Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

The role of SNX19 in aging brains at single cell resolution and cerebral organoids

Award Number: K01AG084813
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/01/2024
PERIOD OF PERFORMANCE END DATE: 07/31/2029

Group Awards By:

View Award Description

The role of SNX19 in aging brains at single cell resolution and cerebral organoids - PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) and related dementia are devastating neurodegenerative disorders. Despite intensive investigations, there remains an urgent need to identify the root cause of AD in order to develop efficacious treatment regimens. SNX19 plays a role in endolysosomal and autophagy pathways, extensively correlated with neuronal dysfunction and neurodegenerative diseases. Although genetic and cellular evidence suggest SNX19 contributes to neuropathology, the underlying mechanism remains unknown. Here, we propose to study the mechanism in aging postmortem brain tissue at the single-cell resolution and model SNX19 in human induced pluripotent stem cell (hiPSCs) derived brain organoids. Using single molecule in situ hybridization experiments, SNX19 was found to be highly expressed in neurons, particularly excitatory neurons, compared to glia in human postmortem brains. Our single-nucleus RNA-seq data further demonstrated that SNX19 gene expression is significantly associated with neuritic plaques in excitatory neurons in postmortem brains. In Aim 1, we propose to study the link between SNX19 and AD-related pathologies (i.e., neurofibrillary tangle, cognitive impairment) across six major cell types. Despite the development of animal and in vitro models for AD, they fail to fully recapitulate all essential aspects of the disease. Brain organoids developed from hiPSCs provide an ideal experimental model to delineate underlying AD biology before the onset of symptoms. The application of CRISPR/Cas9 gene editing in iPSCs offers an unprecedented opportunity to functionally assess the role of SNX19 in affecting neuronal phenotypes. By using genetically modified organoid models, we aim to take the first crucial step to define neuronal function and the AD-related pathologies associated with SNX19. Our preliminary data show that SNX19 knockout can increase synaptic markers’ expression in hiPSC-derived neurons and brain organoids. Our findings implicate aberrant synaptic processes in the underlying AD pathophysiology. Hence, we propose to assess the impact of SNX19 on synaptic density using the 3D brain organoid model. Given that SNX19 regulates the endolysosome system, we will test the hypothesis that autophagy might be activated in SNX19 depletion lines to clear the accumulation of aggregated proteins. We have also observed reduced calcium responses in co-cultured astrocytes due to SNX19-null organoids. Intracellular calcium levels and glutamatergic hypofunction are well-established signaling in AD pathogenesis. Accordingly, we will test the hypothesis that SNX19 impacts neuronal hyperactivity through the overactivation of synapses. Our work integrates techniques in imaging and biochemistry with rigorous experimental designs using isogenic-engineered hiPSCs from both sexes, and the differentiation of organoids with defined synaptic characteristics. Our research findings will provide mechanistic insights into the molecular and cellular roles of SNX19 in neurodegenerative diseases.


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: 2026 ( Subtotal = $118,557 )
2026	2026	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Aging Research	000	3	7/17/2026	NON-COMPETING CONTINUATION	$118,557
														Subtotal = $118,557

Issue Date FY: 2025 ( Subtotal = $118,557 )
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Aging Research	000	2	7/29/2025	NON-COMPETING CONTINUATION	$118,557
														Subtotal = $118,557

Issue Date FY: 2024 ( Subtotal = $118,557 )
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Aging Research	000	1	7/25/2024	NEW	$118,557
														Subtotal = $118,557

Grand Total All Awards = $355,671

Top

All Categories

About

Search

Reports

Data Submission

Award Information

The role of SNX19 in aging brains at single cell resolution and cerebral organoids

Award Number: K01AG084813

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/01/2024

PERIOD OF PERFORMANCE END DATE: 07/31/2029

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer