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. THr•. qCOiTrcIL Fon ToBncco WsEAxcx- U.S.A.. INC. cc: 11 ccH FwN July 25, 1973 MEMORANDI]M FOR THE FILE SUBJECT: Gsant 808R2 Allen 8. Cohen, M.D., Ph.D. "Human Alveolar dKacrophages and Emphysema." Site Visit: July 12, 1973. HKO1140004 Dr. Cohen's current grant runs to March 31, 1974. He will subalit an application for renewaJl in December. Y have 3 preprints -- 2 in press and 1 about to be sent -- that will be a part of his request fcdr renewal. Dr. Cohen must be an excellent teacher. He outlines his presentation very well and fills in well. The problem: What is the cause of embhysema? (No d,AT) A Related to decrease of dAT (1) Related to enzl+me inhibitory T g Unrelated to decrease of KAT function. (1) A common cause of k AT and factor causing emphysema. (2) Related to some other function. (2) No common biochemital causes. ZZ abnormal qAT and not inducible. MM ? but inducible. Proteolytic enzymes 1. Trypsin / 2. Chymotrypsin / 3. Plasmin / argin e- 1y sine - histidine cleavage. 4. Thrombin / S. Elastin /- aromatic cleavage (leuc~ne - alalnne) 6. Subtilysin - different basic structure (serine, histidine, aspartic) It is possible to cleave the different cathepsins specifically. Arginine blockers inhibit trypsin but not chymotrypsin. He is designing leupepsins , AC - aa - aaTaa - binding (small molecules) to block r% AT. Starch gel;'electrophorgsgs gives two double peaks in ZM individuals. He is trying to dissect qAT deficiency which seems to be a genetic 1 point mutation. What is the difference between MM and ZZ? It may be differences in CHO structure which makes up much of.tAT. The puptide maps may :,e easier to work out peptide component than the CHO component. CHO may have more to do with packaging and permeability.

-s- NU1140005 At this time Cohen has a number of basic approaches that should enable him to get at fundamental aspects of emphysema. Elderly MZ patients may or may not show emphysema. 5% ZZ show no emphysema. It's difficult to find these persons and it's also hard to justify lavages of emphysematous ZZ patients. New request may be4#50=70,000 and will include an item for salary of a research assistant or senior fellow and 1 technician. He has a well-equipped laboratory but congested. The labs have a core unit of scintillation counters, separating centrifuges and other major supnlies. Dr. Cohen' has just been awarded a Career Development Award which will assure 5 years with 80% of his time to do research. Cohen and Finley h+ill make a great team. Methods have been developed to obtain relatively pure pulmonary macrophages. W.U.G. WUG:ek ` I