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	Senlin Li Associate Professor of Medicine and Pharmacology M.D., University of Geneva Office: 210-567-1905 Email: lis1@uthscsa.edu My primary research interest is to develop autologous hematopoietic stem cell (HSC) gene therapy, particularly HSC-derived macrophage gene therapy for neurodegenerative diseases, atherosclerosis and other inherited blood disorders. Macrophages are recruited from bone marrow to most tissues of the body, including the central nervous system, thus making them an attractive option to deliver therapeutic genes. In macrophage-mediated gene therapy, HSCs will be mobilized from bone marrow, isolated by apheresis, and transduced ex vivo to establish stable expression of therapeutic genes. The transduced HSCs are given back to the same patients and thereafter graft will form various lineages of blood cells, including macrophages. Because they are under the control of macrophage-specific promoters, the therapeutic genes will be expressed at high levels of macrophages only. Neurotrophic factors can be beneficial to degenerative neurons, such as glial cell-derived neurotrophic factor (GDNF) to Parkinson's disease (PD) and nerve growth factor (NGF) to Alzheimer's disease (AD). Over-expression of apoE, apoAI, LXR (liver X receptor), etc. in macrophages has been shown to ameliorate atherosclerosis. These projects capitalize on the super-macrophage promoters that we have recently developed and lentiviral vectors that are superior in transduction of HSCs while maintaining their stem cell nature. Recent advance in stem cell research has demonstrated the feasibility to produce patient-specific ES cells by nuclear transfer (ntES). Mouse ES cells have been differentiated in vitro into HSCs that can rescue leathally-irradiated syngeneic recipients. HSCs created by nuclear transfer can give old animals youthful blood cells. Taken together, ntES cells can be coaxed in vitro to HSCs that will rejuvenate the blood. Those HSCs will be the best carrier of the gene therapy described above. Other ongoing projects in Dr. Li's laboratory include transcriptional regulation of PD-related genes, genome-wide mapping of histone acetylation in cancer cells, age-related oxidative DNA damage and repair, and cellular mechanism of parkin in neurodegenerative diseases. Selected Publications Imam SZ, Sriram SR, Liao X, Zhou Q, Yamamoto A, Valente AJ, Ko, HS, Pletnikova O, Troncoso JC, Ali SF, Kahle PJ, Dawson VL, Clark RA, Dawson TM, and Li S. Inhibition of Parkin's E3 ubiquitin ligase activity through c-Abl-mediated tyrosine phosphorylation: Implications for Parkinson's Disease. Revised to Nature Medicine, 2007. He W, Qiang M, Ma W, Valente AJ, Quinones M, Wang W, Reddick RL, Qifu X, Ahuja SS, Clark RA, Freeman GL, and Li S. Development of a synthetic promoter for macrophage gene therapy. Human Gene Therapy 11:949-959, 2006. Zhao S, Venkatasubbarao K, Li S, Freeman JW. Requirement of a specific Sp1 site for HDAC-mediated repression of transforming growth factor bata type II receptor expression in human cancer cells. Cancer Research 63:2624-2630, 2003. Li S, Valente AJ, and Clark RA. Multiple PU.1 binding is required for p40phox gene transcription in myeloid cells. Blood 99:4578-4587, 2002. Li S, Valente AJ, Wang L, Gamez MJ, and Clark RA. Transcriptional regulation of the p67phox gene: Role of AP-1 in concert with myeloid-specific transcription factors. J Biol Chem 276:39368-39378, 2001. Li S, Schlegel W, Valente AJ, and Clark RA. Critical flanking sequences of PU.1 binding sites in myeloid-specific promoters. J Biol Chem 274:32453-32460, 1999.