The Molecular Basis of Familial and Sporadic PPH"""""""" (Project 1) will incorporate and extend our current Lnvestigation """"""""Pulmonary Hypertension: Mechanisms and Family Registry"""""""" [HIA8164]. Primary pulmonary hypertension (PPH) is a progressive disease characterized by occlusion of small pulmonary arteries. This project discovered linkage of familial PPH four years ago and recently identified that mutations in bone morphogenetic arotein receptor II (BMPR2) cause PPH. Although our database of 100 families with 250 PPH patients had aower that was sufficient to link and identify BMPR2, more PPH families are now required to provide robust malytic power for all subgroups. Recruitment of new families for the subgroup in whom BMPR2 mutations are not yet identified will further increase the power in our search for other mutations. New families in the subgroup in whom BMPR2 mutations are found will augment power in both our search for the modifier gene, and the subsequent comparison ofphenotype to the mutation type and location within BMPR2. In families with BMPR2 mutations not yet identified, but who link to the same 2q33 locus, we will search for chance recombination events which would confirm another locus near 2q33. To identify a modifier gene, we will conduct both a genome wide single nucleotide polymorphism and micro-satellite scan in the two largest families with known BMPR2 mutations. To learn what portion of all PPH has genetic origin, we will test a large cohort of sporadic PPH patients for known and newly discovered mutations. To optimally define its role, we will study the perceived risks and benefits of genetic testing and counseling in individuals in families at risk for PPH. The conduct of this project will provide a database and specimen bank to support all relevant investigations in the entire program, and will further advance the mechanistic understanding of the molecular pathogenesis of PPH. Vanderbilt University Medical Center The Center for Lung Research Division of Allergy, Pulmonary, and Critical Care Medicine T-1218 Medical Center North Nashville, TN 37232-2650 KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information Investigator. List all other key personnel in alphabetical order, last name first. Name Organization Loyd, James E., M.D. Vanderbilt University Medical Center Clayton, Ellen Wright, J.D., M.D. Vanderbilt University Medical Center Hannig, Vickie Vanderbilt University Medical Center Meyrick, Barbara O., Ph.D. Vanderbilt University Medical Center Newman, John H., M.D. Vanderbilt University Medical Center Robbins, Ivan M., M.D. Vanderbilt University Medical Center Sandberg, Joanne C., M.Div., Ph.D. Vanderbilt University College of Arts and Sciences (Sociology) Vanderbilt University Divinity School PHS 398 (Rev. 05101) Page 100 Number pages consecutively at the bottom throughout the application. Do not use suffices such as 3a, 3b. in the format shown below. Start with Principal Role on Project Project Leader Investigator Investigator Investigator Project Leader Investigator Investigator Form Page 2 e Project Z: The Molecular Basis of Familial and Sporadic PPH Principal Investigator/Program Director (Last, first, middle): Loyd r James Ev M.D. DETAILED BUDGET FOR INITIAL BUDGET PERIOD FROM THROUGH DIRECT COSTS ONLY 7/1/2003 6/30/2004 PERSONNEL (AppI/cant o_anization only) % DOLLAR AMOUNT REQUESrED (omffcents) TYPE EFFORT INST. NAME ROLE ON APPT ON BASE SALARY FRINGE PROJECT (months) PROJ. SALARY REQUESTED BENEFITS TOTALS Principal James E. Loyd, M.D. 12 30% 159,101 47,730 9,832 57,562 Investigator Ivan M. Robbins, M.D. Investigator 12 10% 122,470 0 0 0 Barbara O. Meyrick, Ph.D. Investigator 12 10% 133,380 13,338 3,001 16,339 John Newman, M.D.-VU Investigator 4 30.3% 64,109 16,670 3,434 20,104 John Newman, M.D.-VA Investigator 8 0% 0 0 0 0 Ellen Clayton, M.D. Investigator 12 20% 151,510 30,302 6,242 36,544 Personnel from Page 2 114,542 28,920 143,456 222,582 51,429 274,005 SUBTOTALS CONSULTANT COSTS 0 EQUIPMENT (Itemize) 0 SUPPLIES (Itemizeby category) BloodCollectioKnits(65 kits/y@r $5 each) 325 MailingExpensesforKits 800 3 Desktop computerswith printer(seedetailisnjustification) 8,100 OfficeSuppliesforInterviewer(sdiskettes_tationarytapesret)c. 600 9r825 TRAVEL PATIENT CARE COSTS INPATIENT 0 OUTPATIENT ALTERATIONS AND RENOVATIONS (itemize by category) 0 OTHEREXPENSE(SItemizeby category) DNA Extraction (65 samples/year at $48.50/sample) 3,153 Lymphoblast Cell Lines (10 samples/yr @ $223/cell line) 2,230 Telephone interviewer time 10,728 Separation and Cryopreservation of WBC(10/yr @ $55/sample) 55O Single Nudeotide Poly Analysis (60 pts x 2000 analyses x $0.54/each) 12,960 Long DistanceCosts(telephone) 2,690 PostageCosts(for sending mailwith SASEenvelopesto participants) 3OO 32(611 SUBTOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD s316,4411 0 CONSORTIUM/CONTRACTUAL DIRECT COSTS COSTS FACILITIES AND ADMINISTRATION COSTS 0 TOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD (Item7a,FacePage) $316,4411 SBIR/STTR Only: FIXED FEE REQUESTED PHS 398 (Rev.05/01) (Page) I0 I Form Page 4 Number pagesconsecutivealtythebottomthroughoutheapplicatioDno.notusesuffixessuchas3a,3b.
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