Thursday, November 21, 2024 11/21/2024

Mitogenic Activities in Neurofibromatosis

Award Number: R01NS028840
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract. We study neurofibromas, benign peripheral nerve tumors characteristic of patients with the common dominantly inherited disease neurofibromatosis type 1 (NF1). In the 30-year history of this project we have developed cell and animal models and studied many of the cell types that are recruited to neurofibromas: neurofibroma cells include Schwann cells (SC), which we now know are outnumbered by a combination of fibroblasts, macrophages, and other immune cells. We use a neurofibroma mouse model in which, in the peripheral nervous system, biallelic Nf1 mutations are present only in Schwann cell precursors (SCP) and Schwann cells; other wild type stromal and immune cells are recruited to neurofibromas as they form. We showed that neurofibroma SC and SCP express CXCL10, whose receptor, CXCR3, is expressed on immune cells-- T cells and dendritic cells (DC)-- and that CXCR3 is required for neurofibroma formation. Further, we observed a strong interferon signature in SC and neurofibroma macrophages; interferons are known to stimulate the production of CXCL10 and of CXCL9, chemokines that signal through CXCR3. Our striking Preliminary Data show that neurofibromas require T cells to form, that transfer of T cells back to mice lacking them is sufficient to promote neurofibromas. Mice deficient in a key type of APC, dendritic cells (DCs), also show reduced neurofibroma numbers. Finally, immune cells are known to secrete factors that influence appear to promote Nf1-/- SCP self-renewal and neurofibroma formation. Based on these observations we propose that: (i) Schwann cells/SCP require type I IFN signaling to produce CXCL10 to recruit DCs and T cells. (ii) subset(s) of DCs stimulate tumor-specific T cells to produce IFN-g, which induces Cxcl9 expression by macrophages. (iii) Cxcl9/10 act redundantly to sustain T cell recruitment; and (iv) cytokines produced by immune cells themselves promote SC de-differentiation and neurofibroma development, in a feed-forward loop.


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: 2024 ( Subtotal = $663,282 )
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	32	2/19/2024	NON-COMPETING CONTINUATION	$546,646
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	32	5/1/2024	NON-COMPETING CONTINUATION	$42,517
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	32	2/22/2024	SUPPLEMENT FOR EXPANSION	$74,119
2024	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	31	11/17/2023	COMPETING CONTINUATION	$667
2024	2021	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	30	11/17/2023	NON-COMPETING CONTINUATION	-$667
														Subtotal = $663,282

Issue Date FY: 2023 ( Subtotal = $607,383 )
2023	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	31	3/8/2023	COMPETING CONTINUATION	$5,676
2023	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	31	3/1/2023	COMPETING CONTINUATION	$601,707
														Subtotal = $607,383

Issue Date FY: 2021 ( Subtotal = $445,976 )
2021	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	30	6/23/2021	NON-COMPETING CONTINUATION	$445,976
														Subtotal = $445,976

Issue Date FY: 2020 ( Subtotal = $445,976 )
2020	2020	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	29	7/15/2020	NON-COMPETING CONTINUATION	$445,976
														Subtotal = $445,976

Issue Date FY: 2019 ( Subtotal = $445,976 )
2019	2019	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	28	5/17/2019	NON-COMPETING CONTINUATION	$445,976
														Subtotal = $445,976

Issue Date FY: 2018 ( Subtotal = $445,976 )
2018	2018	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	27	7/13/2018	NON-COMPETING CONTINUATION	$445,976
2018	2015	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	25	2/6/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $445,976

Issue Date FY: 2017 ( Subtotal = $416,302 )
2017	2017	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	26	8/8/2017	COMPETING CONTINUATION	$416,302
														Subtotal = $416,302

Issue Date FY: 2015 ( Subtotal = $353,813 )
2015	2015	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	25	8/20/2015	NON-COMPETING CONTINUATION	$353,813
														Subtotal = $353,813

Issue Date FY: 2014 ( Subtotal = $350,274 )
2014	2014	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	24	7/16/2014	NON-COMPETING CONTINUATION	$350,274
														Subtotal = $350,274

Issue Date FY: 2013 ( Subtotal = $341,429 )
2013	2013	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	23	7/18/2013	NON-COMPETING CONTINUATION	$341,429
														Subtotal = $341,429

Issue Date FY: 2012 ( Subtotal = $353,813 )
2012	2012	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	22	8/8/2012	NON-COMPETING CONTINUATION	$353,813
														Subtotal = $353,813

Issue Date FY: 2011 ( Subtotal = $353,813 )
2011	2011	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	21	9/7/2011	COMPETING CONTINUATION	$353,813
2011	2010	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	20	9/2/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $353,813

Issue Date FY: 2010 ( Subtotal = $425,581 )
2010	2010	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	20	1/29/2010	NON-COMPETING CONTINUATION	$425,581
														Subtotal = $425,581

Issue Date FY: 2009 ( Subtotal = $498,114 )
2009	2009	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Trans-NIH Recovery Act Research Support	002	19	9/17/2009	SUPPLEMENT FOR EXPANSION	$80,750
2009	2009	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	19	1/14/2009	NON-COMPETING CONTINUATION	$375,629
2009	2009	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	19	3/30/2009	NON-COMPETING CONTINUATION	$41,735
														Subtotal = $498,114

Issue Date FY: 2008 ( Subtotal = $324,008 )
2008	2008	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	18	2/13/2008	NON-COMPETING CONTINUATION	$324,008
														Subtotal = $324,008

Issue Date FY: 2007 ( Subtotal = $418,401 )
2007	2007	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	17	2/6/2007	NON-COMPETING CONTINUATION	$393,401
2007	2007	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	17	8/17/2007	SUPPLEMENT FOR EXPANSION	$25,000
														Subtotal = $418,401

Issue Date FY: 2006 ( Subtotal = $413,041 )
2006	2006	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	16	3/22/2006	COMPETING CONTINUATION	$413,041
														Subtotal = $413,041

Issue Date FY: 2004 ( Subtotal = $340,090 )
2004	2004	UNIVERSITY OF CINCINNATI	PO BOX 210225	CINCINNATI	OH	45221	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	2/20/2004	NON-COMPETING CONTINUATION	$340,090
														Subtotal = $340,090

Issue Date FY: 2003 ( Subtotal = $340,288 )
2003	2003	UNIVERSITY OF CINCINNATI	PO BOX 210225	CINCINNATI	OH	45221	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13		NON-COMPETING CONTINUATION	$340,288
														Subtotal = $340,288

Issue Date FY: 2002 ( Subtotal = $340,477 )
2002	2002	UNIVERSITY OF CINCINNATI	PO BOX 210225	CINCINNATI	OH	45221	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	2/7/2002	NON-COMPETING CONTINUATION	$340,477
														Subtotal = $340,477

Grand Total All Awards = $9,363,776

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Mitogenic Activities in Neurofibromatosis

Award Number: R01NS028840

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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