The primary objective of this K01 application is to provide the applicant with a specific research development plan and the opportunity to obtain advanced training in the field of cellular and molecular immunology with a focus on the delineation of the various biological functions of IL-16, a cytokine with pleiotropic functions ranging from the regulation of airway hyperactivity in athsma, regulation of lymphoid cell apoptosis to regulation of lentiviral replication. The studies will be conducted under the mentorship of a senior immunologist and will include supervision by both local and nationally reknowned scientists who are experts in various scientific disciplines pertinent to the goals of this application including expertise in IL-16 biology. The applicant has cloned, sequenced, and prepared recombinant rhesus macaque IL-16 as a means to address the issues outline below. In addition, the applicant has acquired knowledge, technical skills and expertise which will help to accomplish the goals outlined. There are three specific aims of this proposal.
These aims are formulated based on the unique availability of a set of cryopreserved samples of PBMCs and plasma regularly collected and archived from a large number (n=34) of rhesus macaques prior to and following infection with SIV. These rhesus macaques had varied clinical outcomes ranging from rapid progression (RP, n+7) with disease and death within 6 months, long term nonprogression (LTNP, n+8) with normal immune responses for >3 years post infection, and normal progression (NP, n=19) with disease and death within 12-18 months post-infection. It is our working hypothesis that differential levels of IL-16 has distinct influence on the progression of lentiviral disease. This is orchestrated by the ability of IL-16 to influence several responses that each contribute to disease prevention and progression and include regulation of apoptosis, chemotaxis, complexing with the CD4 molecule, regulation of lentiviral replication, enhancement of IL-2 mediated cell proliferation, and induction of immune suppression.
Specific aim #1 is focused on defining the quantitative levels of caspase-3 (which regulates IL-16 levels), total and bioactive IL-16 in the plasma and PBMC samples from RP, LTNP, and NP animals with the aim to identify those with relatively low, medium, and high levels of IL-16.
Specific aim #2 is focused on performing various bioassays.
Specific aim #3 is focused on defining the correlation of the findings from Specific aims #1 and #2 with clinical findings. Such detailed studies of the role of IL-16 in SIV induced disease progression under senior guidance will be invaluable to the development of an independent scientist career for the applicant.
