2001 — 2011 |
Kew, Richard R |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Mechanisms of a Novel Chemotactic Cofactor For C5a @ State University New York Stony Brook
DESCRIPTION (provided by applicant): Chemotaxis of leukocytes into various tissues is known to be a critical step in the pathogenesis of several inflammatory disorders. Complement pro-inflammatory peptides C5a and C5a des Arg also have been implicated in disease pathogenesis. C5-derived peptides are very potent chemoattractants for a wide variety of cell types. Much is known about the bioactivities of C5-derived peptides but the regulation of these functions is poorly understood. Previously, we were the first of several groups to demonstrate that the vitamin D binding protein (DBP), also known as Gc-globulin, can enhance the chemotactic activity of C5a and C5a des Arg, i.e., function as a co-chemotaxin. Moreover, the co-chemotactic activity of DBP is specific for the C5-derived peptides. Although DBP appears to be a physiologically important regulator of the chemotactic activity for activated complement, the mechanism of chemotaxis enhancement by DBP is not known. Recently, we have reported several important observations that should help define the mechanism by which DBP acts as a co-chemotactic factor for C5a. (1) DBP needs to be bound to the cell surface in order to function as a co-chemotaxin for C5a. (2) The neutrophil DBP binding site is a chondroitin sulfate proteoglycan. (3) Expression of the DBP binding site is regulated by cell surface-bound neutrophil elastase, which cleaves and sheds the proteoglycan. (4) Preliminary studies have shown that activated platelets modify DBP to an active co-chemotactic form. (5) Clinical samples from patients with inflammatory disorder (ARDS) contain the modified co-chemotactic form of DBP. It is our hypothesis that a modified form of DBP binds to the cell surface and initiates an enhanced chemotactic response to C5a. In this proposal, we endeavor to investigate the mechanism by which DBP augments the leukocyte chemotactic activity of C5a by utilizing human neutrophils and the U937 cell line transfected with the C5a receptor (U937-C5aR). The process of co-chemotaxis will be divided into component parts and examined individually. First, determine how activated platelets modify DBP by focusing on the most likely alteration: extracellular phosphorylation by ubiquitous protein kinases. Second, investigate how modified DBP interacts with cells by examining binding and shedding on the cell surface. Third, determine how cells terminate the co-chemotactic signal by focusing on dephosphorylation by phosphatases. Finally, clinical samples from patients with inflammatory disorders will be analyzed using a proteomic approach to determine if modified DBP is correlated with disease outcome. This study will bridge basic knowledge derived from in vitro biochemical approaches and apply it to examine samples obtained from patients with inflammatory disorders. Results of this study will demonstrate a novel mechanism for a chemotactic cofactor and could serve as a prototype for other cofactors yet to be discovered.
|
1 |
2010 |
Kew, Richard R |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Xxiii International Complement Workshop @ State University New York Stony Brook
DESCRIPTION (provided by applicant): This R13 grant proposal requests financial support for graduate students and postdoctoral fellows to attend the XXIII biennial meeting of the International Complement Society (ICS) in New York City from August 1st to 5th 2010. The meeting, known as the International Complement Workshop (ICW), is the premier international meeting dedicated to the advancement and dissemination of knowledge about the complement system, the primary humoral component of the innate immune system. It is anticipated that the 5-day meeting will attract over 400 participants, of which 50 to 60 will be graduate students and postdoctoral fellows. Moreover, it is expected that over 300 abstracts will be presented in 10 scientific sessions encompassing all aspects of complement research. Scientific topics will include: Complement Structure and Function, Complement Activation and Regulation, Interactions with Innate and Adaptive Immunity, Interactions with Pathogens, Deficiencies and Polymorphisms of Complement Proteins, Complement in Inflammatory and Autoimmune Diseases, Complement in Transplantation. In addition, there will be two keynote presentations, one clinical lecture and basic science talk. There are several objectives for this meeting which are as follows: (1) to provide a better understanding of the molecular basis for the activation and regulation of the complement system;(2) to better comprehend the complex interrelationships between complement system and the innate and adaptive arms of the immune system;(3) to bring together a diverse group of basic scientists from several disciplines (biochemistry, biophysics, cell biology, immunology, molecular biology, structural biology) together with clinicians from numerous specialties (allergy, clinical immunology, infectious diseases, pathology, rheumatology) to better understand the role complement plays in immune and infectious diseases;(4) to promote the development of new research approaches, identification of disease mechanisms and targets for therapeutics, and diagnostic tests and treatments;and (5) to educate, motivate and foster the next generation of scientists in the field of complement research. The requested grant funds will permit many young scientist trainees to participate in this meeting, and hopefully, both the ICS and the students/fellows will reap long-term benefits from this experience. This R13 proposal is a very worthwhile use of this grant mechanism.
|
1 |