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Seminar Series
Pharmacology and Chemical Biology Seminar Series
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Seminar Series
Pharmacology & Chemical Biology Seminar Series
3/21/2024 - 12:00 PM-1:00 PM
“Position-dependent mechanistic heterogeneity in age-dependent cerebral small vessel disease associated with
Col4a1
mutations.”
Scott Earley, PhD
Professor of Pharmacology
University of Nevada
Reno School of Medicine
Humans and mice with mutations in the genes encoding the essential basement membrane protein type IV collagen (
COL4A1
and
COL4A2)
manifest hallmarks of cerebral small vessel disease (cSVD), including white matter hyperintensities, dilated perivascular spaces, lacunar infarcts, microbleeds, and intracerebral hemorrhages. Our recent studies using mice with
Col4a1
mutations in different positions have revealed striking mechanistic heterogeneity in the disease process. Age-dependent cerebral vascular dysfunction in mice with a glycine to valine substitution at position 394 (
Col4a1
+/G394V
) is caused by the loss of depolarizing TRPM4 (transient receptor potential melastatin 4) currents in smooth muscle cells and inwardly rectifying K
+
(K
IR
) channel activity in endothelial cells due depletion of PIP
2
, a co-factor required by channels. Blocking PI3 kinase to prevent the conversion of PIP
2
to PIP
3
repaired the defects in TRPM4 and K
IR
channel activity and restored vascular function. Cerebral vascular disease in 12-month-old mice with a
Col4a1
mutation at 1344 (
Col4a1
+/G1344D
) was linked to impaired sarcoplasmic regimen (SR) dependent Ca
2+
signaling in smooth muscle cells. As these mice aged, they became more susceptible to intracerebral hemorrhaging and showed defects in TRPM4 and large-conductance Ca
2+
activated K
+
(BK) channel signaling in smooth muscle cells. Alleviating SR stress caused by the accumulation of misfolded collagen with a small molecule chaperone attenuated intracerebral hemorrhages and restored SR Ca
2+
signaling and vascular function, suggesting that perturbations in SR function induced by misfolded proteins may underlie some types of cerebral blood vessel diseases. Our findings underscore the striking pathogenic diversity inherent in cSVDs.
Pharmacology & Chemical Biology Seminar Series
3/28/2024 - 12:00 PM-1:00 PM
“Hepatic Ubiquinone Imbalance Drives Reverse Electron Transport and Pathological mROS in Obesity”
Renata Goncalves, PhD
Research Associate
Harvard School of Public Health
Mitochondrial reactive oxygen species (mROS) are central to physiology. While excess mROS production has been associated with several disease states, its precise sources, regulation, and mechanism of generation
in vivo
remain unknown, limiting translational efforts. Here we show that in obesity, hepatic ubiquinone (Q) synthesis is impaired, which raises the QH
2
/Q ratio, driving excessive mROS production via reverse electron transport (RET) from site I
Q
in complex I. Using multiple complementary genetic and pharmacological models
in vivo
we demonstrated that RET is critical for metabolic health. In patients with steatosis, the hepatic Q biosynthetic program is also suppressed, and the QH
2
/Q ratio positively correlates with disease severity. Our data identify a highly selective mechanism for pathological mROS production in obesity, which can be targeted to protect metabolic homeostasis.
Pharmacology & Chemical Biology Seminar Series
4/4/2024 - 12:00 PM-1:00 PM
“Sex-specific neurovascular and metabolic trajectories of brain aging”
Bistra Iordanova, PhD
Assistant Professor
Department of Bioengineering
Swanson School of Engineering
University of Pittsburgh
This talk will cover the development and application of multiscale imaging platforms to probe cellular activity
in vivo
. The focus is on the interactions between neurons, astrocytes, and brain vessels to assure proper blood supply to active brain areas, a phenomenon commonly referred to as “neurovascular coupling”. The underlying signaling mediators are poorly understood, yet very important because the dysfunction of specific populations of cells could have dramatic repercussions on the local blood flow and the energy supply to the brain. Moreover, several neurological conditions are associated with a cerebrovascular pathology and impaired neurovascular coupling responses. One such condition is Alzheimer's disease, in which the cerebrovascular dysfunction is an integral part of the disease process. Particularly, I will focus on the sex-specific changes in the brain metabolism and neurovascular health that drive differences in etiology, onset, and progression of Alzheimer’s disease with examples from our work in rodent models. The end goal is to provide mechanistic insights into the neurometabolic and vascular deficits of vulnerable populations and motivate tailored dementia therapeutics that can benefit all humans.
Pharmacology & Chemical Biology Seminar Series
4/11/2024 - 12:00 PM-1:00 PM
"Exploring the role of progranulin on blood pressure regulation"
Thiago Bruder do Nascimento, PhD
Assistant Professor
Department of Pediatrics
University of Pittsburgh School of Medicine
Calendar