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Peripheral TGF-beta Pathway Inhibitor Therapy in Alzheimer's Rats

Award Number: R01NS076794
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: 06/01/2011
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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Peripheral TGF-beta Pathway Inhibitor Therapy in Alzheimer's Rats - PROJECT SUMMARY While amyloid plaques and neurofibrillary tangles are Alzheimer's disease (AD) defining features, Alzheimer himself originally identified a third pathology– inflammation of the brain's glial support cells. Neuroinflammation in AD is characterized by reactive astrocytes and microglia that surround amyloid plaques and chronically secrete inflammatory innate immune cytokines. The dominant view for decades has been that all forms of inflammation damage the AD brain. Yet, non-steroidal anti-inflammatory drugs failed to produce a positive signal for AD primary prevention. This raises a fundamental question: should we be blocking or possibly even promoting inflammation as an AD therapeutic? While the focus has mainly been on pro-inflammatory cerebral innate immunity, little attention has been paid to factors that curtail peripheral innate immune responses. The unifying theme of our work is that `rebalancing' peripheral innate immunity to homeostasis by releasing immunosuppression will limit AD progression. Strikingly, our focus on innate immunity in AD has just recently been validated by genome-wide association studies. These results have taken the field by storm; identifying clusters of AD risk alleles in core peripheral macrophage pathways. As a key cytokine suppressor of innate immunity and inflammation, transforming growth factor-beta (TGF-β) mRNA abundance is increased in AD patient brains. We hypothesize that the AD brain over- compensates to pro-inflammatory signals by producing these abnormally high levels of TGF-β. Paradoxically, this sets up early, low-level and chronic neuroinflammation that fails to support amyloid-β (Aβ) clearance. I and my team have shown in published and preliminary data that genetic or pharmacologic blockade of TGF-β- Smad 2/3 signaling in peripheral macrophages leads to brain entry of these cells and Aβ phagocytosis; sparing neurons from injury and restoring learning and memory. To further explore this theme, we have now generated the TgF344-AD rat that recapitulates cognitive impairment and the full array of human AD pathological features: neuroinflammation, plaques, tangles, and frank neuronal loss. In AIM 1, we will use non-invasive longitudinal imaging approaches to determine whether early neuroinflammation preempts later cognitive impairment, Aβ deposition, structural connectivity changes and neuronal death in TgF344-AD rats. AIM 2 is designed to longitudinally evaluate if blocking peripheral innate immune TGF-β signaling licenses Aβ phagocytosis and mitigates AD-like changes by delivering cutting- edge nanoparticles containing small molecule TGF-β-Smad 2/3 signaling inhibitor payload to hematogenous macrophages. Finally, we will pharmacologically delete peripheral macrophages to definitively establish if they are responsible for the beneficial effects of TGF-β signaling inhibition. While AD animal model studies are typically limited by cross-sectional designs, this project will break this barrier by coupling the most advanced multimodal, longitudinal brain imaging with peripheral TGF-β signaling inhibition in the TgF344-AD rat.


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 = -$177,133 )
2024	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	2/7/2024	NON-COMPETING CONTINUATION	-$177,133
														Subtotal = -$177,133

Issue Date FY: 2021 ( Subtotal = $607,173 )
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	5/20/2021	NON-COMPETING CONTINUATION	$607,173
														Subtotal = $607,173

Issue Date FY: 2020 ( Subtotal = $618,808 )
2020	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	9	6/15/2020	NON-COMPETING CONTINUATION	$618,808
2020	2019	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	2/20/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $618,808

Issue Date FY: 2019 ( Subtotal = $613,749 )
2019	2019	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	5/16/2019	NON-COMPETING CONTINUATION	$613,749
														Subtotal = $613,749

Issue Date FY: 2018 ( Subtotal = $621,456 )
2018	2018	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	7	5/22/2018	NON-COMPETING CONTINUATION	$621,456
2018	2017	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	2/14/2018	COMPETING CONTINUATION	$3,154
2018	2015	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/14/2018	NON-COMPETING CONTINUATION	-$3,154
														Subtotal = $621,456

Issue Date FY: 2017 ( Subtotal = $628,497 )
2017	2017	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	8/3/2017	COMPETING CONTINUATION	$628,497
														Subtotal = $628,497

Issue Date FY: 2016 ( Subtotal = $50,000 )
2016	2016	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/30/2016	SUPPLEMENT FOR EXPANSION	$50,000
														Subtotal = $50,000

Issue Date FY: 2015 ( Subtotal = $360,938 )
2015	2015	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/3/2015	NON-COMPETING CONTINUATION	$360,938
														Subtotal = $360,938

Issue Date FY: 2014 ( Subtotal = $356,425 )
2014	2014	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/30/2014	NON-COMPETING CONTINUATION	$356,425
														Subtotal = $356,425

Issue Date FY: 2013 ( Subtotal = $346,370 )
2013	2013	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	8/29/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$346,370
2013	2012	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/28/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $346,370

Issue Date FY: 2012 ( Subtotal = $365,313 )
2012	2012	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/7/2012	NON-COMPETING CONTINUATION	$365,313
														Subtotal = $365,313

Issue Date FY: 2011 ( Subtotal = $365,313 )
2011	2011	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/23/2011	NEW	$365,313
														Subtotal = $365,313

Grand Total All Awards = $4,756,909

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Peripheral TGF-beta Pathway Inhibitor Therapy in Alzheimer's Rats

Award Number: R01NS076794

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: 06/01/2011

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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