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8, It i 8 ~&.aotad that in the beat fntereetL c I the governneat the followiry type contrect be negotiated: Ironpsmr I t I8 requested that the title to any capftsl equlpmnt prh cured uCsr t h l e contract am1 be vested with: Yaar attention is called to *e fact that we w e eupportiag Meat the lsvel requested on a terrainal basis. and the requfreaents of the Declessificetion hide,It has been detemlned that the fc l loving S@CUrity FreC6UtiOar ehould be taken I n connectiop with tho propoeed reeearch contract: Since t&ere is essential27 no chance for the develqmnt of restsictad data, t h i s project has been placed in Category I as defined in Chapter 3 b 3 of the A E IBunal. *&vi& Guide for the %bn;fsaion of Research
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Title of the project : Physiology of Serum Lipids The institution and department i n which the work will The Tulane University of Louisiana School of Medicine, Department of Xedicine. microns and their possible relations hiD to disease is Although the subject of chyloan old one and there is an extensive literature upon the subject, the reasons for undertaking our proposed study have largely grown out of our own observations. (See. Progress Reports Spring, 1956, and November, 1956, and the next section of this application.) Dur study of serum lipids for several years has been supported by the Atomic Energy Commission, the United States Public Health Service and the United States Department of the Army, and by local funds. Scientific scope of the proposed research: the structure and function of chylomicrons and their role in health and disease along lines which we have developOur general aim is t o continue study of Method of procedure: as follows: - We plan to attack specific problems (a) To further establish standards for concentration and composition of chylomicrons in health by completing the study of a n adequate series of healthy women; this should determine whether the sex differences In lipid metabolism manifested by a greater concentration of cholesterol in serum of men than women, i s also rnanirested by differences as t o chylomicrons. (b)To continue to study appropriate groups of people with a view to determining wnether chylomicronemia i s correlated with development of atherosclerosis and its complications. Apparently healthy adults who have a family history of myocardial infarction,strokes, hypertension and diabetes will be compared with those who have no such family history.Patients will be studied who have diseases which are known t o predispose to atherosclerosis : ne ph ros is, diabetes, myxedema (c)To continue to study the size and number of chylomicrons as determined by modern light scattering techr,iques, with particular reference t o whether mean size is different in the post-absorptive state and i n alimentary lip emi a in health, and i n sone ciiseases. (d) Doctor Hunt will continue the use of his immuno-chemical method for the identification of the protein of chylomicrons, witha view t o determining whether there are consistent differences in health between the ch yl onic ron s of post-absorptive state and alimentary lip emi a, and whether the protein of
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Afoeic Enerqy Com Js sion 6. Other person cel : Two chemical technicians, one ultra - centrifuge and chemical to ch nic ian, one SdCre tary-cls-k, one glass washer, all of whom are full - time with the one mathematical technician devoting 10% of h e r time f'or Health Service has recently renewed its contract for a period of five years. ?he United States Department of the Army continues to support this study by annual grmts. One medical student, working 105 of his ti lie ; 7. Otner financial assistance : The United States Public a 8. Materials, equipment and facilities : equipment owned by the Atomic Energy Commission financed by some other Govornment Agency, but would almost certainly cause serious interruption of work, which goes I slowly enough a t best. No new equipment i s Continued use of the ultra centrifuge and related Replacement of this equipment might be 9. Travel and other items: No funds requested. 10. Budget: No funds requested. 11. Present support Is fr on the following sources : U. S. Put li c Iiealth Service Contribution cf' Tulane University towards $51,357.00s alary of Principal Investigator 7,800.00 Plans have not been made for securing funds for next year which will replace those which have for several years been Supplied by the Atomic Energy Commission.
