MicroRNA Regulation of Helper T Cell Function in Asthma

K. Mark Ansel, Ph.D.

University of California San Francisco

Department of Microbiology and Immunology
Funded in December, 2008: $400000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Learning How Lung Inflammation Occurs in Asthma May Lead to New Treatment Targets

Dr. Ansel will identify processes that immune “helper” T cells use to initiate inflammatory responses in lung tissue of people with asthma, and determine how the information derived may lead to targeted therapies for asthma.

Asthma is an inflammatory disease that affects about one in every ten children in this country.  Symptoms are caused by an allergic reaction in the lung initiated by immune cells, called “helper” T cells.  When immune T cells (the body’s second line of defense) are called into action by the body’s innate immune system, the T cells multiply and acquire the ability to rapidly deploy small proteins, called “cytokines,” that fight infections by initiating inflammatory responses.  In people with asthma, however, this inflammatory response against lung tissue is inappropriate: It is an allergic reaction against otherwise harmless substances.

Tiny molecules called “microRNAs” guide a process that inhibits the translation of DNA instructions into functional proteins.  Dr. Ansel and his colleagues recently discovered that microRNA malfunctions in immune T cells can lead to inappropriate immune responses like those seen in human asthma.  Immune T cells that cannot effectively make microRNAs fail to control the cytokines that they produce, and the cytokines initiate inappropriate inflammatory responses in the lungs. 

Dr. Ansel plans to identify microRNAs that have specific functions in immune helper T cells, and determine which of these microRNAs are involved in asthma.  Additionally, he will develop methods of inhibiting the function of these microRNAs in faulty helper T cells that initiate lung inflammation in asthma.

ABSTRACT

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MicroRNA Regulation of Helper T Cell Function in Asthma

Asthma is a growing public health problem that affects nine percent of children and seven percent of adults in the US.  Allergic inflammation underlies the pathogenesis of most asthma cases.  T helper type 2 (Th2) cells infiltrate the lungs of these patients and coordinate the inflammatory response through the secretion of cytokines, including IL-4 and IL-13.  We previously demonstrated that helper T cell proliferation, survival, differentiation, and cytokine production are all influenced by the microRNA (miRNA) pathway.  The important challenge that remains is to discern specific roles for particular miRNAs in each of these functions.  Here, we propose studies designed to identify T cell-expressed miRNAs that function in asthma pathogenesis, and blaze a path toward the development of miRNA-targeted therapies for asthma. 

We will optimize a system for measuring miRNA expression in small numbers of lung-infiltrating human T cells and use it to search for miRNA biomarkers of asthma pathology and response to inhaled steroid therapy.  In parallel, we will use a miRNA expression library to screen for miRNAs that can rescue the cell proliferation and cytokine expression defects of miRNA-deficient mouse T cells.  Candidates miRNAs identified by these two approaches will be tested for functional activity in human helper T cells using complementary overexpression and “anti-mir” inhibitor approaches. 

Finally, we will devise methods for anti-mir testing in lung explant cultures that preserve interactions between inflammatory cells and the lung epithelium.  Success in the proposed studies would provide both a strong basis for preclinical testing of RNA-based therapeutics and high-quality targets for such interventions.

INVESTIGATOR BIOGRAPHIES

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K. Mark Ansel, Ph.D.

K. Mark Ansel, Ph.D., is a cellular immunologist who is Assistant Professor in the Department of Microbiology and Immunology at the University of California, San Francisco (UCSF).  While earning a B.S. in biochemistry from Virginia Polytechnic Institute and State University, he became fascinated with the way cells respond to environmental factors.  His Ph.D. thesis, completed in the UCSF Biomedical Sciences graduate program, concerned how proteins that direct immune cell migration from the spleen and lymph nodes contribute to the development of these organs and their protective immune responses. 

Through this research, he gained an appreciation of the importance of the differentiation of immune system cells, where external stimuli induce stable changes in genes that direct the functions of immune T lymphocytes.  These lymphocytes are white blood cells that mount attacks against specific invaders.  Such genetic “cell lineage” decisions determine whether an appropriate immune response will be mounted, or whether immune cells will inappropriately respond to otherwise normal stimuli and initiate an allergic response in asthma patients.  Dr. Ansel pursued this research on allergic inflammation in human asthma as a Postdoctoral Fellow at Harvard Medical School, and now is building on this research at UCSF.