Sulfatide deficiency: a novel mechanism leading to reactive astrogliosis in aging and alzheimer's disease
Ended Project Grant Awarded Last action
- Award ID
- R01AG061729
- Recipient
-
The University Of Texas Health Science Center At San Antonio UEI C3KXNLTAAY98
- Awarding agency
-
National Institute on Aging
National Institutes of Health, Department of Health and Human Services
- Obligated
- $5,014,172
Award facts
- Assistance listing
- 93.866 Aging Research
- Completion date
- Originally
- Place of performance
- Texas, USA
Award details come from USAspending.gov.
Description
- Abstract
- Aging is the greatest known risk factor for alzheimer's disease (ad), the most common cause of dementia in older individuals. However, effective ad therapies remain elusive, which underscores the need to better understand disease etiology and its CO-occurrence with advanced age. The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for late-onset ad and IT is associated with decreased lifespan. The apoe protein is crucial to lipid homeostasis through its regulation of the metabolism of various lipids in blood and the brain. Sulfatide (ST) is a key component of myelin and is metabolized through apoe transport. Previous studies from our lab and others revealed a strong association between ST deficiency, a specific metabolic abnormality, and astrogliosis, a pathologic reaction related to neuroinflammation. For example, ST deficiency and astrogliosis both are induced by aging, in APOE4 carriers, and under ad conditions. Our preliminary studies using ST deficiency mice showed (1) marked astrogliosis within myelin regions; (2) astrogliosis independent of microgliosis; (3) marked upregulation of phosphorylated (activated) STAT3 and (4) a significant upregulation of astrocytic oncostatin m receptor (osmr), which is known to interact with ST. Finally, multiple studies have consistently demonstrated that ST recruits and directly interacts with laminin, an extracellular matrix (ECM) protein. Our novel findings led US to hypothesize that ST loss is directly sensed by astrocytic processes through a mechanism that involves a disruption of ST-ECM-integrin/osmr interactions that lead to STAT3 activation. To test this central hypothesis, we propose three specific aims: 1) to examine the effects of brain ST deficiency on astrocyte reactivity, neuroinflammation, and cognitive function using a novel inducible mouse model of conditional ST deficiency; 2) to unravel the molecular mechanism(s) underlying ST deficiency-induced astrogliosis; and 3) to determine if restoring brain ST content ameliorates astrogliosis, neuroinflammation, and cognitive impairment in the context of ad and aging. To the best of our knowledge, the proposed research (in response to PAR-17-031, "role of age-associated metabolic changes in alzheimer's disease") is the first to study the potential role of ST deficiency in astrogliosis and neuroinflammation, and to examine the molecular mechanism by which ST deficiency promotes neurodegeneration in ad. If our hypothesis is borne out, this work also will provide proof-of-concept to support the development of novel ST-based therapeutic strategies seeking to treat ad and other ST deficiency- associated pathologic conditions.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $0 | |
| Amendment | $50,842 | |
| Amendment | $50,842 | |
| Amendment | $571,995 | |
| Amendment | $571,995 | |
| Amendment | $571,995 | |
| Amendment | $30,020 | |
| Amendment | $30,020 | |
| Amendment | $30,020 | |
| Amendment | $71,301 | |
| Amendment | $71,301 | |
| Amendment | $71,301 | |
| Amendment | $71,301 | |
| Amendment | $564,248 | |
| Amendment | $564,248 | |
| Amendment | $564,248 | |
| Amendment | $564,248 | |
| Original award | $564,248 |
Show all 18
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Richmond Institute For Veterans Research | $73,098 |
Quick answers
Who received award R01AG061729?
R01AG061729 was awarded to The University Of Texas Health Science Center At San Antonio by National Institute on Aging (National Institutes of Health) on February 15, 2021.
How much is award R01AG061729 worth?
$5,014,172 has been obligated on R01AG061729.
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