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GENETICS OF PRION SUSCEPTIBILITY IN VITRO

Award Number: P01NS041997
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2001
PERIOD OF PERFORMANCE END DATE: 06/30/2012

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GENETICS OF PRION SUSCEPTIBILITY IN VITRO - Prion diseases are neurodegenerative disorders of humans and animals caused by misfolding of prion protein (PrP). Diseases caused by prions can be transmitted to experimental animals whether their origin is genetic, infectious, or sporadic. The transmission of prion disease to humans by ingestion of bovine spongiform encephalopathy (BSE) prions has been documented. The spread of chronic wasting disease (CWD) through herds of deer and elk in North America is a serious concern and the susceptibility of humans to CWD prions is unknown. All prion diseases involve changes in the conformation of PrP from its benign cellular isoform, PrPc, to a disease-specific isoform, PrPSc. PrPSc is sufficient to transmit disease and its conformation enciphers prion strain properties. Appreciation of the biological significance of PrP came from incubation time studies in normal and transgenic mice. However, genes in addition to the prion protein gene (Prnp) also are important in prion replication and disease susceptibility but their identification has proven exceptionally difficult due to the length and expense of incubation time studies in mice. Similarly, synthetic prions created from recombinant PrP produced in E. coli cause disease in transgenic (Tg) mice but incubation times often exceed 500 days. Only a few cell lines were available that could be infected with prions, offering limited genetic diversity and sensitivity to only one or two prion strains. CNS stem cells can be isolated from adult or fetal brains of normal or Tg mice and grown in culture. Aggregates of these cells, called neurospheres, can be infected with prions and offer an exciting new technology for prion research. Efficiency of infection, spread from cell to cell, and rate of prion replication can be discriminated in neurosphere cultures and conformation dependent epitopes allow identification of individual cells with intracellular PrPSc. The four senior investigators on this Program Project application will apply this novel in vitro model to develop rapid and sensitive bioassays for prions, including those of humans and ungulates. The influence of conformational stability of infectious prions on the rate of prion propagation can be addressed more efficiently in culture than in mice. The ability to isolate neurosphere lines from any strain or Tg line offers the opportunity for genetic analysis of prion disease in culture and a system to screen candidates for the genes within chromosomal regions containing prion incubation time modifier loci. Neurosphere lines also offer a refinement over mice for the systems approach to identify gene networks perturbed by prion replication and pathogenic processes. CNS stem cells can be directed to differentiate to neurons and glia. Effects of infection on differentiation and effects of infection on differentiated cells will be evaluated in neurospheres and in "matured brain spheres", emphasizing the Notch-Hes pathway.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2011 ( Subtotal = $1,401,699 )
2011	2011	MCLAUGHLIN RESRCH INSTITUTE FR BIOMEDICAL SCIENCES, INC	1520 23RD STREET, SOUTH	GREAT FALLS	MT	59405	CASCADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	6/27/2011	NON-COMPETING CONTINUATION	$1,401,699
														Subtotal = $1,401,699

Issue Date FY: 2010 ( Subtotal = $1,442,094 )
2010	2010	MCLAUGHLIN RESRCH INSTITUTE FR BIOMEDICAL SCIENCES, INC	1520 23RD STREET, SOUTH	GREAT FALLS	MT	59405	CASCADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	6/7/2010	NON-COMPETING CONTINUATION	$1,379,300
2010	2010	MCLAUGHLIN RESRCH INSTITUTE FR BIOMEDICAL SCIENCES, INC	1520 23RD STREET, SOUTH	GREAT FALLS	MT	59405	CASCADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	9	9/9/2010	NON-COMPETING CONTINUATION	$62,794
														Subtotal = $1,442,094

Issue Date FY: 2009 ( Subtotal = $1,510,604 )
2009	2009	MCLAUGHLIN RESRCH INSTITUTE FR BIOMEDICAL SCIENCES, INC	1520 23RD STREET, SOUTH	GREAT FALLS	MT	59405	CASCADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	7/28/2009	NON-COMPETING CONTINUATION	$1,373,036
2009	2009	MCLAUGHLIN RESRCH INSTITUTE FR BIOMEDICAL SCIENCES, INC	1520 23RD STREET, SOUTH	GREAT FALLS	MT	59405	CASCADE	USA	Trans-NIH Recovery Act Research Support	001	8	9/15/2009	SUPPLEMENT FOR EXPANSION	$137,568
														Subtotal = $1,510,604

Issue Date FY: 2008 ( Subtotal = $1,366,440 )
2008	2008	MCLAUGHLIN RESRCH INSTITUTE FR BIOMEDICAL SCIENCES, INC	1520 23RD STREET, SOUTH	GREAT FALLS	MT	59405	CASCADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	6/21/2008	NON-COMPETING CONTINUATION	$1,366,440
														Subtotal = $1,366,440

Issue Date FY: 2007 ( Subtotal = $1,362,984 )
2007	2007	MCLAUGHLIN RESRCH INSTITUTE FR BIOMEDICAL SCIENCES, INC	1520 23RD STREET, SOUTH	GREAT FALLS	MT	59405	CASCADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	9/1/2007	COMPETING CONTINUATION	$1,362,984
														Subtotal = $1,362,984

Issue Date FY: 2005 ( Subtotal = $1,576,610 )
2005	2005	MCLAUGHLIN RESRCH INSTITUTE FR BIOMEDICAL SCIENCES, INC	1520 23RD STREET, SOUTH	GREAT FALLS	MT	59405	CASCADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/16/2005	NON-COMPETING CONTINUATION	$1,576,610
														Subtotal = $1,576,610

Issue Date FY: 2004 ( Subtotal = $1,572,933 )
2004	2004	MCLAUGHLIN RESRCH INSTITUTE FR BIOMEDICAL SCIENCES, INC	1520 23RD STREET, SOUTH	GREAT FALLS	MT	59405	CASCADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	8/16/2004	NON-COMPETING CONTINUATION	$1,572,933
														Subtotal = $1,572,933

Issue Date FY: 2003 ( Subtotal = $1,569,184 )
2003	2003	MCLAUGHLIN RESRCH INSTITUTE FR BIOMEDICAL SCIENCES, INC	1520 23RD STREET, SOUTH	GREAT FALLS	MT	59405	CASCADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	9/12/2003	NON-COMPETING CONTINUATION	$1,569,184
														Subtotal = $1,569,184

Issue Date FY: 2002 ( Subtotal = $1,561,788 )
2002	2002	MCLAUGHLIN RESRCH INSTITUTE FR BIOMEDICAL SCIENCES, INC	1520 23RD STREET, SOUTH	GREAT FALLS	MT	59405	CASCADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/6/2002	NON-COMPETING CONTINUATION	$1,561,788
														Subtotal = $1,561,788

Issue Date FY: 2001 ( Subtotal = $1,593,334 )
2001	2001	MCLAUGHLIN RESRCH INSTITUTE FR BIOMEDICAL SCIENCES, INC	1520 23RD STREET, SOUTH	GREAT FALLS	MT	59405	CASCADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/30/2001	NEW	$1,593,334
														Subtotal = $1,593,334

Grand Total All Awards = $14,957,670

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GENETICS OF PRION SUSCEPTIBILITY IN VITRO

Award Number: P01NS041997

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2001

PERIOD OF PERFORMANCE END DATE: 06/30/2012

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