losing that function, T cells can respond to cancer in a more robust manner. Alternatively, we will determine whether HPK1's role as a caspase-3 substrate and a regulator of apoptosis plays a more significant role in anti-cancer immunity. We will also identify proteins that bind to HPK1-C fragment and determine which of these proteins are involved in regulating the anti-cancer immunity. Not only will these studies reveal the importance of each HPK1-regulated function in anti-cancer immunity, but the identification of HPK1 kinase substrates and isolation of small molecule compound(s) that could inhibit HPK1 kinase activity will greatly advance our understanding of the role HPK1 play in T cell biology. Successful identification of small molecule inhibitor of HPK1 could one day develop into anti-cancer drugs that stimulate T cells to attack cancer cells more robustly.
Jobs Summary: One job for a Trainee was created. (Total jobs reported: 0)
Project Status: Less Than 50% Completed
This award's data was last updated on Jul. 14, 2009. Help expand these official descriptions using the wiki below.