BB Principa_ _tigator/PrograDmirecto(rLast,firstm, idd/e): La!' Edward T. DESCRIPTSIOtaNteh. eapplication'bsread,long-teorbmj_iveasndspeciafimc sm,akingreferentoctehehealrthelatedne_Jp'Crofj'tehcDete.scrciboencisely thereseardcehsiagndmethofodraschievtihnegsgeoalAs.vosidummaorifpesasatccomplishamnedthnetuseofthefirsptersoTnh.isdescripItsimoneant toservaesasuccinacntdaccuradtescripotifothneproposweodrwkhesneparaftreodmtheapplicatIifotnh.eapplicaItsifoundetdh,isdescription, asIs,willbecompueblIincformatTiohne.refodreon, otIncludpereprietary/conInfidfoernmtialtDioONn.OTEXCEETDHESPACPEROVIDED. Periodontal diseases are a diverse group of clinical entities in which induction of an inflammatory process results in destruction of the structures supporting the teeth. Historically, theories examining the etiology of periodontal disease have focused on bacterial plaque, microbial by-products and the host immune response. While environmental, behavioral and genetic risk factors may have supporting roles in disease progression, most, if not all, forms of periodontal disease are infectious diseases. Although positive correlations have been shown to exist between the presence of specific organisms and the occurrence of periodontitis, our understanding of the etiology of periodontal disease has been hindered by the nature of the polymicrobial infection compilcated by indigenous organisms that have little pathogenic potential. One disease, which differs from this pattern, is localized juvenile periodontitis (LJP). This relatively rare form of periodontitis is characterized by its' age of onset, rapid rate of progression, clustering of the disease within families and a close relationship with the presence of a single organism, A. actinomycetemcomitans (Aa). Although Aa produces a number of different virulence factors, it is a leukotoxin (Ltx) that stands out as being particularly important in LJP. Strains of Aa found in children with LJP contain a deletion mutation in the Ltx promoter region that allows the organism to produce 20 to 50 times more Ltx than the Aa species isolated from either normal children or adult periodontitis patients. Ltx is a member of the pore-forming RTX toxin family that selectively kills human lymphocytes, PMNs and macrophages because it binds to LFA-1, a 132integrin that is expressed exclusively on immune cells. The present application is built upon past progress in understanding the relationship of the structure of the leukotoxin to its molecular function. The proposal has four areas of investigation: 1) To identify regions of the LFA-1 heterodimer that are recognized by leukotoxin 2) To analyze the affinity and kinetics of the molecular interaction of Ltx and its receptor 3) To identify and characterize signal transduetion pathways initiated by the Ltx/LFA-1 interaction 4) To determine if cytokines are upregulated by Ltx-LFA-I interactions. PERFORMANSCIETE(S()Organizatiocnit,y.state) University of Pennsylvania, Philadelphia, Pennsylvania KEYPERSONNESLe.einstructionsPage11.UsecontinuatiopnagesasneededtoprovidtheerequireIndformationntheformasthowbnelow. Name Organization RoleonProject Edward T. Lally, DMD, PhD University of Pennsylvania Principal Investigator James D. Lear, PhD University of Pennsylvania Co-Principal Investigator Irene R. Kieba, MS University of Pennsylvania Research Specialist Jian Fei Wang, DVM University of Pennsylvania Postdoctoral Fellow PHS398(Rev4. /98) Page2 BB Number pages consecutively at the bottom throughoutthe application. Donot use suffixessuch as 3a. 3b. ========================================Section End===========================================
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