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Atomic Energy Commission TUNE UNIVERSITY OF LOUISIANA Professor of Medicine ATOMIC ENERGY COMMISSION
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THE DFLL’ENCZ OF RADIATION INJrJRY UPON THE . 8~ a proerur. of stujy of cert a i nI h e Qontractor p w lipids and lipid-containing structures, pr ti cula r - ith reference t g the composition and function of chylomicrons and their role in health and disease, with reference t o the clearing phenorcenon, and Identity of t h e protein of chylomicrons studied by immUnologica1 methods. A major objective wfll be t o study relationships of chylomicrons t o the pathogenesis of atheroschlerosis, the role of cholesterols, the cholester ol level in individuals, and mechanism involved i n spontaneous clearing. Chylomicron sanples will be taken by gec lal met hds and will be studied in relation to particle size. Group susceptibility in the hurran t o atheroschlerosis will be studied f r m the point of view of fardly and clinical history.-
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2, The institution and depertment i n which the work will he do:: The Tulane University of Louisiana School of hiedicine, 5epa:-tment of Medicine. 5,sc fen ti fic background: Although the subject of chylonicrons ani their possible relationship to disease is an old one ar,d there is an extensive literature upon the sLibject, the r.easo3s I’or underta1:ing our proposed study have largely grown c,:it of cy; ovm observations. (See Progress Report and the next sF.rtion of this application.) Our study of serum lipid c for sevepal pears has beer_ supported by the Atonic Energy Comrlissior~, the United Stz.tes Fub li c Health Service, and hit ea States Departnent of the Army, and by local funds. 04.Scientific sccpe of the Proposed research :- struct ur3 and function of chylomicrons and their role in health an2 I!ise;lse along lines wnich we have developed. Our general aim is to continue study of the Metk3d of Procedure: We plan to attack specific problems a s (a) Extend our experience witn the spontaneous clearing phediseases characterized by increased concentration of chylomicrons with cholesterol,as conpared t o r:ost ofthe Eormal subjects,serious study of tine phenomenon will be undertaken. biechvlism of clearing and relationship to disease will be Study more noymal ‘subjects 2nd patients with a If velocity or clearing is diminished ir, (b). Doctor Hunt will at te qt to identify the protein or chylomicrons bg immunological netnoas. Rabbits will be injected with washed chylomicrons and the anti-serum obtained will ba tested against chylomicron suspensions and various known lipo - pro te ix s isolated by ultra centrifuge technic s, Tnis stuay i s (c) Doctor Hunter will continue to study the significance of
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Atomic Energy Conmission (d)A major objective will be to study the relationship of chglomicrons t o pathogenesis of atherosclerosis. This i s an 016 subject. The n0w information about chylomicrons permits nes approaches. Le propose to test the following hypotheses whi{:h have grown out of our study : (1) The tendency t o form chylomicrons which are predominantly either "with cholesterol " or form chylomicrons predominantly ".itith cholesterol " are more sus ce-ptible to atherosclerosis than those who form predominant]-y of concentration, are more susceptible to development ~ l "ather;., . sclerosis than those who possess efficient mechanisms which pra - vent accumulation. Expressed differently, one factor in pathogenesis of atherosclerosis may be correlated with the concent ration of chylomicrons "with cholesterol " pos t - abs or pti ve while the person is eating his normal diet. responsible for spontaneous clearing of chylomicrons i n vitzac during incubation of serum isa FhgSiOlOgiC one. Individuals who lack this mechanism o r hzve it only in li rite d activity are more susceptible to atherosclerosis than those with %he fully active mechanism. Features of chylomicrons t o be studied : In all studies chylomicrons will be harvested from each serum by two differ en s- - - ul trs centrifuge procedures. Spinco technic, then from the subnate by the highly efficient Beams type. Both chglomicroh samples w i l l be analyzed separately by chemical and physical methods with quant it ation of two kinds of chylomicrons: (1) Those from post - abs or pti ve serum, while the subject is on his usual diet.(2) Those from alimentary lipemia; response t o standard lipid - rich diet. (It ispot mentioned inthe Progress Report that in seven observations c f alimentary lip emi a with the old procedure the individual tend5d tc follow his post-absorptive pattern as t o predominance of kind of chylomicron formed.) (3) Measurement of velocity of spontaneous clearing of chylomicrons, during standard incubation of serum. (4) ligh t-sca tte ring te chic. First, by the less efficient, ideasurement of particle size and number by People t o be Studied: We plan to study two contrasting groups o f people, those with diminished and those with increase ? group susceptibility to development of atherosclerosis. control group will be healthy individuals with the best family history for health in respect to myocardial infarction,stroke ? and diabetes. In the contrasting group there will be two subgroups, one of patients with diabetes, myxedema, and ne ph roti c type of nephritis and the other of pmsumably healthy in divi - duals who have a family history of high incidence of myocardia' infarction,strokes, and diabetes, of same sex..and age as the control group, ne first step will be t o extend our study of patients with predisposing diseases. The results of this stud.,
