Friday, May 17, 2024
5/17/2024
Principal Investigator/Program Director (Last, first, middle): Qu, Cheng-Kui RESEARCH & RELATED Other Project Information 1. * Are Human Subjects Involved? m Yes l No 1.a. If YES to Human Subjects Is the IRB review Pending? m Yes m No IRB Approval Date: Exemption Number: 1 2 3 4 5 6 Human Subject Assurance Number 2. * Are Vertebrate Animals Used? l Yes m No 2.a. If YES to Vertebrate Animals Is the IACUC review Pending? m Yes l No IACUC Approval Date: 05-17-2005 Animal Welfare Assurance Number A3145-01 3. * Is proprietary/privileged information m Yes l No included in the application? 4.a.* Does this project have an actual or potential impact on m Yes l No the environment? 4.b. If yes, please explain: 4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or environmental impact statement (EIS) been performed? m Yes m No 4.d. If yes, please explain: 5.a.* Does this project involve activities outside the U.S. or m Yes l No partnership with International Collaborators? 5.b. If yes, identify countries: 5.c. Optional Explanation: 6. * Project Summary/Abstract 8136-Qu-R01-Project_description.pdf Mime Type: application/pdf 7. * Project Narrative 3519-Qu-R01-Narrative.pdf Mime Type: application/pdf 8. Bibliography & References Cited 4761-Qu-R01-References.pdf Mime Type: application/pdf 9. Facilities & Other Resources 330-Qu_Resources_.pdf Mime Type: application/pdf 10. Equipment 8321-Qu_MAJOR_EQUIPMENT.pdf Mime Type: application/pdf Tracking Number: Other Information Page 5 OMB Number: 4040-0001 Expiration Date: 04/30/2008 Principal Investigator/Program Director (Last, first, middle): Qu, Cheng-Kui Project Description Genetic lesions in SHP-2, a protein tyrosine phosphatase that plays an overall positive role in hematopoietic cell development and function, have been identified in various childhood leukemias. These mutations cause hyperactivation of its catalytic activity [referred as to gain-of-function (GOF) mutations]. Recent studies suggest that the SHP-2 GOF mutations play a causal role in the leukemogenesis. However, the molecular mechanisms by which the SHP-2 mutations induce these diseases are not well understood. Lack of such knowledge is an important barrier to a rational design of new therapeutics for the related diseases. The objective of this application is to determine what acquired functions of the GOF mutant SHP-2 contribute to hematopoietic malignancies. The central hypothesis of the application is that although GOF mutations result in hyperactivation of catalytic activity, enhanced catalytic activity alone is not sufficient for the mutant SHP-2 to induce hematopoietic malignancies; altered protein-interacting capability (and thus substrate specificity) also plays a vital role. This hypothesis has been formulated on the basis of preliminary data produced in our laboratory. Firstly, SHP-2 functions in IL-3-induced signaling and cellular responses in both catalytic-dependent and -independent manners. The catalytic-independent function promotes IL-3 signaling. Secondly, a 5-to-6 fold access of wild-type SHP-2 in hematopoietic stem/progenitor cells compromises, rather than increases, hematopoietic potential due to accelerated dephosphorylation of STAT5. Thirdly, E76K, the most frequent SHP-2 mutation found in leukemias, also alters physical and functional interactions of SHP-2 with signaling partners Gab2 and STAT5, leading to enhanced downstream signaling. We plan to test our central hypothesis and accomplish the objective of this application by pursuing the following three Aims. 1) Characterize phosphoprotein interaction property of the GOF mutant SHP-2. 2) Define the mechanisms by which the elevated catalytic activity and the altered protein-interacting capability of the GOF mutant SHP-2 disturb hematopoietic cell signaling. 3) Determine the contribution of elevated catalytic activity and altered protein-interacting capability of the GOF mutant SHP-2 to in vivo leukemogenesis. It is expected that these studies collectively will yield new insight into the underlying mechanisms of the hematopoietic malignancies induced by SHP-2 mutations as well as providing a molecular basis for a future rational design of new therapeutics that specifically target SHP-2 or downstream intermediates for treatment of related diseases. In addition, the results are expected to fundamentally advance the field of cell signaling. Project Description Page 6
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