Professor and Chair of Biochemistry and Biophysics
Pharmacology - joint appointment
(PhD - University of Illinois, Chicago)
Parise Lab Website
HONORS AND AWARDS
- American Assoc. for Biochemistry & Molecular Biology Elected Member, Public Advisory Committee
- Association of Medical & Graduate Departments of Biochemistry, Board of Directors
- Member, AHA MidAtlantic Research Council
- Permanent Member, NIH HT Study Section
- Associate Editor, Blood
- Fellow, American Association for the Advancement of Science
- Stewart-Niewiarowski Award for Women in Vascular Biology
- Fellow, Executive Leadership in Academic Medicine
Cancer and CIB
Cancerous tumor cells often proliferate rapidly. Some cancer cell types appear to be addicted to CIB1 for survival. We find that when we knockdown CIB1 in breast and neuroblastoma cancer cells, the cells die by an unusual mechanism that involves GAPDH translocation to the nucleus. We also find that this cell death appears to be so potent because loss of CIB1 causes two oncogenic pathways to fail: the PI3K/AKT pathway and the RAS/RAF/MEK/ERK pathway. However, normal cells do not appear to be addicted to CIB1 for survival. Moreover, once tumors grow beyond a few mm in size, they require blood vessels to provide nourishment in order to grow further. Endothelial cells are essential for blood vessel formation. CIB1 is expressed in multiple cell types, including endothelial cells. We found that efficient tumor-induced blood vessel growth depends upon CIB1. If endothelial cells do not express CIB1, the cells grow more slowly and tumor-induced blood vessel formation is impaired. We have also generated a CIB1 knockout mouse and studied the consequences of a lack of CIB1 on tumor growth in vivo. These data suggest that CIB1 may be a promising anti-cancer target.
Heart attacks, strokes and related thrombotic disorders kill more people each year in the US than any other disease. Circulating platelets, which normally aggregate at sites of vascular injury to prevent blood loss, also induce these thrombotic events. Under pathologic conditions, when the blood vessel has formed cholesterol-containing atherosclerotic plaques, these plaques can rupture, causing platelets become activated and aggregate at these sites, potentially completely blocking blood flow. We wish to better understand the biochemical pathways and mechanisms involved in platelet aggregation in order to identify new targets for drug development.
In our newest platelet projects we have:
- Used a chemical proteomics approach to identify an enzyme, never before described in platelets, that is required for platelet activation and aggregation. Rotation projects are available to further characterize the mechanism of action of this enzyme and to use proteomic approaches to identify additional enzymes critical for platelet activation.
- Improved a platelet-like cell line for use in high throughput screening assays to identify new anti-platelet drug targets. Rotation projects are available to help us further optimize this cell line for RNAi or small molecule screening.
Sickle Cell Disease
Sickle cell patients suffer from painful vaso-occlusive crises, which are believed to be due to the abnormal adhesion of multiple blood cell types to the blood vessel wall. These cell types appear to include the red cells themselves, white cells and platelets. This adhesion blocks blood flow in capillaries and causes severe pain and organ damage. Our lab is interested in understanding the mechanisms of the vaso-occlusive crisis. We previously discovered that the sickle cell has the ability to upregulate its state of adhesion in response to physiologic/pathologic agonists such as thrombospondin and epinephrine. This is an important discovery, since signal transduction pathways in sickle cells are not well characterized, but are likely to provide drug targets to control vaso-occlusive crises.
In our newest sickle cell projects we have:
- Identified the existence of heterotypic multicellular aggregates composed of red cells, leukocytes and platelets in the blood of patients with sickle cell disease. We hypothesize that these aggregates may directly lead to vaso-occlusive events. Rotation projects are available to further identify the multiple adhesive mechanisms involved in their formation and approaches to prevent or disrupt their formation by studying cells in human blood and in mouse models of sicke cell disease.
- Identified additional naturally occurring agonists that activate the sickle red cells to make them more adhesive. Rotation projects are available to help us further characterize the mechanisms of these agonists and their relationship to the clinical state of sickle cell patients.
- Black JL, Harrell JC, Leisner TM, Fellmeth MJ, George SD, Reinhold D, Baker NM, Jones CD, Der CJ, Perou CM, Parise LV. CIB1 depletion impairs cell survival and tumor growth in triple-negative breast cancer. Breast Cancer Res Treat. 2015 Jul;152(2):337-46. doi: 10.1007/s10549-015-3458-4. Epub 2015 Jun 24. PubMed PMID:26105795.