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Atomic Energy Comission will help establish methods for the statistical groups of presumably healthy subjects. The nextstep will be to initiate systematic study of two groups of medical students chosen frcm family history questionnaires. The questionnaire survey has a l - ready been made. If our study of two groups of 15 each show: promise of significant differences, the groups Will be extended; if the results are equivocal other groups in a higher age range will be studied.In any case, among subjects studied, some wil ? . bo selected for repeated study to3hOW how great is the tendeasy toward constancy of chylomicron pattern,particularly subjects who show marked tendency t o form one kind of chylomicron i n g r e a t predominance. If the tendency toward constancy of chylomicron pattern is demonstrated to be great,attempts will be made t o modify the reaction by radical changes in diet. The habitual diets in the medical student groups will be evaluated from lists of foods eaten,prepared by the student. The first objective in comparing, two groups of presumably healthy people is to find out whether any or several features of chylomicrons are correlated with family history. The final evaluation of any feature cf serum lipids in pathogen es is of atherosclerosis mzst depend upon long-time observation of individuals studied, The possibility of such a study growing out of the proposed cbservat ions will be kept in mind with the idea that one of the younger memheTs of the group might carry out the prolonged follovr-up necessary.Insetting up and analyzing the contrasting groups of presumably healthy individuals we will have the advice of a competent bio - statistician. (e)A new technic will be established and used, .he measuremec-> of particle number, size, and'shape, by light - scattering technic, When the results of these measurements are correlated with results of chemical analysis it may be possible to strengthen or refute our working hypothesis that chylomicrons i n alimentary lip emi a are bigger than those of the post - abs or pti ve state, the difference being principally in size of fat globule. The usefulness of light - scattering measurements of chylomicrons as a substitute for chemical determinations for certain purposes will be explored. The relationship of big chylomicrons t o small vessel obstruction in the heart, pancreas, and brain will be tentat iv ely explored if a suitable clinical collaborator is found. W e plan t o use the Brice-Speiser instrument and will have the a d - vice and assistance of workers inthe Biophysics Laboratory who are familiar with the physics and mathematics of the method. The three professional members o f the group and percent of time devoted to the project are as follows: Senior Investigator, Roy H. Turner, M.D., 90%; Fred M. Hunter, technician, one secretary - clerk,all of whom devote full time t o Two chemical technicians, one ultra centrifuge
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Atomic Energy Commission 7. Other Financial Assistance8 The personnel deFcribed in this ProFoSal are not involved i n any other projects. Support for our study of serum lipids is currently being received from three principal sources, one of which is the Atomic Energy Commission, ~ 1 1t h ree are being asked t o continue support for the pro jest described in this renewal proposal. The total of the funds requested from the three agencies is considered the minimum necessary for the successful prosecution of the study described, Our grant of four years from the United States Public EIealth Service will expire with the end of the current year and we requesting renewal for three additional pars. 9, Materials, Equipment, and Facilities : We have all the equip:,l\.,n” and facilities needed for the proposed work except for two item: of permanent equipment, a light scatter photometer and a Beamstype ultra centrifuge which are being requested of the Tjnited 9.Travel and Other Items: No funds re qu s s ted for travel. Ths principal items i n our proposed budget are for salaries which include the two senior technicians whose training and abilities ape of extreme importance to continuation of our work, Idis3 Townsend, the secret arg - clerk,will active lg participate in the investigative proqram. As in the past our data will be e x - ten sive for eachs ecimen of serum examined and the computati:r.-F and calculations w Rich she will assist in will be laborious. h e will begin soon to get family history questionnaires fi1ie.g out for all the presumably normal individuals we have stud iec from 1949 to present. Many of these were medical students at the time the study was made and considerable correspondence will be necessary for this purpose. Other than for salaries the pri rr ci pal items are for service and repair of the Spinco Edodel E ultra centrifuge, which is the property of the Atomic Energy C ommi s si on.
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Ron ewa 1 Prop o s a 1 Atomic Energy Commission (Overhaad coq utada s 3470 of' total salaries and wages. This :s based on a survey Of cost of res ear cn at Tulane made by Arm17 …
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