- Elsherif L, Ozler M, Zayed MA, Shen JH, Chernoff J, Faber JE, Parise LV. Potential compensation among group I PAK members in hindlimb ischemia and wound healing. PLoS One. 2014 Nov 7;9(11):e112239. doi: 10.1371/journal.pone.0112239. eCollection 2014. PubMed PMID: 25379771; PubMed Central PMCID: PMC4224450.
- Freeman, TC, Black, JL, Bray, HG, Dagliyan, O, Wu, YL, Tripathy, A, Dokholyan, NV, Leisner, TM, Parise, LV: Identification of novel integrin binding partners for CIB1: structural and thermodynamic basis of CIB1 promiscuity. Biochemistry. 2013, In press
- Holly SP, Chang JW, Li W, Niessen S, Phillips R,Piatt R, Black JL, Smith M, Boulaftali Y, Weyrich A, Bergmeier W, Cravatt BF and Parise LV: Chemoproteomic Discovery of AADACL1 as a Novel Regulator of Human Platelet Activation, Chemistry and Biology, 2013, In press
- Desai PC, Brittain JE, Jones SK, McDonald A, Wilson DR, Dominik R, Key NS, Parise LV, Ataga KI: A Pilot Study of Eptifibatide for Treatment of Acute Pain Episodes in Sickle Cell Disease, Thromb Hemost 2013, In press
- Xie L., Liu, C., Wang, L., Gunawardena, H.P., Yu, Y., Du, R., Taxman, D.J., Dai, P.,Yan, Z., Yu, J., Holly, S.P., Parise, L.V., Wan, Y., Ting, J.P. and X. Chen. (2013). ProteinPhosphatase 2A Catalytic Subunit α Plays a MyD88-Dependent, Central Role in theGene-Specific Regulation of Endotoxin Tolerance. Cell Reports 2013 Feb 19, e-pub ahead of print
- Leisner TM, Moran, C., Holly SP Parise LV: CIB1 prevents nuclear GAPDH accumulation and non-apoptotic tumor cell death via AKT and ERK signaling. Oncogene, 2013 32:4017-27 [Epub ahead of print, 2012 Sep 10.] PMCID:PMC3530648
- Xie L, Liu C, Wang L, Gunawardena HP, Yu Y, Du R, Taxman DJ, Dai P, Yan Z, Yu J, Holly SP, Parise LV, Wan YY, Ting JP, Chen X. Protein phosphatase 2A catalytic subunit α plays a MyD88-dependent, central role in the gene-specific regulation of endotoxin tolerance. Cell Rep. 2013 Mar 28;3(3):678-88.
- Riazuddin, S, Belyantseva, IA, Giese A, Lee K, Indzhykulian AA, Nandamuri SP. Yousaf , R, Lee S, Terrell, D, Hegde RS, Husnain RA, Khan SN, Parise LV, Basit S, Wali A, Ayub M, Ansar M, Swaroop A, Ahmad W, Tekin M, Riazuddin , Cook T, Buschbeck EK, Frolenkov GI, Leal SM, Friedman TB, Ahmed ZM: Mutations of CIB2, a calcium and integrin binding protein, cause Usher syndrome type 1J and nonsyndromic deafness DFNB48. Nature Genetics, 2012 Nov;44(11):1265-71.
- Leisner TM, Moran, C., Holly SP Parise LV (2012) CIB1 prevents nuclear GAPDH accumulation and non-apoptotic tumor cell death via AKT and ERK signaling. Oncogene, 2012 Sep 10.
- Willis MS, Homeister JW, Rosson GB, Annayev Y, Holley D, Holly SP, Madden VJ, Godfrey V, Parise LV, Bultman SJ. Functional Redundancy of SWI/SNF Catalytic Subunits in Maintaining Vascular Endothelial Cells in the Adult Heart. (2012) Circ Res 111: e111-22.
- Chantrathammachart P, Mackman N, Sparkenbaugh E, Wang J-G, Parise LV, Kirchhofer D, Key NS, and Pawlinski R. (2012) Tissue Factor Promotes Activation of Coagulation and Inflammation in a Mouse Model of Sickle Cell Disease. Blood 120:636-46
Lab Rooms: 2070F Genetic Medicine
Lab Phone: 919-966-7409